Schistosome infection and its effect on pulmonary circulation

Ghazwan Butrous

doi:10.21542/gcsp.2019.5

. 2019 Mar 31;2019(1):5. doi: 10.21542/gcsp.2019.5

Schistosome infection and its effect on pulmonary circulation

Ghazwan Butrous ^1,^✉

PMCID: PMC6472693 PMID: 31024947

Abstract

Schistosomiasis is the most common parasitic disease associated with pulmonary hypertension. It induces remodelling via complex inflammatory processes, which eventually produce the clinical manifestation of pulmonary hypertension. The pulmonary hypertension shows clinical signs and symptoms that are not distinguishable from other forms of pulmonary arterial hypertension.

Introduction

Schistosomiasis (bilharziasis) is a disease caused by infection with blood flukes of the genus Schistosoma. The disease is transmitted to human by contact with infested water with special fresh water snails, which act as intermediary for the life cycle of the parasite (see below). The condition remains one of the most prevalent parasitic infections in the world. An estimated 240 million people are affected in 78 countries, and close to 800 million are at risk. Africa, and in particular sub-Saharan Africa, is the main affected area with about 80% of the infected global population (Figure 1). Other areas affected include Eastern Mediterranean region, South Americas and Western Pacific regions. The condition is not present Europe or North America^1–4. Current statistics suggests that almost 120 million people have symptoms, and 20 million have severe illness with hepatic or urological involvement, and a subset, reported between 5–54%, have evidence of pulmonary involvement^1–3,5,6. As such, along with malaria, schistosomiasis is one of the most important of all human parasitic diseases. It continues to be a global public health concern in the developing world.

Figure 1. — The yellow bubbles are examples of incidences that increase the prevalence of Schistosomiasis (see text).

Schistosomiasis is a chronic infection that is rarely recognized in its early stages. Chronic schistosomiasis is the most prevalent form of the disease in regions endemic for schistosomiasis, due to repeated exposure and re-infection. In general, a child’s initial infection occurs by age 2 years. There is a noticeable increase in intensity during the next 10 years with the burden of re-infection. Thus, the highest prevalence and intensities of infection occur in young adolescents, that is 60–80% of school age children and 20–40% of adults. The prevalence can persist among sub populations of adults who have frequent contact with water during their daily activities—e.g., laundry, bathing, fishing, or washing animals or cars^7,8. Typically, the disease is largely a rural problem. Urban foci can be found in many endemic areas, and sex-related patterns vary in relation to behavioural, professional, cultural, and religious factors⁹. The disease disables men and women during their most productive years. It is estimated to be as high as 29 million disability-adjusted life years (DALYs)¹⁰.

Over the last 50 years there has been an international control program with success in many parts of the world¹¹. The World Health organization in May 2012 urged member states to eliminate schistosomiasis with a dual strategy for the control of schistosomiasis: a strategy for morbidity control adapted to the public health context in high burden areas, and a strategy to consolidate control in areas where a low endemic level has been reached and elimination may be feasible^12,13. The preventive chemotherapy (i.e., periodic large-scale administration of the anti-schistosomal drugs to school-aged children and other high-risk groups is the main practical approach^13–15. Currently the main anthelmintic drug used in the treatment of schistosomiasis is praziquantel¹⁶, discovered in the mid-1970s. From a public health point of view it requires adequate monitoring of current mass drug administration programs. Alternative compounds like Artemisinins, Oxamniquine or Furoxan have been tested, but none so far is completely satisfactory and are not in general use^17,18.

Schistosomiasis vaccine development has been an uphill battle, and there are still several hurdles to overcome in the future. There are currently few schistosomiasis vaccines in clinical trials¹⁹.

Further important measures like the elimination of intermediate host snails, and the prevention of human contact with water containing infected snails, can help to prevent the transmission^18,20–22.

Despite these efforts, the control was not universal because of the economical and developmental projects and environmental changes¹² that affect the snail’s habitat, one of the crucial determinants of transmission.

For example, the development of new irrigation programs leads to a remarkable redistribution of schistosomiasis worldwide, e.g., the construction of Diana Dam in the Senegal River led to the introduction of schistosomiasis into Mauritania and Senegal.

Construction of the Egyptian Aswan High Dam in 1960s led to the virtual elimination of S. haematobium from the Nile Delta, but has brought about the establishment of S. mansoni in upper Egypt^14,23–26.

The Three Gorges Dam, currently being built on China’s Yangtze River is between two areas where schistosomiasis is endemic. The Chinese Ministry of Health is currently evaluating the potential effect of the dam on schistosomiasis transmission.

The movement of refugees and the displacement of populations resulted in the introduction of schistosomiasis into Somalia and Djibouti. Furthermore, there are reports of resistance to praziquantel^27–31. Thus, despite major efforts and advances in control and substantial decreases in morbidity and mortality, schistosomiasis continues to spread to new geographic areas^12,31.

Discovery of Schistosomiasis

Schistosomiasis was one of the oldest diseases known to mankind. It was discovered in 5000-year-old Egyptian mummies. Its characteristic symptoms are described in early Egyptian papyri^32–34. Theodor Maximilian Bilharz, a German physician and pathologist, who worked in various hospitals in Cairo in the middle of the 19th century, noticed the worm in white bumps on the mucous membranes of the bladder, ureters, seminal glands and intestine in 1851³⁵. His discovery was the beginning of a new era for tropical parasitology and finding preventive and curative measures. Other discoveries and observations followed in the second half of the 19th century and the beginning of the 20th century. Figure 2 is an infographic of the main milestones of the early discovery of the schistosomiasis.

The Parasite

The etiologic agents of the schistosomiasis are the blood flukes, which belong to the genus Schistosoma of the class of Trematoda of the phylum of Platyhelminthes (flatworms). It is white-greyish cylindrical body approximately 1 to 1.5 cm in length. It can survive for up to 30–40 years with an average of 3 to 10 years in their human hosts. The schistosomes have separate sexes and live in the blood vessels of the abdominal cavity.

The male holds the slender female fitted into the gynaecophoric canal in a continuous monogamous embrace. She produces eggs and he fertilizes them. The worm has two suckers, a complex tegument, a blind digestive tract, and reproductive organs. They feed on blood cells and globulines, which they digest in their intestinal tract. They have no anus and cannot excrete waste products, so they regurgitate waste into the bloodstream which can be useful for blood-based and urine-based diagnostic assays^36,37. The worm takes energy via anaerobic metabolism, which serves mainly for the movements of the male schistosomes and the egg production of the females^38,39.

Schistosoma is invisible to human immune defences and, like many other parasites, they show a unique ability to manipulate the immune system^40,41. This invisibility can be attributed to some schistosome genes that resemble human ones. Furthermore, the unusual covering known as the tegument³⁷, a second external body layer, may contribute to the parasite’s ability to hide from the immune system. The tegument provides ample protection to the worm as it migrates through human blood. The nature of tegument function is still under investigation; some thought that this outer coat could acquire human molecules from the blood, covering the parasite’s own molecules and making them invisible to immune surveillance⁴². This subject is of interest to vaccine designers, because the targets of most successful vaccines are proteins or other molecules that appear on the outside of a pathogen.

Schistosome populations are genetically heterogeneous^43,44. Genetic diversity and inbreeding were higher in East compared to West African populations, and differ between schistosome species. This has implications for the transmission of schistosomiasis and the potential establishment of drug resistance⁴⁵. Genomic characterisation of human schistosomes can help establish epidemiological patterns of transmission, including insights into interspecies hybridization among some schistosome species. The new release of SchistoDB (http://SchistoDB.net) provides a rich resource of genomic data for genus Schistosoma⁴⁶.

The three most important human schistosomes are Schistosoma mansoni, S. japonicum, and S. haematobium. They live within either the perivascular (S haematobium) or mesenteric (S mansoni, S japonicum, and others) venules. There are several other species of lesser importance which infect humans in Africa and Asia⁴.

S. mansoni has the widest geographic distribution. S. mansoni remains endemic in Africa, Arabian Peninsula, parts of Brazil, Venezuela, the Caribbean and Puerto Rico. It is found in primates and rodents, but humans are the main reservoir. Adult worms live in the portal system of the liver and the small venules of the lower ileum and colon. The prepatent period for the infection is approximately 6 weeks. In chronic schistosomiasis, eggs will accumulate in the liver, walls of the intestine and rectum. Fewer eggs will be found in faeces. The eggs in the faeces help in the reliable diagnosis of the infection. Rectal biopsies may also be useful in diagnosis.

S. japonicum is found in China, Indonesia, and the Philippines. It has been virtually eliminated in other countries of Southeast Asia, including Japan. Infection rates remain high in China and the Philippines because in these regions the infection is with a zoophilic strain of the parasite (i.e., it is also maintained in animal hosts including water buffaloes, pigs, dogs, cats, and wild rodents)⁴⁷. The adult worms live in mesenteric veins, and the prepatent period is 5 to 6 weeks. In addition, the surface of the egg frequently has faecal debris adhering to it, which can make the eggs difficult to see or recognize. Rectal biopsy may be an important diagnostic tool when faecal examinations are negative.

S. haematobium occurs in some parts of Africa, Egypt, Middle East, Iran, and the Arabian Peninsula. It causes urinary schistosomiasis. Adult worms reside in the venous plexuses of the bladder, and eggs that are laid move through the wall of the bladder and pass in urine. In chronic infections, accumulation of eggs in the bladder wall can lead to the bladder and ureter pathology. Haematuria is frequently present with this infection and diagnosis is made by finding eggs in urine sediment. Eggs can sometimes be found in faeces and in the wall of the rectum as well as in the bladder.

Other less common species can also infect human like S. mekongi, which like S. japonicum is a zoophilic strain. It is mainly seen in countries bordering on the Mekong River, specifically Laos and Cambodia. S. intercalatum is a human schistosome that occurs in Zaire, Gabon, Cameroon, and the Central Africa Republic. The eggs of this species are found in faeces, have a terminal spine, and thus must be differentiated from S. haematohium eggs. Eggs are usually larger than those of S. haematobium, measuring 140–240 µm long by 50–85 µm wide.

The Different Forms of the Parasite and its Life Cycle

Schistosomes have a complex life cycle (Figure 3) involving both a snail intermediary and a vertebrate definitive host. Understanding the schistosome life cycle and the parasite’s movement between intermediate (snail) and definitive hosts (man or other mammalian) is fundamental to understand the pathological changes, the control and elimination of human schistosomiasis.

Eggs are thin-shelled that lack an operculum and contain a miracidium⁴⁸. The size, shape, and the location of the spine, varies according to the species (Figure 4). S. mansoni eggs measure 114–175 µm long by 45–70 µm wide. S. japonicum eggs are round and measure 70–100 µm long by 55–65 µm wide with a small, inconspicuous spine, which frequently is not seen. The thin-shelled eggs of S. haematobium measure 112–170 µm long by 40–70 µm wide and have a terminal spine.

Some eggs allow make their way into faeces, or urine in the fresh water and thus out of the body to continue the life cycle. Eggs can stay viable for up to 7 days with low osmolality; but with bright sunlight the eggs hatch and release miracidium^48,49. These larvae (about 150 µm long) are non-feeding and swim rapidly (2 mm/s for about 6 hours) using cilia attached to epidermal plates to locate a compatible snail-intermediate host. Swimming behaviour is photokinetic, and possibly chemokinetic towards snail components. The sensory terebratorium (apical papilla) facilitates attachment to the snail surface. They penetrate the snail by release of proteases from their lateral and apical glands with the support of the mechanical movement. Thus, schistosomes require a snail host to complete the life cycle they develop. Only freshwater snails are involved with mammalian transfer. Each of the schistosomes utilizes specific and different snail intermediate hosts. The most important snail species are

1.
Biomphalaria snails for S. mansoni (purely aquatic snails)
2.
Bulinus snails for S. haematobium (purely aquatic snails)
3.
Oncomelania snails for S. japonicum (spend part of their lives in the mud where they can survive low temperatures).

Inside the snail host, the miracidium sheds its ciliated plates and becomes a post-miracidium. A new syncytial tegument is formed and the larva differentiates into a mother sporocyst that subsequently produce asexually germ-cell daughter sporocysts⁵⁰. These migrate to the hepatic and gonadal tissue of the snail. The mechanisms by which the parasite evades the snail-host defines response are not currently well understood but are likely to be multi-factorial. Within 4-6 weeks, these daughter sporocysts metamorphose into cercariae; which also multiply asexually, producing large number of cercariae to complete its life in the snail. Under the stimulation of light, typically between 10am and 4pm when the sun is high and human water contact most frequent, hundreds of free-swimming, fork-tailed cercariae leave the snail^51,52.

The cercariae is a free-living, non-feeding form with a length of about 325 µm. There are many similarities of cercariae of mammalian schistosome and it is difficult to differentiate them. The body and bifurcated tail are a muscular temporary locomotor organ of a cercaria that is enveloped with a single continuous syncytial tegument, covered by a carbohydrate-rich glycocalyx. They swim backward (tail-first) using intermittent bursts of activity to locate a suitable definitive host⁵³. The swimming continues for several hours (up to 72 h) seeking the skin of a suitable definitive host until cercarial glycogen reserves are depleted.

Water turbulence, shadows and certain skin chemicals influence host finding (human or animals). Ciliated sensory papillae exist and are thought to facilitate host detection. The acetabulum (ventral sucker) is well developed. Various glands exist that contain multiple enzymes including proteases and are important for host penetration and cercarial function^51,54. Once the definitive host in penetrated, the bifurcated tail of cercariae is shed and they become schistosomules⁵⁵. This new form passes through the epidermis and dermis before exiting via the blood or lymphatic vessels.

There seems to be a difference in the way different schistosome species move through the human skin. S. mansoni and S. haematobium move through the human skin layers slower than S. japonicum. It takes about 48 hours for the majority of S. mansoni and S. haematobium schistosomula to reach the dermis, and 72 hours for these species to be found near the dermal blood vessels.

Successful transformation is considered essential for parasite survival. They then embark on a complicated journey, first penetrating the host dermis and venule wall and entering the circulation via the venous or lymphatic vessels. Next, they migrate through the pulmonary capillaries (lung schistosomula), which is the greatest obstacle (not the skin). A proportion of schistosomula entered the alveoli, from where they do not recover or enter the systemic circulation later^56,57. The successful schistosomula of S. mansoni then pass to the hepatic portal system and begin to blood feed, pair up, and migrate to the portal vessels and mesenteric venules. For S. haematobium, the worms finally pass to the vesical venules around the bladder where they reside. In these final locations, schistosomula grow rapidly and the tegument matures. Males grow larger than females and display higher mitotic activity. Development of the sex organs occurs after approximately 3 weeks (for S. mansoni) or 9 weeks for S. haematobium. The females produce hundreds (S. mansoni and S. haematobium) to thousands (S. japonicum) of eggs per day^52,58 and continue producing eggs throughout their lifetime.

Pathological Effects of Schistosome Infection

The cardinal feature of schistosomiasis is not the mature worm, which has evolved immune evasion mechanisms that allow them to remain incognito within the bloodstream⁵⁹, but by the highly antigenic egg-associated pathology that is central to the morbidity and mortality. When eggs are trapped in various tissues or the areas of venous drainage (liver or lung), they cause the formation granulomatous inflammation around the parasite within maximal 8 weeks post-infection. This process is wholly dependent on CD4⁺ T lymphocytes^59,60. The exact mechanism by which eggs pass across the endothelium, intervening tissues and mucosal epithelium remains unknown, but clearly is dependent upon the host immune response, as egg excretion does not occur in animals that are immunocompromised.

The granuloma is the aggregation of mononuclear inflammatory cells, macrophages resembling epithelial cells, lymphocytes, multinucleated giant cell eosinophils, and plasma cells, monocytes and T cells in addition to eosinophils, lymphocytes and mast cells (Figure 5). The proportion of cells differ in different organs around the egg, with the liver being more sensitive than the lung in its response^61,62. Furthermore, granuloma formation around S. mansoni eggs is much more intense than that around S. japonicum eggs^63,64. It prevents diffusion of the toxic egg substances and eventually destroys them. It also leads to tissue destruction and may cause fibrosis after many years^64–66.

Figure 5. — The proportion and types of cells, which comprise granulomas varies depending on the species of infecting schistosome. The process of granuloma development is driven by the egg’s antigens and its growth by cytokines and chemokines released by T lymphocytes. Granuloma formation begins with the initial recruitment of macrophages, eosinophils, and neutrophils around the entrapped egg (Panel 1). These cells cause an inflammatory reaction causing the recruitment of more cells and the development of the granuloma size (Panel 2). Panel (3) shows the final stage of, resolve the granuloma once the antigenic stimulus (mainly the eggs) has been destroyed, resulting in deposition of fibrils of chromatin and collagens, and subsequent collagen degradation and remodelling that contribute to the final tissue fibrosis.

Hepatic Pathology

Liver disease develops secondary to entrapment of eggs in portal venules (<50 mm in diameter) and is initially presinusoidal⁶. Eggs remain viable in the liver for about 3 weeks, with immunological resection to egg antigens started with type 1 helper (Th1) in response, evolving to a dominant Th2 immune and the peri-ovular granulomas development. Subsequently there will be recruitment of eosinophils, associated with angiogenesis, and these will lead to the fibrogenesis of the liver^67,68.

These pathological changes can be scattered in the liver parenchyma and in periportal spaces, resulting in periportal fibrosis, and the development of “Symmers pipe stem fibrosis”^69,70. In addition to the development of granuloma and fibrosis, other pathological changes have been noticed, including hepatovascular endothelium proliferation, smooth muscle cell dedifferentiation, hyperplasia of elastic tissue, and the presence of several collagen isotypes. Distortion of the small and medium-sized capillaries and the appearance of small vessels sprouting from the largest portal veins, but with preservation of arterial, liver lobular architecture and ductal structures, were also observed⁶⁸.

Later, periportal collagen deposition leads to a gradual obstruction of venous blood flow, so that often the entire portal vein wall is destroyed, transforming an open circulation to a partly closed one, leading to decreased blood flow^71,72. This is associated with hepatomegaly, splenomegaly and portal hypertension⁶⁴. Approximately 5–10% of patients chronically infected with schistosomiasis develop the hepatosplenic form of the disease (collectively known as hepatosplenic schistosomiasis)⁷³. Clinically, portal hypertension in the first 25 years of life may cause oesophageal varices and ascites^74–77. In general, the natural history of portal hypertension is closely related to the number of eggs deposited in the liver⁷⁸. However, unlike the fibrosis with hepatic cirrhosis, Symmers pipe stem fibrosis may show occasional degradation and subsequent signs of portal hypertension (as splenomegaly and oesophageal varices) can progressively disappear^79,80.

Eggs that are retained in the gut also induce inflammation, ulceration and colonic polyposis⁶⁴ which may cause diarrhoea. A small increase in colorectal cancer has also been reported^64,65. These pathological changes usually do not interfere with liver function until the passage of many years of heavy infection.

Lung Pathology

The eggs can occasionally become trapped in the lungs. It is thought that the development of portal-systemic collateral circulation leads to a hyperdynamic circulatory state, contributing to an increased flow and sheer stress to the pulmonary circulation⁸¹. It also facilitates the shunting of eggs from the liver to the lungs, thus increasing the immunological burden on the lungs and pulmonary circulation^56,82.

Like the liver, the highly antigenic eggs will develop an immunological reaction that leads to the development of granuloma, and subsequent remodelling of pulmonary arterioles (Figure 6). Severe intimal, medial, and adventitial hypertrophy and proliferation of a plethora of inflammatory cells occurs in the pulmonary vasculature, which contributes to the development of pulmonary hypertension^74,82–86. There was also evidence that eggs are destroyed completely and more rapidly in the lungs than in the liver⁸⁷.

Figure 6. — Panel A shows control normal lung tissue Panel B is showing remodelled arteriole inside a granuloma (black arrow). Panel C shows a peripheral granuloma surrounding an egg (black arrow), with a remodelled arteriole (red arrow) in the periphery of the granuloma. Panel D shows various remodelled vessels nearby a granuloma (red arrows). Staining (alpha-smooth muscle actin and von Willebrand Factor). Scale bar = 20 µm. Source: the author laboratory.

Autopsy studies from Brazil of 78 patients with hepatosplenic schistosomiasis showed that 72% had periovular granulomas in the lung, but only 18% showed obliterative endarteritis endothelial cell hyperplasia, fibrin depositions and vascular hypertensive changes⁸². These are followed by complex fibrin thrombus and revascularization, congestion and dilatation of focal blood vessels, with angiogenesis which results in plexiform lesions^84,88,89. In the author’s laboratory the same trend⁹⁰ was noticed in mice infected with cercariae for 12 weeks. Seventy-nine percent of the lungs harvested from these animals contained evidence of granulomatous changes. Remodelled pulmonary vessels were seen in 46% of the lungs, and were observed in close proximity to the granuloma, but only 15% or less showed evidence of severe right ventricular hypertrophy (Figure 7).

Figure 7. — However, the right panel shows that only half of the lungs show some form of remodelling pulmonary arteries; but only 15% showed a feature that can be presented as pulmonary hypertension (mainly severe remodelling and presence of right ventricular hypertrophy). (Adopted from the author laboratory data originally published in 90).

Thus, granuloma due to chronic schistosoma infection in the lung may cause nearby vascular changes. These include endothelial cell dysfunction, loss of endothelial barrier integrity, proliferation of endothelial cells and fibroblasts, thrombi, intimal fibrosis, and formation of new endothelial lined channels ‘plexiform-like lesions’^87,91,92 with some similarities to the pulmonary vascular remodelling reported in idiopathic pulmonary hypertension^93–97 (Figure 6).

In one recent observation in patients with pulmonary hypertension due to schistosomiasis, dark pigments were frequently observed adjacent to pulmonary vascular lesions. The origin of these pigments is still unknown and is thought unlikely to be parasite-derived⁹⁸.

Curative treatment can promote reversion of the periovular granulomatous lesions formed in the alveolar tissue but not always. The changes in the arterial and arteriolar lesions were defectively repaired, with segmental vascular fibrosis, narrowing, and angiomatoid changes remaining for up to 120 days after treatment. This persistence of pulmonary vascular diseases after complete parasitic infection resolution was originally observed in experimental animals by de Almeida and Andrade in 1983⁸⁷. Portal vein ligation–induced portal hypertension, but after S. mansoni infection, the pulmonary vascular abnormalities persisted even after the eggs were eradicated and granulomas were resolved after treatments.

The same observations were seen in the liver, where remodelling of the vasculature remained after the resolution of the infection by chemotherapy⁷⁹. Furthermore, it was noticed in mice models infected with schistosomiasis eggs that the granulomas contained degraded eggs as well as egg antigens and macrophage lysosomes⁹⁸. On the other hand, the lung tissue of patients who died of pulmonary hypertension due to schistosomiasis showed granulomas and remodelled pulmonary vasculature as well as plexiform lesions, but no visible eggs or significant egg antigen⁹⁸.

Schistosomiasis vasculopathy is not rare⁹⁰, but frequently seen in patients with Symmers fibrosis⁹¹. There were suggestions this is possibly due a mechanical obstruction by the ova or worm of the pulmonary arteries leads to a focal arthritis^99,100, but most investigators believe it is due to some sort of allergic reaction, intense immunological and inflammatory reaction^101–103. The portal hypertension may contribute to the pathological changes by opening the collateral vessels that help schistosoma eggs to escape to the lung tissue. This will increase the antigen burden on the lung and thus aggravates pulmonary hypertension¹⁰⁴.

Aggravation of pulmonary hypertension has also been described after the surgical treatment of schistosomiasis-associated portal hypertension with a shunt procedure^105,106. Pulmonary hypertension has been seen in 2–12% of patients with portal hypertension in general¹⁰⁷, and in 21% of the cases with portal hypertension due to hepatosplenic mansonic infection¹⁰⁶.

Immunology and inflammatory role on the pathogenesis of pulmonary hypertension due to schistosomiasis

Inflammation plays a central role in both the causes and consequences of the pathogenesis of pulmonary hypertension due to schistosomiasis^{73,92,108–112}. T cells, B cells, mast cells, macrophages, and dendritic cells, as well as inflammatory cytokines and chemokines, are found in the lungs of patients with pulmonary hypertension, in various parts of the remodelled small pulmonary arteries, and in plexiform lesions^113–116. The athymic mouse model failed to respond to the schistosome eggs with a granulomatous response in either the liver or the lung¹¹⁷.

Crosby et al. described marked perivascular inflammation, and showed a time-dependent increase in the levels of circulating cytokines, when the Th1 cytokine (mainly TNF-α and IL-1β) peaked at 12 weeks, while Th2 cytokines (IL-10, IL-13, IL-6, and IL-4) peaked at 17 weeks⁹². Furthermore, the macrophage marker (CD68 and CD45) lymphocytes cells increased. The degree of pulmonary vascular remodelling correlated with lung egg burden and various inflammatory cytokines⁹².

Evidence of inflammatory markers is accumulating in schistosomiasis pulmonary vascular diseases, and elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension¹¹⁸ –but the role of inflammatory mediators in general is not universal. There are differences in results from patients and animal models. A recent study showed that pulmonary arterial hypertension patients exhibited significant elevations in TNFα, IL-6, and MCP-1, versus healthy participants; while this was not the case in animal models of monocrotaline, after SU5416 alone after SU5416 plus hypoxia¹¹⁹.

The granulomas, are the dynamic structures that require the persistent stimulation of activated macrophages and cytokines from other inflammatory cells and in particular the T cells^61,120,121.

Initially there is a disorganized aggregation of cells (the pre-granulomatous stage) followed by a gradual accumulation of mononuclear and eosinophils around the freshly deposited egg. As the granuloma matures, dendritic and stellate cells, tissue macrophages, epithelioid cells and fibrocytes begin to appear at the periphery, leading to gradual degeneration of the schistosoma eggs and appearance of fibrocytes and collagen fibres. This results in the reduction of the granuloma size, which contains only pigmented macrophages and may exhibit hyalization of collagen fibres, whereas the egg is typically is integrated and may become calcified^122–125.

The cellular and chemical factors controlling granuloma formation are considerable, incompletely understood, and show some difference in among different schistosoma species. It also varies according to the strain, species, age, gender, duration or intensity of infection, genetic predisposition, co-infection, reinfection, the chronological changes of the maturing egg, and other environmental factors^58,126.

As mentioned above the early immunological response involves CD4⁺ and CD8⁺ T helper (Th) cells, and thus generalised type 1 response dominates (Figure 8). It is also associated with an expansion in the frequency of cytotoxic T cells (Tc1) and Th1 causing an increase in the expression of the Th1 proinflammatory cytokines IL-1, IL-12, tumour necrosis factor (TNFα) and interferon gamma (IFNγ).

Figure 8. — Th1 phase is a short and immunologically aggressive initial stage, which starts a longer Th2 phase. The 2 phase helps in suppressing the Th1 activities reducing its the aggressive nature. At the same time a less understood Th17 started and remained for a longer period (see text for more details). During Th2 the most active cytokines (see the lower panel (inflammatory mediators) help in further development and maturation of the granuloma (second panel (granuloma). The major remodelling process of the pulmonary arteries can happen during this stage (Th2) (see the bottom panel) although other staff (ex Th1 and Th17) can play a part. This will be followed the appearance of Treg cells and the predominance of B cells, with the resolution of the granuloma and in most occasion the development of fibrosis.

These mediators can be measured in the plasma and infected tissue and in the peripheral-blood mononuclear cells^58,127. They may modulate the release of chemokines such as CXCL2, CXCL5, CXCL9, CXCL10, CXCL11, CXCL22, CCL3, CCL7, and lymphotactin (XCL1)¹²⁸.

By about 6-8 weeks after infection the cytokine response changes to type 2 with an increase in the numbers of Th2 cells and a which dramatic downregulate of Tc1 cells via apoptosis process and reducing the effect of type 1 inflammatory responses. The increase in Th2 activities enhances growth of the granuloma, the mobilization of other cells like eosinophils and eosinophils, and increases the process of collagen deposition (Figure 8)^67,129.

The polarising inflammation toward Th2 response and the Th-1/Th-2 cross-regulation and the growth of granuloma formation is mainly mediated by IL-4 and IL-13. This results the production of high levels of Th2 cytokines such as IL-4, IL-5, IL-10, IL-13, IL-21, IL-17, IL-31 and the synthesis of immunoglobulin E (IgE), AMCase, Ym1, and RELM α^58,129–134. These different cytokines have various roles. For example, some of the cytokines can enhance fibrosis, whereas others can prevent it.

Th2 response starts to down-modulate by around 12 weeks, and is associated with the reduction of the granuloma size, which is thought to be induced by IL-10 and TGFβ^{58,121,132,135}. Furthermore, Th17 response has also been reported in various schistosoma species^136,137. The cytokine IL-17 has been shown to significantly contribute to the development of a severe granulomatous¹³⁸.

B cell distribution and their absolute numbers of B cells in the spleen, lymph nodes and blood increased dramatically during the early Th2 phase of infection, and remained high throughout the chronic infection. B cells also play a central role in mediating the transition from Th1 to Th2 responses and in the regulation of the granulomatous response during acute and chronic infection.

B cell-deficient mice developed significantly smaller hepatic granulomas¹³⁹. L-10, a cytokine implicated in plasma cell development, is important for the role of B cells. It was noticed that IL-10 receptors blockade precipitated the development of portal hypertension together with the shunting of eggs, resulting in the development of severe pulmonary pathology and the accumulation of parasite eggs in the lungs and heart^140–142 – confirming the vital role of the B cells in during schistosoma infection, and probably the development of pulmonary vasculopathy¹⁴³.

Extrinsic apoptosis pathways (mainly via TNF path, but in particular FAS path) play an important role in the regulation of the immunological reaction to schistosome a eggs and the development of the granulomas, thus mitigating further host damage^144–147.

The first apoptosis signal (Fas) receptor (also known as Apo-1 or CD95) binds the Fas ligand (FasL), a transmembrane protein part of the TNF family^148,149. They trigger the death of lymphocytes and thus are fundamental to regulating T-cell and B-cell lymphocyte maturation, receptor repertoire selection, and homeostasis¹⁵⁰.

Thus the granuloma maturation, and consequently their effect on pulmonary vascular disease remodelling, can be influenced to a certain degree by the role of FAS-FASL pathways¹³⁸. But until now there have been very few studies on the direct role of extrinsic apoptosis on schistosomiasis-induced pulmonary vascular disease. For example, soluble FAS is significantly higher in schistosomiasis pulmonary hypertension compared with those in patients with cor pulmonale resulting from chronic obstructive pulmonary disease¹⁵¹. Furthermore, soluble FAS (SFas) is shed from the cell surface through the action of certain enzymes like metalloproteinases¹⁵². SFas can antagonize FAS pathway (FAS-FASL pathways) and thus inhibit apoptosis, which may contribute to the remodelling process of schistosome pulmonary vascular disease. This subject is still being studied and needs further investigation.

Th-1 proinflammatory mediators

Earlier studies showed that, in general, patients with pulmonary hypertension demonstrated TNFα serum levels within the normal range, but had increased serum levels of IL-1 beta and IL-6 in severe primary pulmonary hypertension. These observations suggest a role for proinflammatory cytokines in primary pulmonary hypertension and remodelling of the pulmonary vessels in certain animal models¹⁵³. Proinflammatory cytokines such as IL-1 and TNFα may contribute to the vasoconstriction tone, or as mediators of oxidative stress and endothelial dysfunction¹⁵⁴. Other mechanisms are explained below for each of the specific cytokines of Th1 type.

Interleukin-1

Interleukin-1 (IL-1) is a potent proinflammatory cytokine. The best-known members are IL-1α, IL-1β, and IL-1Ra (receptor antagonist). Various cells can produce this cytokine, such as macrophages, lymphocytes, endothelial cells, vascular smooth muscles cells, and fibroblasts¹⁵⁵. It can be a positive or negative mediator of cell apoptosis.

IL-1 is released in the early stages of schistosoma infection, and may participate in the pathogenesis of some forms of pulmonary hypertension. Treatment with human IL-1 receptor antagonist inhibits the development of pulmonary hypertension in monocrotaline, but not in chronically hypoxic rats^156,157; the latter probably due to the effect of lL-1 as proapoptotic during hypoxia¹⁵⁸.

It was noticed in patients with pulmonary hypertension that increased levels of IL-1 increased unadjusted hazard of death¹⁵⁹. IL-1β impairs the cyclic AMP pathway in response to prostacyclin analogues in pulmonary artery smooth muscles cells, resulting in an imbalance of the vasoactive components that may lead to pulmonary hypertension¹⁶⁰. The combination of TGF-β1, IL-1β and TNF-α, induced morphological and phenotypic changes consistent with of endothelial-to-mesenchymal transition with a dominant effect by IL-1⁹⁶.

Interleukin 12

Interleukin 12 (IL-12) is mainly produced by dendritic cells, macrophages, neutrophils, and some B-lymphocytes^161,162. IL-12 binds to the IL-12 receptors (IL-12R and IL-12Rβ2). Its main function is the differentiation of the naïve T cells into Th1 cells and help to produce Th1 cytokines like interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α)^161–163. It also reduces IL-4 mediated suppression of IFN-γ. IL-12 blocks the formation of new blood vessels. Elevated IL-12 cytokine expression inhibits secondary granuloma formation, fibrosis and blocks the formation of new blood vessels in mice pre-sensitized with schistosoma eggs^164,165.

Interferon-gamma

Interferon-gamma (IFNγ) is the primary cytokine secreted by CD4 Th1 cells and natural killer (NK) CD8 cytotoxic T lymphocyte, mainly by the effect of IL-12 (see above) and Interleukin 18 (IL-18 ) on T-cell receptors ( TCR )¹⁶⁶. IFNγ activates specific receptors that orchestrate various signalling selectivities within the JAK/STAT pathway. IFNγ also plays an important role in differentiation of T helper 1 (Th1) cell population via a positive feedback mechanism. The IFN-γ level is elevated after Schistosoma infection^167,168. Th1 helper cells in the granuloma aggregate around the macrophages and secrete IFN-γ and TNF, demonstrating the critical role of IFN-γ (and also TNF - see below) in the development of the granuloma function and endothelial damage^169–173.

IFN-γ also induces a potent vasoconstriction on human pulmonary smooth muscles cells by helping in the release endothelin-1¹⁷⁴. Thus, IFN-γ exhibits pleiotropic effects that could similarly influence differential immune regulation in early pulmonary arterial hypertension development. Other types of interferon (mainly type I interferon) were also associated with pulmonary hypertension and mediate signalling mechanisms that cause further remodelling of the pulmonary vessels and right ventricle on increased serum ET-1 in hypoxia model¹⁷⁵.

Tumour necrosis factor

Tumour necrosis factor (TNFα) is a cytokine involved Th1 inflammation. It is produced many cell types chiefly mainly activated macrophages, but also CD4⁺ lymphocytes, natural killer cells, neutrophils, mast cells, eosinophils, and neurons. TNFα works on various signalling pathways like the activation of NF-κB, Mitogen-Activated Protein Kinases (MAPK) pathways and enhancement of apoptosis mainly via the extrinsic apoptosis pathways. Pulmonary hypertension developed spontaneously in transgenic mice overexpressing TNF α¹⁷⁶. TNFα plays an important role in the development of pulmonary hypertension, even though the concrete mechanisms remain unknown, but the evidences are mounting. Recently it was demonstrated that TNFα reduces BMPR2 expression in vascular cells¹⁷⁷. It induces morphological and phenotypic changes consistent with endothelial-to-mesenchymal transition, which contributes to the remodelling process. In addition the monocrotaline-treated rats that were injected with Etanercept (a TNFα antagonist) showed protection from development of pulmonary hypertension¹⁷⁸. An increased release of TNFα has been implicated in triggering the progression of the disease¹⁵⁹. Furthermore, the high plasma levels of TNFα increased unadjusted hazard of death¹⁵⁹.

Th-2 proinflammatory mediators

Chronic schistosoma infection, like that of other helminths, drives a strong Type-2 inflammation, thought to be largely mediated by a CD4⁺T helper 2 (Type -2 (Th2)) response, while suppressing the Type-1 response. This Th2 response, triggered by egg-derived antigens, includes cytokines IL-4, IL-5, IL-10 and IL-13. Some Type-2 cytokines, mainly IL-4 and IL-13, play critical roles in activation of signalling pathways within cells that regulate cascades of immunological response of transformation from Th1 to Th2¹⁷⁹. This signalling may then regulate downstream targets involved in inflammation, maturation and dissolution of granulomas and later fibrosis and vascular remodelling^124,180.

Interleukin 4

Interleukin 4 (IL-4) is a compact globular folded protein that binds to a cellular receptor (IL-4Rα)¹⁸¹. It is one of the major Th2 cytokines and is produced mainly by mast cells, basophils natural killer T (NKT) cells, and Th2 cells themselves (positive feedback loop)^182–184. IL-4 has pleiotropic effects on many cell types¹⁸⁵. Its effects depend on binding to a receptor complex, resulting in a series of phosphorylation events mediated by associated kinases. Stat 6 plays a central role in exerting IL-4-mediated biological responses that lead to various cellular functions. These include cell growth, resistance to apoptosis, and of gene activation and differentiation. It also influences transcription (JAK/STAT) signalling cascades, which may contribute to allergic responses^{179,181,185–187}. Some of its effect is closely related to the functionality of IL-13¹⁸⁶ (see below).

IL-4’s main roles in the regulation of the immune response include:

1.
It is one of the principle cytokines in Th-2 response. It induces differentiation of naive helper T (Th0) to Th2 cells (CD4⁺ Th2 cells)^185,188.
2.
Proliferation of activated B-cells and the differentiation of B cells into plasma cells, thus influence IgG1 and IgE production.
3.
It is a potent survival factor for B cells and induces the expression of class II MHC (major histocompatibility complex), in B cells^185,189.
4.
IL-4 decreases the production of Th1 cells, macrophages, IFN-gamma, and dendritic cell and IL-12¹⁸⁹; thus, plays a protective role during schistosomiasis by controlling the production of other cytokines.
5.
IL-4 induces the so-called “alternative macrophage activation”¹⁹⁰.

Thus IL-4 has been shown to play a major part in the development of granuloma and fibrosis in around S. mansoni eggs in the liver, but its influence was more on the growth of granuloma formation in the lungs of the same animals^191,192. IL-4’s role on the remodelling of pulmonary vascular diseases has been documented and the severity of remodelling may be correlated with high levels of IL-4¹⁹³. However, this not conclusive yet as Crosby et al noticed that there is no correlation between RV/LVIS and any individual cytokine⁹².

The athymic rat model treated with the SU5416 (VEGF receptor 2 inhibitor used in some animal models to induce pulmonary hypertension) also showed elevated levels of IL-4 in lung tissue extracts, which may enhance the number of mast cells, B cells, and macrophages in perivascular infiltrates, despite the deficiency of T-celIs¹⁹⁴.

IL-4 signalling may play a significant role in hypoxia-induced mitogenic factor (HIMF) induced lung inflammation and vascular remodelling¹⁹⁵. Despite all these observations, the role of IL-4 on the remodelling process and pulmonary hypertension is still uncertain and needs further investigation.

Interleukin 13

Interleukin 13 (IL-13) is a pleiotropic cytokine which is produced by many cell types, including Th-2 lymphocytes, mast cells and unique innate lymphoid 2 cells (Nuocytes)¹⁹⁶,¹⁹⁷. IL-13 has been shown to be a crucial mediator of Th-2 dominant immune responses to variety of helminth infections^58,67 and is a major inducer of fibrosis^198,199.

Its role is closely related to the cytokine IL-4 and may work in tandem¹⁸⁶. It is a prime effector molecule, while IL-4 may be of immunoregulatory importance²⁰⁰. IL-13 and IL-4 binding varies in different human cell types, depending on co-expression of IL-4R and IL-13R which form complexes and share common subunit(s)²⁰¹. IL-13 activates the receptors IL-13Rα1, which hetrodiamerizes, and IL-4Rα (which does not by itself bind IL-13)²⁰¹. IL-13 has another receptor subunit, IL-13Rα2, which binds IL-13 exclusively with high affinity. This receptor appears to lack a signalling motif and exists in both membrane-bound and soluble forms. IL-13Rα2 initially was thought to be a “decoy” receptor for IL-13 (i.e., , one that binds IL-13 without producing biological effects)²⁰².

The complex with “decoy” receptors is thought to be a selective and powerful inhibitor of IL-13-induced inflammation, remodelling, and profibrotic effects²⁰³. Thus the signalling mechanism of this cytokine are similar to that of IL-4; that is enhancement of Janus kinase (JAK) activity and subsequently activation of transcription (STAT6) that can initiate transcription of target genes which contribute to production of various inflammatory, profibrotic and regulatory mediators.

IL-13 has many biological effects of interest in our review, such as:

1.
It can be involved in induction of TGF-β (see below) by monocytes and macrophages and subsequently contributing in the process of fibrosis¹⁸⁰.
2.
IL-13 regulates endothelial vascular cell adhesion molecule-1 (VCAM-1) and elicits a spectrum of responses in vascular endothelium expression^204,205.
3.
Production of matrix metalloproteinase-9²⁰⁶.
4.
IL-13 acts as a potent antiproliferative, but not proapoptotic, factor for pulmonary artery smooth muscles.
5.
IL-13 potently down-regulates endothelin-1 production in the lung¹⁹³.

Increased expression of both IL-13 and its receptors in small pulmonary arteries of patients with idiopathic pulmonary arterial hypertension has been reported²⁰⁷. IL-13 was elevated in the plasma of patients with systemic sclerosis with pulmonary arterial hypertension compared with patients without pulmonary arterial hypertension²⁰⁸. IL-4/IL-13 signalling in pulmonary tissue from individuals who died of schistosomiasis associated- pulmonary hypertension, underscoring the potential clinical relevance. Pulmonary hypertension were observed in mice exposed to inhaled Aspergillus¹⁹³ and in IL-13–overexpressing mice developed pulmonary hypertension²⁰⁹. However different observations were reported by Hecker et al, that IL-13 signalling suppressed proliferation of human pulmonary artery smooth muscle cells in vitro²⁰⁷. These authors²⁰⁷ noticed that pulmonary expression of the IL-13 decoy receptor (IL-13Rα2) was up-regulated relative to that of the IL-13 signalling receptors IL-4R and IL-13Rα1 in patients with pulmonary hypertension and some animal models - suggesting the important regulatory role of IL-13 in the remodelling process.

IL-13 has also recently been implicated as a regulator of pulmonary artery remodelling induced by a Th2 immune response¹⁹³, suggesting that this cytokine may contribute to the pathogenesis of pulmonary vascular diseases in schistosomiasis. It is an important mediator of granulomatous and vascular responses in the murine model schistosomiasis infection and consequently the development of pulmonary hypertension¹¹¹. Crosby et al noticed IL-13 has been implicated in pulmonary arterial muscularization and IL-13 (but not IL-4) stimulated migration of mouse pulmonary artery smooth muscle cells⁹².

The signalling mechanism of IL-13 in schistosomiasis pulmonary vascular pathology is still far from fully appreciated (Figure 9). Graham et al observed that IL-3 contribution to the pulmonary vasculopathy may be due to the increase in TGF-β1 synthesis and IL4 and IL13 to be necessary for TGF-β activation via its activation of STAT6^110,210. They noticed an increased expression of the canonical TGF-β target phospho-Smad2/3 in the pulmonary intima, media and adventitia. Blockade of TGF-β signalling prevented the development of experimental schistosoma-induced pulmonary hypertension^212,213 Others observed that TGF-β signalling is higher in mice exposed to Schistosoma and patients who have died of schistosoma-induced pulmonary hypertension²¹².

Thus, it is most likely that remodelling process by IL-13 and IL-4 and dependent TGF-1 showed positive feedback mechanism^212,214 . Furthermore, these two cytokines can also contribute to the remodelling process via other signalling process. Cho et al found that that arginase 2 (see Box 1) is a critical downstream mediator of IL-13-induced pulmonary hypertension²⁰⁹ via enhancing proliferation of vascular cells and expanding extracellular matrix.

BOX 1.

Arginase is a manganese-containing enzyme ubiquitous to all domains of life. It is the focal enzyme of the urea cycle hydrolysing l-arginine to urea and l-ornithine and plays a role in the regulation of nitric oxide synthesis. It is present mainly in two forms Arg1, a cytosolic protein, mainly expressed in hepatocytes as a key enzyme in the urea cycle and Arg2 is a mitochondrial protein that is expressed in a variety of extra hepatic tissues) are the key enzymes in l-arginine metabolism that convert l-arginine to l-ornithine and urea. This enzyme helped conversion of Arginine to NO (in this case the term Coupled NOS is used). Increase in the activity of Arginase 2 reduces the availability of Arginine and hence enhances the eNOS-uncoupling (see BOX 2 for eNOS). Therefore, resulting in the formation of Reactive oxygen species instead of NO (the term uncouple eNOS is used here because that is, uncoupling of NADPH oxidation and NO synthesis, with oxygen instead of l-arginine as terminal electron acceptor)¹⁵¹.

Arginase may also compete with nitric oxide synthase for the mutual substrate, arginine, leading to decreased bioavailability of NO²¹⁵, recognized as the major mediator of the maintenance of vascular homeostasis. However, it can help in uncoupling of nitric oxide synthase and generates more reactive oxygen species rather than NO, leading to an increase in reactive oxygen species (ROS), which ultimately causes vascular oxidative stress and inflammation contributing to the development of vascular diseases, contributing further to the remodelling process^216,217.

Further, some of the arginase products includes polyamines and L-proline, which are known to stimulate cell growth and differentiation and collagen synthesis^218,219. Recently, an ongoing investigation was based on the hypothesis that hypoxia-inducible transcription factor HIF1α plays a critical role in IL-13-stimulated proliferation pulmonary vascular smooth muscles cells (Figure 9). IL-13Rα2-Arg2-HIF1α pathway regulates mitochondrial metabolism of the mitochondria of proliferation pulmonary vascular smooth muscles cells. This hypothesis still needs further confirmation²²⁰.

The third observation was the that the downstream product of the IL-4 and IL-13 signalling pathways in the lung may lead to an increase in the numbers of RELM-α positive cells that were seen in the borders of remodelled pulmonary arteries in mice models¹⁹³ .

BOX 2.

Endothelial nitric oxide synthase (eNOS) is the critical enzyme in the maintenance of vascular pressure by producing NO that plays a major role in the relaxation of smooth muscle surrounding the arterioles^151–156

Interleukin 6

Interleukin 6 (IL-6) is a pleiotropic cytokine which is produced by professional antigen-presenting cells (APC) such as B cells, dendritic in addition to T-cells, macrophages mast cells, and muscle cells^221,222. IL-6 exerts its biological activities through a unique receptor system. These receptors are composed of a membrane-bound IL-6 receptor and two gp130 molecules. The activation of this receptor leads to the so-called classical signalling pathway. This pathway may have some anti-inflammatory responses and is restricted to hepatocytes, monocytes, macrophages, and lymphocytes.

The other receptor system is the trans-signalling pathway, whereby IL-6 binds to a soluble IL-6 receptor (sIL6R) found in bodily fluids such as urine and blood. That consequently activates membrane gp130 initiating signalling cascades allowing this to affect larger types of cells and some important biological effects, such as growth and pro-Inflammatory activities. The signalling cascade if IL-6 involved JAK/STAT3^223–225.

IL-6 also influences several aspects of the T cell immune response and act as a survival factor for T cells. It promotes the differentiation of naive CD4⁺ T cells into IL-4 –producing effector Th2 cells.

IL-6 regulates IL-4 gene expression mainly by activating nuclear factor of activated T cells (NFAT)^226–228. It also inhibits Th1 differentiation. This generalization is common in IL-6 but detailed signalling pathways differ markedly between various tissues. For example, IL-6 signalling in macrophages, dependent upon activation of the NFkB signalling pathway, other tissues show TGF-β/SMAD3 or MAPK signalling pathways. Thus, IL-6 has a complex mechanism - being proinflammatory, anti-inflammatory as well as profibrotic function. It can play bidirectional role for example up regulation of IL-6 at the early inflammatory and more regulatory role throughout²²⁹.

Both classical and trans-signalling pathways²³⁰ were noticed in the smooth muscle layer of remodelled vessels in human and experimental models, as in monocrotaline and chronic hypoxia rats^222,231,232. The ablation of IL-6 can be protective in the chronic hypoxia model²²². It is unclear whether IL-6 affects pulmonary vascular remodelling by directly targeting vessel-wall cells, or by indirect effects mediated by inflammatory cells. IL-6 may affect vascular remodelling via several complex mechanisms²²². Its effect is still elusive and far from clear. Davies et al²³³ suggested that IL-6 production (and probably IL-1) in the pulmonary vasculature was a result of chronic down regulation of SMAD3 and may mediate several inflammatory mediators. IL-6 induction may become uncontrolled, contributing to the development of pulmonary hypertension ^233,234. IL-6 promotes the development and progression of pulmonary vascular remodelling through pro-proliferative antiapoptotic mechanisms, increased the number of platelets^232,235. Some clinical studies have shown that IL-6, like many other proinflammatory cytokines, increases in patients with pulmonary arterial hypertension and is associated with hazard of death^{118,159,236,237}; though the French Network of Pulmonary Hypertension suggests that IL-6 was not significantly associated with increased hazard of death¹⁵⁹.

Angeli et al noticed that schistosoma eggs selectively induce the synthesis of IL-6 in pulmonary microvascular endothelial cells and may reduce the inflammatory reaction²³⁸. Graham et al²³⁹ noticed that schistosoma-induced pulmonary hypertension in a model which lacked IL-6 signalling (at the level of either IL-6 or blocking STAT3) promoted the remodelling of the endothelial layer after S. mansoni exposure. This was attributed to possible effects of other inflammatory profile like enhancement of Th1 and Th2, which is in schistosoma-induced pulmonary hypertension and not manifested in chronic hypoxia model. At the same time, it decreased smooth muscle remodelling and increased in mice treated with a STAT3 inhibitor. The role of IL-6 may be related to the observations that it promotes the production of TGF-β1 probably by activation of macrophages and mast cells²⁴⁰. which consequently, promotes human pulmonary muscular layer differentiation into contractile smooth muscle-like cells²⁴¹, and later , as per Zabini et al findings²⁴² (Figure 10), the production and colocalization of IL-6, which is also is known to be secreted by macrophages and other cell types, such as mast cells²⁴³, contributing to further remodelling²¹².

Figure 10. — TGF-β can have a complex mechanism as described in the text. In the early stage or short-term exposure to TGF-β (left panel) can stimulate via SMAD3 eNOS and VGEF and thus reduce the remodelling process, and IL-6 can substantiate this. However, with the long chronic exposure to TGF-β (right panel) may lead to a reduction in SMAD3 and with the IL-6 and Th17 cells may cause phenotypic changes in the remodelling process characterised by proliferation and migration in pulmonary smooth muscles and endothelial cells (see text).

These complex mechanisms are in concordance with many recent findings^233,242. Furthermore, IL-21 was noticed to downstream the aggressive role of IL-6-signalling²⁴⁴ (Figure 10).

Transforming growth factor β

Transforming growth factor β (TGF-β) is a pleiotropic cytokine, which regulates a broad range of cellular processes, such as differentiation, proliferation, migration, apoptosis vascular homeostasis, and can influence both acute and chronic inflammation^245–247. TGF-β signalling in pulmonary vascular remodelling is also mediated via several inflammatory mediators, including IL-1 and IL-6²³³ , with IL-6 appearing to play a key role, as documented in monocrotaline and chronic hypoxia rat models of models²⁴⁸.

IL-6 (induces cell signalling via various types of receptors specific for TGFβ which, through the activation of Janus kinases (JAK), lead to the activation of SMAD proteins (mainly SMAD2 and SMAD3) through phosphorylation²⁴⁹. TGF-β signal transduction has multiple transcriptional and non-transcriptional targets of target gene expression which can be influenced by other signalling pathways ²⁵⁰. Loss of BMPR-II (bone morphogenetic protein receptor 2) signalling contributes to the increase in signalling via TGF-β. A long line of research has shown that activation of the TGF-β system stimulates vasculogenesis, including intimal hyperplasia and medial smooth-muscle growth^251,252.

TGF-β has been noted to contribute to pulmonary vascular pathology; but the complexity of the TGF-β signalling mechanism is far from being fully understood and some findings are counterintuitive. It was occasionally observed that the TGF-β signalling mechanism might be impaired, and a significant decrease in pulmonary SMAD3 expression was detected in pulmonary hypertension animal models as well as in patients^253–255, suggesting a decrease in the activity of the canonical TGF-β pathway²⁴². This conundrum of TGF-β has been recently investigated by Zabini and colleagues²⁴² (Figure 10), where perpetual stimulation with TGF-β can down regulate the canonical TGF-β signalling, thus downstream of SMAD3 in the pulmonary vasculature. Reduced SMAD3 expression favours proliferation and migration in pulmonary smooth muscle and endothelial cells. Thus, initial endothelial cell injury may trigger pulmonary smooth muscle cell differentiation to a contractile proliferative phenotype. Later, progress of the inflammation and the reduction of SMAD3 leads to the development of a synthetic phenotype, which acquires migratory capacities. This causes an increase in vascular wall thickness, muscularization of small pulmonary arterioles, progressive excessive endothelial cell growth, and apoptosis-resistant phenotype^{233,242,256–258}.

Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is a key immune regulator is which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses in a murine model of schistosomiasis-induced pulmonary hypertension²¹¹. VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL-4 and IL-13) in both the lung and the liver after S. mansoni exposure and suppressed pulmonary vascular remodelling²¹¹ illustrating the role of VEGF schistosomiasis-induced vascular inflammation and remodelling.

Interleukin 10

Interleukin 10 (IL-10) is a multifunctional cytokine, which is produced by CD4 T lymphocytes and macrophages. It can block NF κB activity, and is involved in the regulation of the JAK-STAT signalling pathway. It has a major regulatory anti-inflammatory function. It down regulates Th1 cytokines by suppressing their excessive response and inhibits the synthesis of pro-inflammatory cytokines such as IFNγ, IL-2, IL-3, TNF α¹⁴⁰. It also enhances B cell survival, proliferation, and antibody production, thus reducing an allergic reaction and immunopathology in many persistent infections, like in schistosomiasis^259,260. Thus IL-10 plays a role in reducing morbidity and prolong survival in schistosomiasis^11,260,261.

The plasma level of IL-10 is elevated with IL-6, along with TNF-α and IL-10 in non-fibrotic groups, but low IL-10 levels were associated with moderate/severe hepatic fibrosis - while IL-13 was raised in this group ¹¹. These findings reveal the central regulatory role of IL-10 in the pathogenesis of schistosomiasis by supressing excessive type 1 and type 2 cytokine responses²⁶¹. Ito et al, demonstrated that injections of IL-10 reduced the mean pulmonary arterial pressure and remodelling in monocrotaline pulmonary hypertension models in rats and inhibits the proliferation of cultured human pulmonary artery smooth muscle cells²⁶².

In mice infected with schistosoma , IL-10 levels increase in a time-dependent manner, in parallel with vascular remodelling⁹². Some investigators notice that IL-10 did not have direct antiproliferative effects on pulmonary artery smooth muscle, but HO-1 and CO may contribute to the anti-proliferative effect, which points to the necessity to decipher the role of the IL-10 pathway in the protection of pulmonary vascular diseases development²⁶³.

Elevated levels of IL-10 are found in patients with pulmonary arterial hypertension²⁶⁴. Patients under a pulmonary arterial hypertension target therapy with prostacyclin agonists showed higher levels of IL-10 compared to patients without such therapy¹¹⁸.

Interleukin 5

Interleukin 5 (IL-5) is an interleukin produced by type-2 T helper cells. IL-5 plays an essential role in recruiting the maturation of eosinophils to the site of antigen deposition^265,266. It also play role in the regulation of other cytokines like IL-13^124,130. With respect to pulmonary arterial hypertension, the effect of IL-5 may be similar to that of IL-4, and the severity of pulmonary arterial muscularization correlates with IL-5–expressing T cells¹⁹³.

Interleukin -21

Interleukin (IL-21) is produced mostly by activated CD4⁺ T cells. It facilitates the differentiation and functional activity of the T helper cells, in particular the differentiation to Th17 cells (Box 3). IL-21 has pleiotropic effects on the proliferation, differentiation of B, T, natural killer, and dendritic cells. It also supporting the development of Th2 responses²⁶⁷, by increasing IL-4 and IL-13 receptor expression on macrophages and enhances the development of alternatively activated macrophages - which therefore, give it a potential role in inducing proliferation of primary pulmonary artery smooth muscle cells and profibrotic effects in the lung exposed to S. mansoni²⁶⁷; but this has not been studied systematically yet.

BOX 3.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). Naive CD4 T cells become activated when exposed to specific antigens differentiate into several possible T helper (Th1, Th2 , Th17 and Treg) cell subsets. This differentiation depends on a number of factors including antigen-presenting cells, cytokines and co-stimulatory molecules^276,277. Th17 cells secrete the inflammatory cytokines IL-17 and IL-22, and their differentiation requires the presence of TGF-β, IL-6, IL-21 and IL-23^276–281. The key factors in the differentiation of Th17 cells are signal transducer and the activator of transcription 3 (STAT3) and retinoic acid receptor-related orphan receptors gamma (RORγ) and alpha (ROR α)²⁸². Further, Th17 cells inhibit Treg differentiation. Th17 cells are important in the control of extracellular and fungal pathogens and contribute to immunopathology in certain autoimmune diseases

Interleukin 17

Interleukin 17 (IL-17) is a pro-inflammatory cytokine produced by a group of T helper 17 (Th17 cells) (Box 3). It has its own receptors in three forms referred to as IL17RA, IL17RB, and IL17RC. The signalling cascades results in induction of chemokines that activate various proinflammatory and inflammatory reactions and mediate many immune/autoimmune related diseases like rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, and transplant rejection. IL-17 plays an essential role in inflammatory cells recruitment and accelerates inflammatory progression and thus can promote the granuloma formation and size in schistosomiasis^268,269. This was opposed by IL-22²⁶⁸.

Experimental studies in animals have suggested Th17 promotes hypoxia-induced pulmonary hypertension^244,270. Patients with idiopathic pulmonary arterial hypertension expressed a higher level of IL-17 and Th17 cells²⁷¹. The role of IL-17 and Th17 in schistosomiasis pulmonary hypertension is still far from being systematically evaluated.

Resistin-like molecule α

Resistin-like molecule α (RELM-α), also referred to as inflammatory zone 1 (FIZZ1), hypoxia-induced mitogenic factor (HIMF), or Retnla (resistin-like molecule alpha), is a cytokine produced during hypoxia in the lung^272,273. RELM-α with HIMF, and the transcription factor HIF-2α, were temporally and spatially expressed in the developing lung and hypoxia. RELM-α was shown to exert an anti-inflammatory effect in parasite-induced Th2 responses and thus primarily functions as a regulatory molecule during helminth infection²⁷⁴. It regulates apoptosis products in allergen- and parasite-associated Th2 responses²⁷⁵.

The Role of Co-Infection

Careful analysis of the published data suggests that the estimated prevalence of HIV-associated pulmonary arterial hypertension ranges from 0.4–5% globally²⁷⁶. It has been reported that many patients with HIV infection in Africa had co-infection with schistosomiasis^277–280. A study in rural Zimbabwe reported that 57% of HIV patients were co-infected with S. mansoni, and that treatment of schistosomiasis could reduce the rate of HIV viral replication and increase CD4⁺ T cell count in the co-infected host²⁸¹.

HIV viral proteins may enhance inflammatory reactions, mediate endothelial cell injury, and promote the remodelling process²⁷⁶. Co-infection with HIV is proposed to create an unusual complex inflammatory response, but biologically plausible circumstance, that would allow for severe and rapidly progressive pulmonary arterial hypertension. The inflammatory response due to schistosomes as described above can also alter the HIV infection. The release of cytokines and chemokines such as IL-6, or increased levels of vasoactive peptides like asymmetrical dimethylarginine, a well-known endogenous inhibitor of endothelial nitric oxide synthase, thus promotes endothelial dysfunction and vascular smooth muscle cell proliferation^282–284. HIV viral proteins like Nef and Tat proteins modulate the release of IL-2 and monocyte chemotactic protein-1 (MCP-1, also known as CCL2), which stimulate pulmonary vascular remodelling particularly in Schistosomiasis^111,285,286.

In addition, S. mansoni also appears to influence HIV replication, cell-to-cell transmission of HIV-1, and HIV disease progression as indicated by lower CD4⁺ T cell counts when co-infection is present. Deworming of HIV-positive individuals living in endemic areas may have an impact on HIV-1 viral loads and the CD4⁺ T cell count^287,288. Schistosomiasis can also impair the response to antiretroviral therapy among HIV-infected patients²⁸⁹. The details and clinical significance of co-infection have not yet been studied, but is due for careful evaluation considering its importance, particularly in Africa where dual HIV-schistosomiasis infection is most prevalent^276,290.

The Prevalence of Pulmonary Hypertension Secondary to Schistosomiasis

The real prevalence of pulmonary vascular diseases caused by schistosoma infection is unknown. One of the earliest report of the presence of schistosoma eggs in the lungs of African natives was in 1885²⁹¹. After that there were several reports from Egypt in the first half of the twentieth century, describing pathological and clinical manifestations of pulmonary vascular diseases secondary to infection by both S. mansoni and S. haematobium ^{74,82,85,86,292}.

In the second half of the twentieth century, reports of many small series appeared in the literature, this time mainly from Brazil and occasionally a few cases from Africa and more recently, China (Figure 11). In these studies, the prevalence ranged from 7.7 to 33%^94,293–295.

Barbosa et al, ²⁹⁶ examining 246 patients of a highly endemic area for schistosomiasis in Brazil, using echo and Doppler cardiograph, found pulmonary hypertension in 16% of the individuals with no case of cor pulmonale

Recently, more carefully controlled methodological studies were conducted in patients with hepatosplenic schistosomiasis and liver fibrosis in Brazil, and found that that 7.7–10.7% were diagnosed with pulmonary hypertension^46,94,294. It is, however, difficult to estimate the real prevalence of pulmonary vascular diseases, worldwide, as it depends on many factors like the geographical distribution, public health status, difference in the antigenicity, and progress of the pathological changes. It is suggested from our experimental observation that the changes in the pulmonary vasculature after schistosoma infection are far more common, but may not always be associated with significant increases in the total vascular resistance, or clinical manifestation of pulmonary hypertension⁹⁰.

Acute Pulmonary Schistosomiasis (Katayama Syndrome)

The pulmonary involvement of schistosomiasis can be as early as the first exposure to infection⁵⁶; causing a usually mild clinical condition called “Acute schistosomiasis”, or Katayama syndrome²⁹⁷. It is common in those infected with any schistosomiasis species for the first time; such as travellers or immigrants to schistosoma-endemic regions^3,298,299. Historical accounts of Katayama disease date back to the discovery of S. Japonicum in Japan in 1904 (Figure 2). The disease was named after an area where it was endemic, Katayama district in Hiroshima prefecture, which was an endemic area in Japan until 1980³⁰⁰. The condition was also recorded historically, when – during the Napoleonic invasion of Egypt at the end of the 18th century – 35,000 French soldiers suffered from outbreaks of abdominal pain, fever, and occasionally haematuria. It is now believed to be due to acute schistosomiasis^301,302.

The initial acute immunological response to schistosomiasis occurs following penetration of the skin by the cercariae, leaving an itchy rash known as cercarial dermatitis, or “swimmers itch”, within a few hours^6,299. This condition can occur with all species of schistosoma, including those in which humans are not a natural host, such as the species that infect birds. Disease onset appears to be related to migrating schistosomula and egg deposition; thought to be an immune complex-mediated hypersensitivity reaction.

Katayama syndrome usually presents 4–8 weeks after water contact exposure with a combination of symptoms such as; general malaise, nocturnal low-grade fever, cough, myalgia, headache, wheezing, dyspnea, tender hepatomegaly, and gastrointestinal disturbances such as diarrhoea and abdominal pain^298,303.

Chest x-rays show widespread transitory nonspecific infiltrates are often seen. Almost all cases have eosinophilia^304,305. Other clinical manifestations include myocarditis³⁰⁶ and neurological involvement. Cerebral schistosomiasis may manifest as an acute or sub-acute encephalitic-like syndrome, as a slowly growing inflammatory pseudotumor with mass effect, or as a stroke syndrome³⁰⁷. Acute schistosomiasis was also reported during pregnancy with a trend of lower birth weights observed in the infants of the pregnant patients who were not treated³⁰⁸.

Acute schistosomiasis usually dissipates within several weeks, although respiratory complaints may continue for months²⁹⁸. Patients respond well to regimens of praziquantel with and without steroids. Artemisinin treatment given early after exposure may decrease the risk of the syndrome. 26% of patients who were initially asymptomatic developed chronic schistosomiasis within 3 years of exposure^298,307.

The Clinical Presentations of Pulmonary Hypertension Secondary to Schistosomiasis

Pulmonary vascular disease secondary to schistosomiasis is more common in endemic areas and may not always produce clinical symptoms⁹⁰. It is only on repeated infection that severe remodelling of the vessels through a high antigenicity load of eggs from the schistosoma can produce pulmonary hypertension, and consequently right heart failure⁹⁰.

The clinical presentation shows signs and symptoms that are not distinguishable from another form of pulmonary arterial hypertension; such as dyspnoea on exertion, anaemia, fatigue, weakness, cough, giddiness fainting, and exercise intolerance. Physical examination may reveal a prominent pulmonic component second heart sound, right ventricular heave, and digital clubbing. Radiographs may reveal cardiomegaly, particularly dilatation of the right ventricle and right atrium, and enlarged pulmonary trunk and arteries, with pruning of the distal vasculature. Clinical and radiological findings are similar to those associated with other causes of pulmonary hypertension. It was, however, demonstrated that pulmonary artery enlargement is more pronounced in schistosomiasis pulmonary hypertension than another form of pulmonary arterial hypertension; which may be a feature of schistosomiases pulmonary hypertension^309–311 (Figure 12 and Figure 13). Few cases of giant pulmonary artery aneurysm in a patient with pulmonary arterial hypertension associated with schistosomiasis have been reported³¹² and may be complicated by pulmonary artery dissection³¹³.

Figure 12. — The X ray to the left and right show the dilatation of left and right pulmonary arteries (arrows). the right panel showing the characteristic dilation of both main right and left pulmonary artery in patients with schistosomiasis pulmonary hypertension (images: courtesy of Dr Angela Bandeira).

Figure 13. — The left panel shows severe pulmonary artery dilatation (X), and in the right panel shows the right ventricular dilatation and hypertrophy. (Images: courtesy of Dr T. Safwat).

Electrocardiography typically shows right ventricular hypertrophy or strain, and right atrial enlargement. It may also reveal a right bundle branch block. Echocardiography demonstrates right ventricular dilatation, potentially compressing the left ventricle with septal bowing, usually accompanied by right atrial dilation, tricuspid valve regurgitation, and an increased pressure gradient across the tricuspid^296,314.

It is important to rule out other causes of pulmonary hypertension to assess causality. Patients in endemic areas should suspect schistosomiasis as the cause of pulmonary hypertension, in particular with the presence of prehepatic portal hypertension³⁰. It is, however, essential to perform right heart catheterization, to provide a direct measurement of the mean pulmonary arterial pressure, and assess the right ventricular function and pulmonary artery wedge pressure. It is worth mentioning that about 13% of patients with schistosomiasis pulmonary hypertension will also have compromised left ventricular function with the increase of the PAWP³¹⁵. Only a small number of patients had significant vasodilatory response acute vasodilator challenge³¹⁶.

There is no pathognomonic feature to diagnose schistosomiasis pulmonary hypertension. We do not yet have biomarkers or serological tests to help in the diagnosis³¹⁷. Most centres depend on an empirical approach that reveals the presence of pulmonary hypertension in the absence of significant lung parenchymal disease (e.g., left ventricular dysfunction or chronic thromboembolic disease, associated with the presence of periportal fibrosis and/or left liver lobe enlargement associated with at least one of the following features: positive epidemiology, previous treatment of schistosomiasis or identification of eggs in stool or rectal biopsy^316,318,319).

Treatment of Schistosomiasis Associated with Pulmonary Arterial Hypertension

There are no clinical trials to confirm the application of any of the currently approved therapies for pulmonary arterial hypertension in schistosomiasis pulmonary hypertension. So far we only have observational data from various centres around the world. It has been conventional in many centres to treat these patients with the current treatment such as phosphodiesterase-5 inhibitors or endothelial receptor antagonists^320–323. These observational small studies showed improvements of functional class, cardiac output and 6-min walking test distance (6MWT)³²².

In a retrospective and prospective observational single centre study involving 102 patients with schistosomiasis pulmonary hypertension, it was suggested that patients receiving the current conventional pulmonary arterial hypertension therapy had better survival rates than a historical untreated group at 60 months (89.1% vs. 69.2% respectively)³²⁴.

It is important to determine if active schistosomiasis infection is present, as treatment with an anthelmintic drug, such as praziquantel, may be warranted. Praziquantel works on the schistosome calcium ion channels, causing paralysis in the contracted element of the parasite that facilitates detachment of adult worms from the host vascular wall, and ultimately leads to their death³²⁵. It has a cure rate of up to 90%. This may help to reduce the antigenic load from the parasite eggs, thus reducing the granuloma, and probably prevent further deterioration^83,326,327.

Experimental studies showed that anti-schistosomal therapy reduces pulmonary vascular remodelling and, consequently, pulmonary hypertension³²⁶. However while this strategy may be useful in acute conditions, it may not be beneficial in chronic pulmonary hypertension, where studies suggest that pulmonary remodelling and clinical pulmonary hypertension may persist even after complete deworming and disappearance of eggs¹⁰⁴.

There is however a small risk of using anti-schistosomal therapy, whereby the dead worm may cause pulmonary embolism with an abrupt increase in pulmonary pressure and development of acute cor pulmonale¹⁰⁴. Managing other consequences of infection, such as the used of corticosteroids, may be useful, but it is uncertain whether they have any effect on the pulmonary vascular pathology.

Another important issue in the management of schistosomiasis is the frequent association of liver diseases, which necessitates closer monitoring of liver function, in particular when endothelial antagonists are used. Anticoagulation drugs in patients with schistosomiasis pulmonary hypertension should be considered with care, because the presence of portal hypertension and related complications such as oesophageal varices and the risk of bleeding^105,328,329.

Furthermore, the surgical malmanagement of the oesophageal varices, like trans jugular intrahepatic Porto systemic shunt and distal splenorenal shunt, can increase the load on the right ventricle, increasing the risk of more shunting of eggs from the portal system³³⁰. Thus, increasing the antigenic load to the lung increases the risk of more granuloma and pulmonary vascular remodelling – leading to the risk of fatal pulmonary hypertension¹⁰⁵. However, prognosis of this condition has not been systematically studied. Initial small observations showed a more benign clinical course than idiopathic pulmonary arterial hypertension³¹⁶.

References

1.Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis [Internet] 2006;6:411–425. doi: 10.1016/S1473-3099(06)70521-7. Available from: http://www.sciencedirect.com/science/article/pii/S1473309906705217. [cited 2014 Jan 11] [DOI] [PubMed] [Google Scholar]
2.Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet [Internet] 2013;380:2163–2196. doi: 10.1016/S0140-6736(12)61729-2. Available from: http://www.sciencedirect.com/science/article/pii/S0140673612617292. [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Colley DG, Bustinduy AL, Secor WE, King CH. Human schistosomiasis. The Lancet [Internet] 2014;383:2253–2264. doi: 10.1016/S0140-6736(13)61949-2. Available from: http://www.sciencedirect.com/science/article/pii/S0140673613619492. [cited 2015 May 3] [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Littlewood DTJ, Webster BL. Schistosoma. CRC Press; 2017. Origins and evolutionary radiation of Schistosoma; pp. 9–16. [Google Scholar]
5.Robotham JL. Schistosomal cor pulmonale: A fluke in the fas lane? Respiration [Internet] 2003;70:569–571. doi: 10.1159/000075199. Available from: https://www.karger.com/Article/FullText/75199. [cited 2018 Aug 24] [DOI] [PubMed] [Google Scholar]
6.Ross AGP, Bartley PB, Sleigh AC, Olds GR, Li Y, Williams GM, McManus DP. Schistosomiasis. N Engl J Med [Internet] 2002;346:1212–1220. doi: 10.1056/NEJMra012396. Available from: http://www.nejm.org/doi/full/10.1056/NEJMra012396. [cited 2014 Jan 11] [DOI] [PubMed] [Google Scholar]
7.Bustinduy AL, Parraga IM, Thomas CL, Mungai PL, Mutuku F, Muchiri EM, Kitron U, King CH. Impact of polyparasitic infections on anemia and undernutrition among kenyan children living in a Schistosoma haematobium-endemic area. Am J Trop Med Hyg [Internet] 2013;88:433–440. doi: 10.4269/ajtmh.12-0552. Available from: http://www.ajtmh.org/content/88/3/433. [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Mott KE, Desjeux P, Moncayo A, Ranque P, De Raadt P. Parasitic diseases and urban development. Bull World Health Organ [Internet] 1990;68:691. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2393177/ [cited 2015 May 21] [PMC free article] [PubMed] [Google Scholar]
9.Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. The Lancet [Internet] 368:1106–1118. doi: 10.1016/S0140-6736(06)69440-3. Available from: http://www.sciencedirect.com/science/article/pii/S0140673606694403 , 23 [cited 2014 Jan 11] [DOI] [PubMed] [Google Scholar]
10.van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, Habbema JDF, Engels D. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop [Internet] 2003;86:125–139. doi: 10.1016/s0001-706x(03)00029-9. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X03000299 . [DOI] [PubMed] [Google Scholar]
11.Mutengo MM, Mduluza T, Kelly P, Mwansa JCL, Kwenda G, Musonda P, Chipeta J. Low IL-6, IL-10, and TNF-α and high IL-13 cytokine levels are associated with severe hepatic fibrosis in Schistosoma mansoni chronically exposed individuals. J Parasitol Res [Internet] 2018 doi: 10.1155/2018/9754060. Available from: https://www.hindawi.com/journals/jpr/2018/9754060/ [cited 2018 Aug 23] [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Engels D, Chitsulo L, Montresor A, Savioli L. The global epidemiological situation of schistosomiasis and new approaches to control and research. Acta Trop [Internet] 2002;82:139–146. doi: 10.1016/s0001-706x(02)00045-1. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X02000451. [cited 2014 Jan 11] [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Alan Fenwick OBE, Fleming FM, Blair L. Control of schistosomiasis. Schistosoma Biol Pathol Control. 2017:440. [Google Scholar]
14.El-Khoby T, Galal N, Fenwick A, Barakat R, El-Hawey A, Nooman Z, Habib M, Abdel-Wahab F, Gabr NS, Hammam HM, Hussein MH, Mikhail NN, Cline BL, Strickl GT. The epidemiology of schistosomiasis in Egypt: summary findings in nine governorates. Am J Trop Med Hyg [Internet] 2000;62:88–99. doi: 10.4269/ajtmh.2000.62.88. Available from: http://www.ajtmh.org/content/journals/10.4269/ajtmh.2000.62.88. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]
15.Fenwick A, Savioli L, Engels D, Bergquist NR, Todd MH. Drugs for the control of parasitic diseases: current status and development in schistosomiasis. Trends Parasitol. 2003;19:509–515. doi: 10.1016/j.pt.2003.09.005. [DOI] [PubMed] [Google Scholar]
16.Doenhoff MJ, Cioli D, Utzinger J. Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis [Internet] 2008;21:659–667. doi: 10.1097/QCO.0b013e328318978f. Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00001432-200812000-00013. [cited 2015 May 21] [DOI] [PubMed] [Google Scholar]
17.Utzinger J, Xiao S-H, Tanner M, Keiser J. Artemisinins for schistosomiasis and beyond. Curr Opin Investig Drugs Lond Engl 2000. 2007;8:105–116. [PubMed] [Google Scholar]
18.Cioli D, Pica-Mattoccia L, Basso A, Guidi A. Schistosomiasis control: praziquantel forever? Mol Biochem Parasitol [Internet] 2014;195:23–29. doi: 10.1016/j.molbiopara.2014.06.002. Available from: http://www.sciencedirect.com/science/article/pii/S0166685114000759. [cited 2015 Jul 31] [DOI] [PubMed] [Google Scholar]
19.Ricciardi A, Ndao M. Still hope for schistosomiasis vaccine. Hum Vaccines Immunother [Internet] 2015;0:00–00. doi: 10.1080/21645515.2015.1059981. Available from: [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Grimes JE, Croll D, Harrison WE, Utzinger J, Freeman MC, Templeton MR. The roles of water, sanitation and hygiene in reducing schistosomiasis: A review. Parasit Vectors. 2015;8 doi: 10.1186/s13071-015-0766-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Utzinger J, N’Goran EK, Caffrey CR, Keiser J. From innovation to application: Social–ecological context, diagnostics, drugs and integrated control of schistosomiasis. Acta Trop [Internet] 2011;120(Supplement 1):S121–S137. doi: 10.1016/j.actatropica.2010.08.020. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X10002330. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]
22.Rollinson D, Knopp S, Levitz S, Stothard JR, Tchuem Tchuenté L-A, Garba A, Mohammed KA, Schur N, Person B, Colley DG, Utzinger J. Time to set the agenda for schistosomiasis elimination. Acta Trop [Internet] 2013;128:423–440. doi: 10.1016/j.actatropica.2012.04.013. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X1200191X. [cited 2014 Apr 11] [DOI] [PubMed] [Google Scholar]
23.Abdel-Wahab MF, El-Sahly A, Zakaria S, Strickland GT, El-Kady N, Ahmed L. Changing pattern of schistosomiasis in egypt 1935-79. The Lancet [Internet] 1979;314:242–244. doi: 10.1016/s0140-6736(79)90249-6. Available from: http://www.sciencedirect.com/science/article/pii/S0140673679902496. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]
24.Abdel-Wahab MF, Yosery A, Narooz S, Esmat G, Hak SE, Nasif S, Strickl GT. Is Schistosoma mansoni replacing Schistosoma haematobium in the fayoum? Am J Trop Med Hyg [Internet] 1993;49:697–700. doi: 10.4269/ajtmh.1993.49.697. Available from: http://www.ajtmh.org/content/journals/10.4269/ajtmh.1993.49.697. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]
25.Michelson MK, Azziz FA, Gamil FM, Wahid AA, Richards FO, Juranek DD, Habib MA, Spencer HC. Recent trends in the prevalence and distribution of schistosomiasis in the Nile Delta region. Am J Trop Med Hyg [Internet] 1993;49:76–87. doi: 10.4269/ajtmh.1993.49.76. Available from: http://www.ajtmh.org/content/journals/10.4269/ajtmh.1993.49.76. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]
26.Talaat M, El-Ayyat A, Sayed HA, Miller FD. Emergence of Schistosoma mansoni infection in upper Egypt: the Giza governorate. Am J Trop Med Hyg [Internet] 1999;60:822–826. doi: 10.4269/ajtmh.1999.60.822. Available from: https://www.ajtmh.org/content/journals/10.4269/ajtmh.1999.60.822. [cited 2018 Sep 4] [DOI] [PubMed] [Google Scholar]
27.Ross AG, Li Y, Williams GM, Jiang Z, McManus DP. Dam worms. Biol Lond Engl. 2001;48:121–124. [PubMed] [Google Scholar]
28.Li YS, Sleigh AC, Ross AG, Williams GM, Tanner M, McManus DP. Epidemiology of Schistosoma japonicum in China: morbidity and strategies for control in the Dongting Lake region. Int J Parasitol. 2000;30:273–281. doi: 10.1016/s0020-7519(99)00201-5. [DOI] [PubMed] [Google Scholar]
29.McManus DP, Gray DJ, Li Y, Feng Z, Williams GM, Stewart D, Rey-Ladino J, Ross AG. Schistosomiasis in the People’s Republic of China: the era of the Three Gorges Dam. Clin Microbiol Rev. 2010;23:442–466. doi: 10.1128/CMR.00044-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.McManus DP, Gray DJ, Ross AG, Williams GM, He H-B, Li Y-S. Schistosomiasis research in the dongting lake region and its impact on local and national treatment and control in China. PLoS Negl Trop Dis. 2011;5:e1053. doi: 10.1371/journal.pntd.0001053. [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Schistosomiasis: number of people receiving preventive chemotherapy in 2012. Relevé Épidémiologique Hebd Sect Hygiène Secrétariat Société Nations Wkly Epidemiol Rec Health Sect Secr Leag Nations. 2014;89:21–28. [PubMed] [Google Scholar]
32.Deelder AM, Miller RL, Jonge ND, Krijger FW. Detection of schistosome antigen in mummies. The Lancet [Internet] 1990;335:724–725. doi: 10.1016/0140-6736(90)90838-v. Available from: https://www.thelancet.com/journals/lancet/article/PII0140-6736(90)90838-V/abstract. [cited 2018 Aug 27] [DOI] [PubMed] [Google Scholar]
33.Miller RL, Armelagos GJ, Ikram S, De Jonge N, Krijger FW, Deelder AM, et al. Palaeoepidemiology of Schistosoma infection in mummies. BMJ [Internet] 1992;304:555–556. doi: 10.1136/bmj.304.6826.555. Available from: http://www.bmj.com/content/bmj/304/6826/555.full.pdf. [cited 2015 Jun 13] [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Bella SD, Riccardi N, Giacobbe DR, Luzzati R. History of schistosomiasis (bilharziasis) in humans: from Egyptian medical papyri to molecular biology on mummies. Pathog Glob Health [Internet] 2018;0:1–6. doi: 10.1080/20477724.2018.1495357. Available from: [cited 2018 Aug 27] [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Eltawil KM, Plassmann M. Theodor maximillian Bilharz (1825-1862): the discoverer of schistosomiasis. Int J Parasitol Res. 2011;3:17. [Google Scholar]
36.Jamieson BGM. Schistosoma: Biology, pathology and control. CRC Press; 2017. [Google Scholar]
37.Gobert GN, Schulte L, KJones M. Tegument and external features of Schistosoma (with particular reference to ultrastructure) Schistosoma Biol Pathol Control. 2017;213 [Google Scholar]
38.Barrett J. Forty years of helminth biochemistry. Parasitology [Internet] 2009;136:1633–1642. doi: 10.1017/S003118200900568X. Available from: http://journals.cambridge.org/article_S003118200900568X. [cited 2015 May 20] [DOI] [PubMed] [Google Scholar]
39.Huang SC-C, Freitas TC, Amiel E, Everts B, Pearce EL, Lok JB, Pearce EJ. Fatty acid oxidation is essential for egg production by the parasitic flatworm Schistosoma mansoni. PLoS Pathog [Internet] 2012;8:e1002996. doi: 10.1371/journal.ppat.1002996. Available from: [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE. Helminth parasites –masters of regulation. Immunol Rev [Internet] 2004;201:89–116. doi: 10.1111/j.0105-2896.2004.00191.x. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.0105-2896.2004.00191.x. [cited 2018 Aug 28] [DOI] [PubMed] [Google Scholar]
41.Allen JE, Maizels RM. Diversity and dialogue in immunity to helminths. Nat Rev Immunol [Internet] 2011;11:375–388. doi: 10.1038/nri2992. Available from: http://www.nature.com/nri/journal/v11/n6/full/nri2992.html. [cited 2017 Jun 12] [DOI] [PubMed] [Google Scholar]
42.Schmid-Hempel P. Immune defence, parasite evasion strategies and their relevance for ‘macroscopic phenomena’ such as virulence. Philos Trans R Soc Lond B Biol Sci [Internet] 2009;364:85–98. doi: 10.1098/rstb.2008.0157. Available from: http://rstb.royalsocietypublishing.org/content/364/1513/85. [cited 2018 Aug 28] [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Rollinson D, Webster JP, Webster B, Nyakaana S, Jørgensen A, Stothard JR. Genetic diversity of schistosomes and snails: implications for control. Parasitology [Internet] 2009;136:1801–1811. doi: 10.1017/S0031182009990412. Available from: http://journals.cambridge.org/article_S0031182009990412. [cited 2015 May 20] [DOI] [PubMed] [Google Scholar]
44.Anderson TJC, LoVerde PT, Le Clec’h W, Chevalier FD. Genetic crosses and linkage mapping in Schistosome parasites. Trends Parasitol [Internet] 2018 doi: 10.1016/j.pt.2018.08.001. Available from: http://www.sciencedirect.com/science/article/pii/S1471492218301533. [cited 2018 Aug 28] [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Gower CM, Gouvras AN, Lamberton PHL, Deol A, Shrivastava J, Mutombo PN, Mbuh JV, Norton AJ, Webster BL, Stothard JR, Garba A, Lamine MS, Kariuki C, Lange CN, Mkoji GM, Kabatereine NB, Gabrielli AF, Rudge JW, Fenwick A, Sacko M, Dembelé R, Lwambo NJS, Tchuem Tchuenté L-A, Rollinson D, Webster JP. Population genetic structure of Schistosoma mansoni and Schistosoma haematobium from across six sub-Saharan African countries: implications for epidemiology, evolution and control. Acta Trop [Internet] 2013;128:261–274. doi: 10.1016/j.actatropica.2012.09.014. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X12003336. [cited 2015 May 20] [DOI] [PubMed] [Google Scholar]
46.Zerlotini A, Aguiar ERGR, Yu F, Xu H, Li Y, Young ND, Gasser RB, Protasio AV, Berriman M, Roos DS, Kissinger JC, Oliveira G. SchistoDB: an updated genome resource for the three key schistosomes of humans. Nucleic Acids Res [Internet] 2012 doi: 10.1093/nar/gks1087. gks1087. Available from: http://nar.oxfordjournals.org/content/early/2012/11/16/nar.gks1087. [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]
47.Chen M. Assessment of morbidity due to Schistosoma japonicum infection in China. Infect Dis Poverty [Internet] 2014;3:6. doi: 10.1186/2049-9957-3-6. Available from: https://www.idpjournal.com/content/3/1/6/abstract. [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Jamieson B, Haas W. Miracidium of Schistosoma. Schistosoma Biol Pathol Control. 2017;77 [Google Scholar]
49.Chia-Tung Pan S. The fine structure of the miracidium of Schistosoma mansoni. J Invertebr Pathol [Internet] 1980;36:307–372. doi: 10.1016/0022-2011(80)90040-3. Available from: https://www.cabdirect.org/cabdirect/abstract/19800879091. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]
50.Théron BGA, Yoshino TP. Schistosoma. CRC Press; 2017. Schistosoma sporocysts; pp. 126–156. [Google Scholar]
51.Kašnỳ M, Haas W, Jamieson BG, Horák P. Cercaria of Schistosoma. Schistosoma Biol Pathol Control. 2017;149 [Google Scholar]
52.Gryseels B. Schistosomiasis. Infect Dis Clin North Am [Internet] 2012;26:383–397. doi: 10.1016/j.idc.2012.03.004. Available from: http://www.sciencedirect.com/science/article/pii/S089155201200013X. [cited 2015 May 21] [DOI] [PubMed] [Google Scholar]
53.Graefe G, Hohorst W, Dräger H. Forked tail of the cercaria of Schistosoma mansoni—a rowing device. Nature [Internet] 1967;215:207–208. doi: 10.1038/215207a0. Available from: https://www.nature.com/articles/215207a0. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]
54.Haas W. Physiological analyses of host-finding behaviour in trematode cercariae: adaptations for transmission success. Parasitology [Internet] 1994;109:S15–S29. doi: 10.1017/s003118200008505x. Available from: https://www.cambridge.org/core/journals/parasitology/article/physiological-analyses-of-hostfinding-behaviour-in-trematode-cercariae-adaptations-for-transmission-success/E3B9752C932E3B29D00D4E1046FF3DCE. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]
55.Gobert G. Schistosoma: Biology, pathology and control. CRC Press; 2017. Nawaratna.Sujeevi. Schistosomula; pp. 184–212. [Google Scholar]
56.Wilson RA. The saga of schistosome migration and attrition. Parasitology [Internet] 2009;136:1581–1592. doi: 10.1017/S0031182009005708. Available from: https://www.cambridge.org/core/journals/parasitology/article/saga-of-schistosome-migration-and-attrition/70AC43F6399DC161E22443E0C2D9C545. [cited 2018 Sep 3] [DOI] [PubMed] [Google Scholar]
57.Gobert GN, Chai M, McManus DP. Biology of the schistosome lung-stage schistosomulum. Parasitology [Internet] 2007;134:453–460. doi: 10.1017/S0031182006001648. Available from: http://journals.cambridge.org/article_S0031182006001648 . [DOI] [PMC free article] [PubMed] [Google Scholar]
58.Wilson MS, Mentink-Kane MM, Pesce JT, Ramalingam TR, Thompson R, Wynn TA. Immunopathology of schistosomiasis. Immunol Cell Biol [Internet] 2007;85:148–154. doi: 10.1038/sj.icb.7100014. Available from: http://www.nature.com/icb/journal/v85/n2/abs/7100014a.html. [cited 2013 Apr 21] [DOI] [PMC free article] [PubMed] [Google Scholar]
59.Pearce EJ. Priming of the immune response by schistosome eggs. Parasite Immunol [Internet] 2005;27:265–270. doi: 10.1111/j.1365-3024.2005.00765.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3024.2005.00765.x/abstract. [cited 2015 May 21] [DOI] [PubMed] [Google Scholar]
60.Grzych JM, Pearce E, Cheever A, Caulada ZA, Caspar P, Heiny S, Lewis F, Sher A. Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis mansoni. J Immunol [Internet] 1991;146:1322–1327. Available from: http://www.jimmunol.org/content/146/4/1322. [cited 2015 May 21] [PubMed] [Google Scholar]
61.Almadi MA, Aljebreen AM, Sanai FM, Marcus V, AlMeghaiseeb ES, Ghosh S. New insights into gastrointestinal and hepatic granulomatous disorders. Nat Rev Gastroenterol Hepatol [Internet] 2011;8:455–466. doi: 10.1038/nrgastro.2011.115. Available from: http://www.nature.com/nrgastro/journal/v8/n8/full/nrgastro.2011.115.html. [cited 2015 Jul 2] [DOI] [PubMed] [Google Scholar]
62.Hirata, Takushima M, Kage M, Fukuma T. Comparative analysis of hepatic, pulmonary, and intestinal granuloma formation around freshly laid Schistosoma japonicum eggs in mice. Parasitol Res. 1993;79 doi: 10.1007/BF00932188. [DOI] [PubMed] [Google Scholar]
63.Warren, Boros DL, Hang LM, Mahmoud AA. The Schistosoma japonicum egg granuloma. Am J Pathol. 1975;80 [PMC free article] [PubMed] [Google Scholar]
64.Peterson WP, Lichtenberg F von. Studies on granuloma formation. IV in vivo antigenicity of schistosome egg antigen in lung tissue. J Immunol [Internet] 1965;95:959–965. Available from: http://www.jimmunol.org/content/95/5/959. [cited 2015 Jun 25] [PubMed] [Google Scholar]
65.von LF, Je B. Pulmonary cell reactions in natural and acquired host resistance to Schistosoma mansoni. Am J Trop Med Hyg [Internet] 1980;29:1286–1300. doi: 10.4269/ajtmh.1980.29.1286. Available from: http://europepmc.org/abstract/med/7446820. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]
66.Silveira-Lemos D, Teixeira-Carvalho A, Martins-Filho OA, Oliveira LFA, Costa-Silva MF, Matoso LF, de Souza LJ, Gazzinelli A, Corrêa-Oliveira R. Eosinophil activation status, cytokines and liver fibrosis in Schistosoma mansoni infected patients. Acta Trop [Internet] 2008;108:150–159. doi: 10.1016/j.actatropica.2008.04.006. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X08000892. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]
67.Wynn TA, Thompson RW, Cheever AW, Mentink-Kane MM. Immunopathogenesis of schistosomiasis. Immunol Rev [Internet] 2004;201:156–167. doi: 10.1111/j.0105-2896.2004.00176.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.0105-2896.2004.00176.x/abstract. [cited 2015 May 21] [DOI] [PubMed] [Google Scholar]
68.Andrade ZA, Santana TS. Angiogenesis and schistosomiasis. Mem Inst Oswaldo Cruz [Internet] 2010;105:436–439. doi: 10.1590/s0074-02762010000400013. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S0074-02762010000400013&lng=en&nrm=iso&tlng=en. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]
69.Warren The pathogenesis of “clay-pipe stem cirrhosis” in mice with chronic schistosomiasis mansoni, with a note on the longevity of the schistosomes. Am J Pathol. 1966;49:477–489. [PMC free article] [PubMed] [Google Scholar]
70.Symmers W. Note on a new form of liver cirrhosis due to the presence of the eggs of Bilharzia haematobia. J Pathol Bacteriol. 1904;9:237–239. [Google Scholar]
71.Grimaud, Borojevic R, Borojevic R, Borojevic R. Chronic human schistosomiasis mansoni. Pathology of the Disse’s space. Lab Invest. 1977;36 [PubMed] [Google Scholar]
72.Grimaud, Borojevic R, Borojevic R, Borojevic R. Portal fibrosis: intrahepatic portal vein pathology in chronic human schistosomiasis mansoni. J Submicrosc Cytol. 1986;18:783–793. [PubMed] [Google Scholar]
73.Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM. Schistosomiasis-associated pulmonary hypertension. Chest. 2010;137:20S–29S. doi: 10.1378/chest.10-0048. [DOI] [PMC free article] [PubMed] [Google Scholar]
74.Cheever, Andrade ZA, Andrade ZA, Andrade ZA. Pathological lesions associated with Schistosoma mansoni infection in man. Trans R Soc Trop Med Hyg. 1967;61:626–639. doi: 10.1016/0035-9203(67)90125-3. [DOI] [PubMed] [Google Scholar]
75.Andrade, Cheever AW, Cheever AW, Cheever AW. Characterization of the murine model of Schistosomal hepatic periportal fibrosis. Int J Exp Pathol. 1993;74:195–202. [PMC free article] [PubMed] [Google Scholar]
76.Lichtenberg F von. Portal Hypertension and schistosomiasis*. Ann N Y Acad Sci [Internet] 1970;170:100–114. Available from: https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.1970.tb37006.x. [cited 2018 Aug 29] [Google Scholar]
77.Nel CJC, Honiball PJ, Wyk V, K FA. Portal hypertension in schistosomiasis. S Afr J Surg [Internet] 1974;12:233–9. Available from: https://www.cabdirect.org/cabdirect/abstract/19752901254. [cited 2018 Aug 29] [PubMed] [Google Scholar]
78.Elbaz T, Esmat G. Hepatic and intestinal schistosomiasis: Review. J Adv Res [Internet] 2013;4:445–452. doi: 10.1016/j.jare.2012.12.001. Available from: http://www.sciencedirect.com/science/article/pii/S2090123212001087. [cited 2018 Aug 29] [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Andrade ZA, Baptista AP, Santana TS. Remodeling of hepatic vascular changes after specific chemotherapy of Schistosomal periportal fibrosis. Mem Inst Oswaldo Cruz [Internet] 2006;101:267–272. doi: 10.1590/s0074-02762006000900041. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S0074-02762006000900041&lng=en&nrm=iso&tlng=en. [cited 2018 Aug 26] [DOI] [PubMed] [Google Scholar]
80.Andrade ZA. Extracellular matrix degradation in parasitic diseases. Braz J Med Biol Res Rev Bras Pesqui Medicas E Biol [Internet] 1994;27:2273–2281. Available from: http://europepmc.org/abstract/med/7787811. [cited 2018 Aug 29] [PubMed] [Google Scholar]
81.Cleva R, Herman P, Pugliese V, Zilberstein B, Saad W-A, Gama-Rodrigues J-J. Fathal pulmonary hypertension after distal splenorenal shunt in Schistosomal portal hypertension. World J Gastroenterol. 2004;10:1836–1837. doi: 10.3748/wjg.v10.i12.1836. [DOI] [PMC free article] [PubMed] [Google Scholar]
82.Andrade ZA, Andrade SG, et al. Pathogenesis of schistosomal pulmonary arteritis. Am J Trop Med Hyg [Internet] 1970;19:305–10. doi: 10.4269/ajtmh.1970.19.305. Available from: http://www.cabdirect.org/abstracts/19702902421.html. [cited 2015 Jul 31] [DOI] [PubMed] [Google Scholar]
83.Bourée, Piveteau J, Gerbal JL, Halpen G. Pulmonary arterial hypertension due to bilharziasis. Apropos of a case due to Schistosoma haematobium having been cured by praziquantel. Bull Soc Pathol Exot. 1990;83:66–71. [PubMed] [Google Scholar]
84.Wünschmann, Ribas E, Ribas E, Ribas E. Chronic cor pulmonale due to granulomatous and obliterating pulmonary arteritis caused by schistosomiasis. Zentralbl Allg Pathol. 1989;135:241–247. [PubMed] [Google Scholar]
85.Ibrahim M, Girgis B. Bilharzial cor pulmonale. A clinico-pathological report of 50 cases. J Trop Med Hyg [Internet] 1960;63:55–8. Available from: https://www.cabdirect.org/cabdirect/abstract/19602901362. [cited 2018 Aug 31] [PubMed] [Google Scholar]
86.Gelfand M. Cor-pulmonale and cardio-pulmonary schistosomiasis. Trans R Soc Trop Med Hyg [Internet] 1957;51:533–540. doi: 10.1016/0035-9203(57)90043-3. Available from: https://www.surgpath.theclinics.com/article/0035-9203(57)90043-3/abstract. [cited 2018 Aug 31] [DOI] [PubMed] [Google Scholar]
87.Almeida, Andrade ZA, Andrade ZA, Andrade ZA. Effect of chemotherapy on experimental pulmonary schistosomiasis. Am J Trop Med Hyg. 1983;32:1049–1054. doi: 10.4269/ajtmh.1983.32.1049. [DOI] [PubMed] [Google Scholar]
88.Sadigursky, Andrade ZA, Andrade ZA, Andrade ZA. Pulmonary changes in Schistosomal cor pulmonale. Am J Trop Med Hyg. 1982;31:779–784. doi: 10.4269/ajtmh.1982.31.779. [DOI] [PubMed] [Google Scholar]
89.Vidal MR, Barbosa Jr AA, Andrade ZA. Experimental pulmonary schistosomiasis: lack of morphological evidence of modulation in Schistosomal pulmonary granulomas. Rev Inst Med Trop São Paulo [Internet] 1993;35:423–429. doi: 10.1590/s0036-46651993000500007. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S0036-46651993000500007&lng=en&nrm=iso&tlng=pt. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]
90.Kolosionek E, King J, Rollinson D, Schermuly RT, Grimminger F, Graham BB, Morrell N, Butrous G. Schistosomiasis causes remodeling of pulmonary vessels in the lung in a heterogeneous localized manner: Detailed study. Pulm Circ [Internet] 2013;3:356–362. doi: 10.4103/2045-8932.114764. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757830/ [cited 2013 Dec 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
91.Warren Experimental pulmonary schistosomiasis. Trans R Soc Trop Med Hyg. 1964;58:228–33. doi: 10.1016/0035-9203(64)90034-3. [DOI] [PubMed] [Google Scholar]
92.Crosby A, Jones FM, Southwood M, Stewart S, Schermuly R, Butrous G, Dunne DW, Morrell NW. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am J Respir Crit Care Med [Internet] 2009;181:279–288. doi: 10.1164/rccm.200903-0355OC. Available from: http://cat.inist.fr/?aModele=afficheN&cpsidt=22362871. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]
93.Mauad T, Pozzan G, Lanças T, Overbeek MJ, Souza R, Jardim C, Dolhnikoff M, Mello G, Pires-Neto RC, Bernardi F del C, Grünberg K. Immunopathological aspects of schistosomiasis-associated pulmonary arterial hypertension. J Infect [Internet] 2014;68:90–98. doi: 10.1016/j.jinf.2013.08.004. Available from: http://www.sciencedirect.com/science/article/pii/S0163445313002363. [cited 2013 Dec 16] [DOI] [PubMed] [Google Scholar]
94.Lapa M, Dias B, Jardim C, Fernandes CJC, Dourado PMM, Figueiredo M, Farias A, Tsutsui J, Terra-Filho M, Humbert M, Souza R. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation [Internet] 2009;119:1518–1523. doi: 10.1161/CIRCULATIONAHA.108.803221. Available from: http://circ.ahajournals.org/content/119/11/1518. [cited 2012 Jun 14] [DOI] [PubMed] [Google Scholar]
95.Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation [Internet] 2004;109:159–165. doi: 10.1161/01.CIR.0000102381.57477.50. Available from: http://circ.ahajournals.org/content/109/2/159. [cited 2014 May 12] [DOI] [PubMed] [Google Scholar]
96.Rieder F, Kessler SP, West GA, Bhilocha S, De LM, Sadler TM, Gopalan B, Stylianou E, Fiocchi C. Inflammation-induced endothelial-to-mesenchymal transition: A novel mechanism of intestinal fibrosis. Am J Pathol. 2011;179:2660–2673. doi: 10.1016/j.ajpath.2011.07.042. [DOI] [PMC free article] [PubMed] [Google Scholar]
97.Good RB, Gilbane AJ, Trinder SL, Denton CP, Coghlan G, Abraham DJ, Holmes AM. Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. Am J Pathol [Internet] 2015;185:1850–1858. doi: 10.1016/j.ajpath.2015.03.019. Available from: http://www.sciencedirect.com/science/article/pii/S0002944015002102 . [DOI] [PubMed] [Google Scholar]
98.Graham B, Bandeira A, Butrous G, Chabon J, Espinheira L, Tuder R. Significant intrapulmonary Schistosoma egg antigens are not present in schistosomiasis-associated pulmonary hypertension. Pulm Circ [Internet] 2011;1:456. doi: 10.4103/2045-8932.93544. Available from: https://www.pulmonarycirculation.org/text.asp?2011/1/4/456/93544. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]
99.Cavalcanti, Tompson G, Tompson G, Barbosa FS. Pulmonary hypertension in schistosomiasis. Br Heart J. 1962;24:363–371. doi: 10.1136/hrt.24.3.363. [DOI] [PMC free article] [PubMed] [Google Scholar]
100.Shaw A, Ghareeb AA, Ghareeb AA, Ghareeb AA. The pathogenesis of pulmonary schistosomiasis in Egypt with special reference to Ayerza’s disease. J Pathol Bacteriol. 1938;46:401–424. [Google Scholar]
101.Jaffe The anatomical pathology and pathogenesis of Bilharziasis mansoni in Venezuela. Trop Bull. 1949;49:269. [Google Scholar]
102.Magalhaes Filho Pulmonary lesions in mice experimentally infected with Schistosoma mansoni. Am J Trop Med Hyg. 1959;8:527–35. doi: 10.4269/ajtmh.1959.8.527. [DOI] [PubMed] [Google Scholar]
103.Doss H. Pulmonary circulation and respiratory function: a symposium held at Queen’s College 1956.
104.Lambertucci JR, Serufo JC, Gerspacher-Lara R, Rayes AA, Teixeira R, Nobre V, Antunes CM. Schistosoma mansoni: assessment of morbidity before and after control. Acta Trop [Internet] 2000;77:101–109. doi: 10.1016/s0001-706x(00)00124-8. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X00001248. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]
105.de Cleva R, Herman P, Pugliese V, Zilberstein B, Saad WA, Gama-Rodrigues JJ. Fatal pulmonary hypertension after distal splenorenal shunt in Schistosomal portal hypertension. World J Gastroenterol WJG [Internet] 2004;10:1836–1837. doi: 10.3748/wjg.v10.i12.1836. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572282/ [cited 2018 Aug 26] [DOI] [PMC free article] [PubMed] [Google Scholar]
106.de Cleva R, Herman P, Pugliese V, Zilberstein B, Saad WA, Rodrigues JJ, Laudanna AA. Prevalence of pulmonary hypertension in patients with hepatosplenic Mansonic schistosomiasis –prospective study. Hepatogastroenterology [Internet] 2002;50:2028–2030. Available from: http://europepmc.org/abstract/med/14696458 . [PubMed] [Google Scholar]
107.Donovan CL, Marcovitz PA, Punch JD, Bach DS, Brown KA, Lucey MR, Armstrong WF. Two-dimensional and dobutamine stress echocardiography in the preoperative assessment of patients with end-stage liver disease prior to orthotopic liver transplantation. Transplantation [Internet] 1996;61:1180–1188. doi: 10.1097/00007890-199604270-00011. Available from: http://journals.lww.com/transplantjournal/Abstract/1996/04270/TWO_DIMENSIONAL_AND_DOBUTAMINE_STRESS.11.aspx . [DOI] [PubMed] [Google Scholar]
108.Ali Z, Kosanovic D, Kolosionek E, Schermuly RT, Graham BB, Mathie A, Butrous G. Enhanced inflammatory cell profiles in schistosomiasis-induced pulmonary vascular remodeling. Pulm Circ. 2017;7:244–252. doi: 10.1086/690687. Available from: [DOI] [PMC free article] [PubMed] [Google Scholar]
109.Butrous G. Pulmonary vascular diseases secondary to schistosomiasis. Adv Pulm Hypertens [Internet] 2017;15:144–148. Available from: http://advancesinph.org/doi/abs/10.21693/1933-088X-15.3.144 . [Google Scholar]
110.Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM. Schistosomiasis-associated pulmonary hypertension: Pulmonary vascular disease: the global perspective. CHEST J [Internet] 2010;137:20S–29S. doi: 10.1378/chest.10-0048. Available from: [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]
111.Graham BB, Mentink-Kane MM, El-Haddad H, Purnell S, Zhang L, Zaiman A, Redente EF, Riches DWH, Hassoun PM, Bandeira A, Champion HC, Butrous G, Wynn TA, Tuder RM. Schistosomiasis-induced experimental pulmonary hypertension: Role of interleukin-13 signaling. Am J Pathol [Internet] 2010;177:1549–1561. doi: 10.2353/ajpath.2010.100063. Available from: http://www.sciencedirect.com/science/article/pii/S0002944010602052. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]
112.Kolosionek E, Graham BB, Tuder RM, Butrous G. Pulmonary vascular disease associated with parasitic infection—the role of schistosomiasis. Clin Microbiol Infect [Internet] 2011;17:15–24. doi: 10.1111/j.1469-0691.2010.03308.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2010.03308.x/abstract. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]
113.Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J [Internet] 2003;22:358–363. doi: 10.1183/09031936.03.00038903. Available from: http://erj.ersjournals.com/content/22/2/358. [cited 2015 Jun 24] [DOI] [PubMed] [Google Scholar]
114.Hassoun PM, Mouthon L, Barberà JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitl ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX-J, Humbert M. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol [Internet] 2009;54:S10–S19. doi: 10.1016/j.jacc.2009.04.006. Available from: [DOI] [PubMed] [Google Scholar]
115.Kherbeck N, Tamby MC, Bussone G, Dib H, Perros F, Humbert M, Mouthon L. The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension. Clin Rev Allergy Immunol [Internet] 2013;44:31–38. doi: 10.1007/s12016-011-8265-z. Available from: http://link.springer.com/article/10.1007/s12016-011-8265-z. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]
116.Meyrick B, Perkett EA, Brigham KL. Inflammation and models of chronic pulmonary hypertension. Am Rev Respir Dis [Internet] 1987;136:765–767. doi: 10.1164/ajrccm/136.3.765. Available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccm/136.3.765. [cited 2014 Apr 19] [DOI] [PubMed] [Google Scholar]
117.Phillips SM, DiConza JJ, Gold JA, Reid WA. Schistosomiasis in the congenitally athymic (nude) mouse. J Immunol [Internet] 1977;118:594–599. Available from: http://www.jimmunol.org/content/118/2/594. [cited 2017 May 27] [PubMed] [Google Scholar]
118.Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, Walker C, Budd DC, Pepke-Zaba J, Morrell NW. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation [Internet] 2010;122:920–927. doi: 10.1161/CIRCULATIONAHA.109.933762. Available from: http://circ.ahajournals.org/content/122/9/920. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]
119.Schlosser K, Taha M, Deng Y, Jiang B, McIntyre LA, Mei SH, Stewart DJ. Lack of elevation in plasma levels of pro-inflammatory cytokines in common rodent models of pulmonary arterial hypertension: questions of construct validity for human patients. Pulm Circ [Internet] 2017 doi: 10.1177/2045893217705878. 2045893217705878. Available from: [DOI] [PMC free article] [PubMed] [Google Scholar]
120.Saunders BM, Britton WJ. Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol [Internet] 2007;85:103–111. doi: 10.1038/sj.icb.7100027. Available from: http://www.nature.com/icb/journal/v85/n2/full/7100027a.html. [cited 2015 Jul 2] [DOI] [PubMed] [Google Scholar]
121.Chuah C, Jones MK, Burke ML, McManus DP, Gobert GN. Cellular and chemokine-mediated regulation in schistosome-induced hepatic pathology. Trends Parasitol [Internet] 2014;30:141–150. doi: 10.1016/j.pt.2013.12.009. Available from: http://www.sciencedirect.com/science/article/pii/S1471492213002158. [cited 2015 Jul 1] [DOI] [PubMed] [Google Scholar]
122.Hurst MH, Willingham AL, Lindberg R. Tissue responses in experimental schistosomiasis japonica in the pig: a histopathologic study of different stages of single low- or high-dose infections. Am J Trop Med Hyg [Internet] 2000;62:45–56. doi: 10.4269/ajtmh.2000.62.45. Available from: http://www.ajtmh.org/content/62/1/45. [cited 2015 Jul 1] [DOI] [PubMed] [Google Scholar]
123.Hurst MH, Willingham AL, Lindberg R. Experimental schistosomiasis japonica in the pig: immunohistology of the hepatic egg granuloma. Parasite Immunol [Internet] 2002;24:151–159. doi: 10.1046/j.1365-3024.2002.00448.x. Available from: http://onlinelibrary.wiley.com/doi/10.1046/j.1365-3024.2002.00448.x/abstract. [cited 2015 Jul 1] [DOI] [PubMed] [Google Scholar]
124.Burke ML, Jones MK, Gobert GN, Li YS, Ellis MK, McManus DP. Immunopathogenesis of human schistosomiasis. Parasite Immunol [Internet] 2009;31:163–176. doi: 10.1111/j.1365-3024.2009.01098.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3024.2009.01098.x/abstract. [cited 2013 Apr 21] [DOI] [PubMed] [Google Scholar]
125.Lenzi HL, Romanha W de S, Santos RZ dos, Rosas A, Mota EM, Manso PPA, Caputo LFG, Pelajo-Machado M. Four whole-istic aspects of schistosome granuloma biology: fractal arrangement, internal regulation, autopoietic component and closure. Mem Inst Oswaldo Cruz [Internet] 2006;101:219–231. doi: 10.1590/s0074-02762006000900034. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S0074-02762006000900034&lng=en&nrm=iso&tlng=en. [cited 2015 Jul 2] [DOI] [PubMed] [Google Scholar]
126.Secor WE. Immunology of human schistosomiasis: off the beaten path. Parasite Immunol [Internet] 2005;27:309–316. doi: 10.1111/j.1365-3024.2005.00778.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3024.2005.00778.x/abstract. [cited 2015 Jul 30] [DOI] [PubMed] [Google Scholar]
127.Boros D. The role of cytokines in the formation of the schistosome egg granuloma. Immunobiology. 1994;191:441–450. doi: 10.1016/S0171-2985(11)80450-X. [DOI] [PubMed] [Google Scholar]
128.Chiu B-C, Freeman CM, Stolberg VR, Komuniecki E, Lincoln PM, Kunkel SL, Chensue SW. Cytokine–chemokine networks in experimental mycobacterial and Schistosomal pulmonary granuloma formation. Am J Respir Cell Mol Biol [Internet] 2003;29:106–116. doi: 10.1165/rcmb.2002-0241OC. Available from: http://www.atsjournals.org/doi/abs/10.1165/rcmb.2002-0241OC. [cited 2015 Jul 30] [DOI] [PMC free article] [PubMed] [Google Scholar]
129.Kaplan MH, Whitfield JR, Boros DL, Grusby MJ. Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. J Immunol [Internet] 1998;160:1850–1856. Available from: http://www.jimmunol.org/content/160/4/1850. [cited 2015 Jun 25] [PubMed] [Google Scholar]
130.Reiman R, Thompson R, Feng C, Hari D, Knight R, Cheever A, Rosenberg H, Wynn T. Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity. Infect Immun. 2006;74 doi: 10.1128/IAI.74.3.1471-1479.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
131.Fallon PG, Smith P, Dunne DW. Type 1 and type 2 cytokine-producing mouse CD4+ and CD8+ T cells in acute Schistosoma mansoni infection. Eur J Immunol [Internet] 1998;28:1408–1416. doi: 10.1002/(SICI)1521-4141(199804)28:04<1408::AID-IMMU1408>3.0.CO;2-H. Available from: http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1521-4141(199804)28:04<1408::AID-IMMU1408>3.0.CO;2-H/abstract. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]
132.Pearce EJ, MacDonald AS. The immunobiology of schistosomiasis. Nat Rev Immunol [Internet] 2002;2:499–511. doi: 10.1038/nri843. Available from: http://www.nature.com/nri/journal/v2/n7/full/nri843.html. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]
133.Stavitsky AB. Regulation of granulomatous inflammation in experimental models of schistosomiasis. Infect Immun [Internet] 2004;72:1–12. doi: 10.1128/IAI.72.1.1-12.2004. Available from: http://iai.asm.org/content/72/1/1. [cited 2017 May 28] [DOI] [PMC free article] [PubMed] [Google Scholar]
134.Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation. 2008;118:1758–1766. doi: 10.1161/CIRCULATIONAHA.107.727289. [DOI] [PubMed] [Google Scholar]
135.Boros, Pelley RP, Warren KS, Warren KS. Spontaneous modulation of granulomatous hypersensitivity in schistosomiasis mansoni. J Immunol. 1975;114 [PubMed] [Google Scholar]
136.Wen X, He L, Chi Y, Zhou S, Hoellwarth J, Zhang C, Zhu J, Wu C, Dhesi S, Wang X, Liu F, Su C. Dynamics of Th17 cells and their role in Schistosoma japonicum infection in C57BL/6 mice. PLoS Negl Trop Dis [Internet] 2011;5:e1399. doi: 10.1371/journal.pntd.0001399. Available from: [cited 2015 Jul 30] [DOI] [PMC free article] [PubMed] [Google Scholar]
137.Shainheit MG, Lasocki KW, Finger E, Larkin BM, Smith PM, Sharpe AH, Dinarello CA, Rutitzky LI, Stadecker MJ. The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1β. J Immunol [Internet] 2011;187:5328–5335. doi: 10.4049/jimmunol.1101445. Available from: http://www.jimmunol.org/content/187/10/5328. [cited 2015 Jul 30] [DOI] [PMC free article] [PubMed] [Google Scholar]
138.Rutitzky L, Lopes da Rosa J, Stadecker M, Stadecker M. Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17. J Immunol. 2005;175 doi: 10.4049/jimmunol.175.6.3920. [DOI] [PubMed] [Google Scholar]
139.Ji F, Liu Z, Cao J, Li N, Liu Z, Zuo J, Chen Y, Wang X, Sun J. B cell response is required for granuloma formation in the early infection of Schistosoma japonicum. PLoS ONE [Internet] 2008;3:e1724. doi: 10.1371/journal.pone.0001724. Available from: http://dx.plos.org/10.1371/journal.pone.0001724. [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]
140.Fairfax KC, Amiel E, King IL, Freitas TC, Mohrs M, Pearce EJ. IL-10R blockade during chronic schistosomiasis mansoni results in the loss of B cells from the liver and the development of severe pulmonary disease. PLoS Pathog [Internet] 2012;8:e1002490. doi: 10.1371/journal.ppat.1002490. Available from: [cited 2012 Jun 14] [DOI] [PMC free article] [PubMed] [Google Scholar]
141.Colley, Garcia AA, Lambertucci JR, Parra JC, Katz N, Rocha RS, Gazzinelli G. Immune responses during human schistosomiasis. XII. Differential responsiveness in patients with hepatosplenic disease. Am J Trop Med Hyg. 1986;35:793–802. [PubMed] [Google Scholar]
142.Tweardy, Osman GS, El Kholy A, Ellner JJ. Abnormalities of immunosuppression in patients with hepatosplenic schistosomiasis mansoni. Trans Assoc Am Physicians. 1983;96:392–400. [PubMed] [Google Scholar]
143.Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science [Internet] 2003;299:1057–1061. Available from: http://www.sciencemag.org/content/299/5609/1057. [cited 2015 Jul 31] [PubMed] [Google Scholar]
144.Rumbley CA, Sugaya H, Zekavat SA, Perrin PJ, Phillips SM. Elimination of lymphocytes, but not eosinophils, by Fas-mediated apoptosis in murine schistosomiasis. Am J Trop Med Hyg. 2001;65:442–449. doi: 10.4269/ajtmh.2001.65.442. [DOI] [PubMed] [Google Scholar]
145.Carneiro-Santos P, Martins-Filho O, Alves-Oliveira LF, Silveira AM, Coura-Filho P, Viana IR, Wilson RA, Correa-Oliveira R. Apoptosis: a mechanism of immunoregulation during human schistosomiasis mansoni. Parasite Immunol. 2000;22:267–277. doi: 10.1046/j.1365-3024.2000.00294.x. [DOI] [PubMed] [Google Scholar]
146.Lundy SK, Lerman SP, Boros DL. Soluble egg antigen-stimulated T helper lymphocyte apoptosis and evidence for cell death mediated by FasL(+) T and B cells during murine Schistosoma mansoni infection. Infect Immun. 2001;69:271–280. doi: 10.1128/IAI.69.1.271-280.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
147.Lundy SK, Lukacs NW. Chronic schistosome infection leads to modulation of granuloma formation and systemic immune suppression. Front Immunol [Internet] 2013;4 doi: 10.3389/fimmu.2013.00039. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576626/ [cited 2015 May 3] [DOI] [PMC free article] [PubMed] [Google Scholar]
148.Wajant H. The Fas signaling pathway: More than a paradigm. Science [Internet] 2002;296:1635–1636. doi: 10.1126/science.1071553. Available from: http://science.sciencemag.org/content/296/5573/1635. [cited 2017 Jun 10] [DOI] [PubMed] [Google Scholar]
149.Siegel RM, Chan FK-M, Chun HJ, Lenardo MJ. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat Immunol [Internet] 2000;1:469–474. doi: 10.1038/82712. Available from: https://www.nature.com/articles/ni1200_469. [cited 2018 Aug 24] [DOI] [PubMed] [Google Scholar]
150.Krammer PH. CD95’s deadly mission in the immune system [Internet] Nature. 2000 doi: 10.1038/35037728. Available from: https://www.nature.com/articles/35037728. [cited 2018 Aug 24] [DOI] [PubMed] [Google Scholar]
151.Salama M, El-Kholy G, El-Haleem SA, Elzamarany E, Freikha MA, Elwan N, El-Masry M, Al-Bacil A, Elhendy A. Serum soluble Fas in patients with Schistosomal cor pulmonale. Respiration [Internet] 2003;70:574–578. doi: 10.1159/000075201. Available from: http://www.karger.com/Article/Abstract/75201. [cited 2017 May 29] [DOI] [PubMed] [Google Scholar]
152.Kayagaki N, Kawasaki A, Ebata T, Ohmoto H, Ikeda S, Inoue S, Yoshino K, Okumura K, Yagita H. Metalloproteinase-mediated release of human Fas ligand. J Exp Med [Internet] 1995;182:1777–1783. doi: 10.1084/jem.182.6.1777. Available from: http://jem.rupress.org/content/182/6/1777. [cited 2018 Aug 25] [DOI] [PMC free article] [PubMed] [Google Scholar]
153.Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med [Internet] 1995;151:1628–1631. doi: 10.1164/ajrccm.151.5.7735624. Available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccm.151.5.7735624 . [DOI] [PubMed] [Google Scholar]
154.Hajjar DP, Gotto Jr AM. Biological relevance of inflammation and oxidative stress in the pathogenesis of arterial diseases. Am J Pathol [Internet] 2013;182:1474–1481. doi: 10.1016/j.ajpath.2013.01.010. Available from: http://www.sciencedirect.com/science/article/pii/S0002944013000941 . [DOI] [PMC free article] [PubMed] [Google Scholar]
155.Dinarello CA. Biology of interleukin- 1. FEBS Lett. 1988 [PubMed] [Google Scholar]
156.Voelkel NF, Tuder RM, Bridges J, Arend WP. Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am J Respir Cell Mol Biol [Internet] 1994;11:664–675. doi: 10.1165/ajrcmb.11.6.7946395. Available from: http://www.atsjournals.org/doi/abs/10.1165/ajrcmb.11.6.7946395 . [DOI] [PubMed] [Google Scholar]
157.Xu X-Q, Jing Z-C. High-altitude pulmonary hypertension. Eur Respir Rev [Internet] 2009;18:13–17. doi: 10.1183/09059180.00011104. Available from: http://err.ersjournals.com/content/18/111/13. [cited 2012 Jun 15] [DOI] [PubMed] [Google Scholar]
158.Friedlander RM, Gagliardini V, Rotello RJ, Yuan J. Functional role of interleukin 1β (IL-1β) in IL-1β-converting enzyme-mediated apoptosis. J Exp Med. 1996;184:717–724. doi: 10.1084/jem.184.2.717. [DOI] [PMC free article] [PubMed] [Google Scholar]
159.Cracowski J-L, Chabot F, Labarère J, Faure P, Degano B, Schwebel C, Chaouat A, Reynaud-Gaubert M, Cracowski C, Sitbon O, Yaici A, Simonneau G, Humbert M. Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension. Eur Respir J [Internet] 2014;43:915–917. doi: 10.1183/09031936.00151313. Available from: http://erj.ersjournals.com/content/43/3/915. [cited 2017 May 28] [DOI] [PubMed] [Google Scholar]
160.Verghese MW, McConnell RT, Strickl AB, Gooding RC, Stimpson SA, Yarnall DP, Taylor JD, Furdon PJ. Differential regulation of human monocyte-derived TNF alpha and IL-1β by type IV cAMP-phosphodiesterase (cAMP-PDE) inhibitors. J Pharmacol Exp Ther [Internet] 1995;272:1313–1320. Available from: http://jpet.aspetjournals.org/content/272/3/1313. [cited 2017 May 28] [PubMed] [Google Scholar]
161.Kaliński P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol [Internet] 1997;159:28–35. Available from: http://www.jimmunol.org/content/159/1/28. [cited 2018 Aug 5] [PubMed] [Google Scholar]
162.Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science [Internet] 1993;260:547–549. doi: 10.1126/science.8097338. Available from: http://science.sciencemag.org/content/260/5107/547. [cited 2018 Aug 5] [DOI] [PubMed] [Google Scholar]
163.Wynn TA, Eltoum I, Oswald IP, Cheever AW, Sher A. Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med [Internet] 1994;179:1551–1561. doi: 10.1084/jem.179.5.1551. Available from: http://jem.rupress.org/content/179/5/1551. [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]
164.Oswald IP, Caspar P, Jankovic D, Wynn TA, Pearce EJ, Sher A. IL-12 inhibits Th2 cytokine responses induced by eggs of Schistosoma mansoni. J Immunol [Internet] 1994;153:1707–1713. Available from: http://www.jimmunol.org/content/153/4/1707. [cited 2018 Aug 5] [PubMed] [Google Scholar]
165.Wynn TA, Cheever AW, Jankovic D, Poindexter RW, Caspar P, Lewis FA, Sher A. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature [Internet] 1995;376:594–596. doi: 10.1038/376594a0. Available from: http://www.nature.com/nature/journal/v376/n6541/abs/376594a0.html. [cited 2013 Apr 21] [DOI] [PubMed] [Google Scholar]
166.Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O’Shea JJ. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev [Internet] 2004;202:139–156. doi: 10.1111/j.0105-2896.2004.00211.x. Available from: http://doi.wiley.com/10.1111/j.0105-2896.2004.00211.x. [cited 2018 Aug 5] [DOI] [PubMed] [Google Scholar]
167.Cytokine responses to Schistosoma haematobium in a Zimbabwean population: contrasting profiles for IFN-γ, IL-4, IL-5 and IL-10 with age. — BMC Infectious Diseases — Full Text [Internet] doi: 10.1186/1471-2334-7-139. Available from: https://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-7-139. [cited 2018 Sep 3] [DOI] [PMC free article] [PubMed] [Google Scholar]
168.El-Kady IM, Lotfy M, Badra G, El-Masry S, Waked I. Interleukin (IL)-4, IL-10, IL-18 and IFN-gamma cytokines pattern in patients with combined hepatitis C virus and Schistosoma mansoni infections. Scand J Immunol. 2005;61:87–91. doi: 10.1111/j.0300-9475.2005.01529.x. [DOI] [PubMed] [Google Scholar]
169.Andert SE, Griesmacher A, Zuckermann A, Müller MM. Neopterin release from human endothelial cells is triggered by interferon-gamma. Clin Exp Immunol [Internet] 1992;88:555–558. doi: 10.1111/j.1365-2249.1992.tb06486.x. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2249.1992.tb06486.x. [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]
170.Schoedon G, Troppmair J, Adolf G, Huber C, Niederwieser A. Interferon-γ enhances biosynthesis of pterins in peripheral blood mononuclear cells by induction of GTP-cyclohydrolase I activity. J Interferon Res [Internet] 1986;6:697–703. doi: 10.1089/jir.1986.6.697. Available from: https://www.liebertpub.com/doi/abs/10.1089/jir.1986.6.697. [cited 2018 Aug 5] [DOI] [PubMed] [Google Scholar]
171.Gordon S. Alternative activation of macrophages. Nat Rev Immunol [Internet] 2003;3:23–35. doi: 10.1038/nri978. Available from: https://www.nature.com/articles/nri978. [cited 2018 Aug 5] [DOI] [PubMed] [Google Scholar]
172.Gallegos AM, Heijst JWJ van, Samstein M, Su X, Pamer EG, Glickman MS. A gamma interferon independent mechanism of CD4 T cell mediated control of M. tuberculosis Infection in vivo. PLOS Pathog [Internet] 2011;7:e1002052. doi: 10.1371/journal.ppat.1002052. Available from: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1002052. [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]
173.Lombardi A, Cantini G, Piscitelli E, Gelmini S, Francalanci M, Mello T, Ceni E, Varano G, Forti G, Rotondi M, Galli A, Serio M, Luconi M. A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-alpha and interferon-gamma inflammatory effects in human endothelial cells. Arterioscler Thromb Vasc Biol. 2008;28:718–724. doi: 10.1161/ATVBAHA.107.160713. [DOI] [PubMed] [Google Scholar]
174.Wort SJ, Woods M, Warner TD, Evans TW, Mitchell JA. Cyclooxygenase-2 acts as an endogenous brake on endothelin-1 release by human pulmonary artery smooth muscle cells: Implications for pulmonary hypertension. Mol Pharmacol [Internet] 2002;62:1147–1153. doi: 10.1124/mol.62.5.1147. Available from: http://molpharm.aspetjournals.org/content/62/5/1147. [cited 2018 Sep 3] [DOI] [PubMed] [Google Scholar]
175.George PM, Oliver E, Dorfmuller P, Dubois OD, Reed DM, Kirkby NS, Mohamed NA, Perros F, Antigny F, Fadel E, Schreiber BE, Holmes AM, Southwood M, Hagan G, Wort SJ, Bartlett N, Morrell NW, Coghlan JG, Humbert M, Zhao L, Mitchell JA. Evidence for the involvement of type I interferon in pulmonary arterial hypertension. Circ Res [Internet] 2014;114:677–688. doi: 10.1161/CIRCRESAHA.114.302221. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006084/ [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]
176.Fujita M, Shannon JM, Irvin CG, Fagan KA, Cool C, Augustin A, Mason RJ. Overexpression of tumor necrosis factor-α produces an increase in lung volumes and pulmonary hypertension. Am J Physiol - Lung Cell Mol Physiol [Internet] 2001;280:L39–L49. doi: 10.1152/ajplung.2001.280.1.L39. Available from: http://ajplung.physiology.org/content/280/1/L39. [cited 2017 May 28] [DOI] [PubMed] [Google Scholar]
177.Hurst LA, Dunmore BJ, Long L, Crosby A, Al-Lamki R, Deighton J, Southwood M, Yang X, Nikolic MZ, Herrera B, Inman GJ, Bradley JR, Rana AA, Upton PD, Morrell NW. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nat Commun [Internet] 2017;8:14079. doi: 10.1038/ncomms14079. Available from: https://www.nature.com/ncomms/2017/170113/ncomms14079/full/ncomms14079.html. [cited 2017 May 28] [DOI] [PMC free article] [PubMed] [Google Scholar]
178.Sutendra G, Dromparis P, Bonnet S, Haromy A, McMurtry MS, Bleackley RC, Michelakis ED. Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension. J Mol Med [Internet] 2011;89:771. doi: 10.1007/s00109-011-0762-2. Available from: http://link.springer.com/article/10.1007/s00109-011-0762-2 . [DOI] [PubMed] [Google Scholar]
179.Jiang H, Harris MB, Rothman P. IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol [Internet] 2000;105:1063–1070. doi: 10.1067/mai.2000.107604. Available from: http://www.jacionline.org/article/S0091-6749(00)70038-8/fulltext. [cited 2017 May 29] [DOI] [PubMed] [Google Scholar]
180.Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nat Med [Internet] 2006;12:99–106. doi: 10.1038/nm1332. Available from: http://www.nature.com/nm/journal/v12/n1/full/nm1332.html. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]
181.Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol. 1999;17:701–738. doi: 10.1146/annurev.immunol.17.1.701. [DOI] [PubMed] [Google Scholar]
182.Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol [Internet] 2008;9:310–318. doi: 10.1038/ni1558. Available from: http://www.nature.com/ni/journal/v9/n3/full/ni1558.html. [cited 2015 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]
183.Mowen KA, Glimcher LH. Signaling pathways in Th2 development. Immunol Rev [Internet] 2004;202:203–222. doi: 10.1111/j.0105-2896.2004.00209.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.0105-2896.2004.00209.x/abstract. [cited 2015 Aug 5] [DOI] [PubMed] [Google Scholar]
184.Oh K, Shen T, Le Gros G, Min B. Induction of Th2 type immunity in a mouse system reveals a novel immunoregulatory role of basophils. Blood. 2007;109:2921–2927. doi: 10.1182/blood-2006-07-037739. [DOI] [PubMed] [Google Scholar]
185.Vazquez MI, Catalan-Dibene J, Zlotnik A. B cells responses and cytokine production are regulated by their immune microenvironment. Cytokine [Internet] 2015;74:318–326. doi: 10.1016/j.cyto.2015.02.007. Available from: http://www.sciencedirect.com/science/article/pii/S1043466615000666. [cited 2015 Aug 6] [DOI] [PMC free article] [PubMed] [Google Scholar]
186.Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD. Interleukin-4 and interleukin-13 signaling connections maps. Science. 2003;300:1527–1528. doi: 10.1126/science.1085458. [DOI] [PubMed] [Google Scholar]
187.Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S. Essential role of Stat6 in IL-4 signalling. Nature [Internet] 1996;380:627–630. doi: 10.1038/380627a0. Available from: http://www.nature.com/nature/journal/v380/n6575/abs/380627a0.html. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]
188.Paul WE. Interleukin 4: signalling mechanisms and control of T cell differentiation. Ciba Found Symp. 1997;204:208–216. doi: 10.1002/9780470515280.ch14. discussion 216-219. [DOI] [PubMed] [Google Scholar]
189.Wedemeyer J, Tsai M, Galli SJ. Roles of mast cells and basophils in innate and acquired immunity. Curr Opin Immunol [Internet] 2000;12:624–631. doi: 10.1016/s0952-7915(00)00154-0. Available from: http://www.sciencedirect.com/science/article/pii/S0952791500001540. [cited 2015 Aug 5] [DOI] [PubMed] [Google Scholar]
190.Luzina IG, Keegan AD, Heller NM, Rook GAW, Shea-Donohue T, Atamas SP. Regulation of inflammation by interleukin-4: a review of “alternatives”. J Leukoc Biol [Internet] 2012;92:753–764. doi: 10.1189/jlb.0412214. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441310/ [DOI] [PMC free article] [PubMed] [Google Scholar]
191.Cheever AW, Williams ME, Wynn TA, Finkelman FD, Seder RA, Cox TM, Hieny S, Caspar P, Sher A. Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis. J Immunol Baltim Md 1950. 1994;153:753–759. [PubMed] [Google Scholar]
192.Vannella KM, Barron L, Borthwick LA, Kindrachuk KN, Narasimhan PB, Hart KM, Thompson RW, White S, Cheever AW, Ramalingam TR, Wynn TA. Incomplete Deletion of IL-4Rα by LysMCre reveals distinct subsets of M2 macrophages controlling inflammation and fibrosis in chronic schistosomiasis. PLoS Pathog [Internet] 2014;10:e1004372. doi: 10.1371/journal.ppat.1004372. Available from: [cited 2015 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]
193.Daley E, Emson C, Guignabert C, Malefyt R de W, Louten J, Kurup VP, Hogaboam C, Taraseviciene-Stewart L, Voelkel NF, Rabinovitch M, Grunig E, Grunig G. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med [Internet] 2008;205:361–372. doi: 10.1084/jem.20071008. Available from: http://jem.rupress.org/content/205/2/361. [cited 2015 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]
194.Taraseviciene-Stewart L, Nicolls MR, Kraskauskas D, Scerbavicius R, Burns N, Cool C, Wood K, Parr JE, Boackle SA, Voelkel NF. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med [Internet] 2007;175:1280–1289. doi: 10.1164/rccm.200608-1189OC. Available from: http://www.atsjournals.org/doi/abs/10.1164/rccm.200608-1189OC. [cited 2015 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]
195.Yamaji-Kegan K, Su Q, Angelini DJ, Myers AC, Cheadle C, Johns RA. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) increases lung inflammation and activates pulmonary microvascular endothelial cells via an IL-4–dependent mechanism. J Immunol [Internet] 2010;185:5539–5548. doi: 10.4049/jimmunol.0904021. Available from: http://www.jimmunol.org/content/185/9/5539. [cited 2013 Apr 21] [DOI] [PubMed] [Google Scholar]
196.Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, McKenzie ANJ. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol. 2012;129:191–198.e1–4. doi: 10.1016/j.jaci.2011.09.041. [DOI] [PubMed] [Google Scholar]
197.Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TKA, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie ANJ. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature [Internet] 2010;464:1367–1370. doi: 10.1038/nature08900. Available from: http://www.nature.com/nature/journal/v464/n7293/full/nature08900.html#ref5. [cited 2015 Aug 6] [DOI] [PMC free article] [PubMed] [Google Scholar]
198.Wynn T. Cellular and molecular mechanisms of fibrosis. J Pathol [Internet] 2008;214:199–210. doi: 10.1002/path.2277. Available from: http://onlinelibrary.wiley.com/doi/10.1002/path.2277/abstract. [cited 2015 Aug 7] [DOI] [PMC free article] [PubMed] [Google Scholar]
199.Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2–dominated inflammatory response. J Clin Invest [Internet] 1999;104:777. doi: 10.1172/JCI7325. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC408441/ [cited 2015 Aug 7] [DOI] [PMC free article] [PubMed] [Google Scholar]
200.Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD. Interleukin-13: Central mediator of allergic asthma. Science [Internet] 1998;282:2258–2261. doi: 10.1126/science.282.5397.2258. Available from: http://www.sciencemag.org/content/282/5397/2258. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]
201.Zurawski SM, Chomarat P, Djossou O, Bidaud C, McKenzie ANJ, Miossec P, Banchereau J, Zurawski G. The primary binding subunit of the human interleukin-4 receptor is also a component of the interleukin-13 receptor. J Biol Chem [Internet] 1995;270:13869–13878. doi: 10.1074/jbc.270.23.13869. Available from: http://www.jbc.org/content/270/23/13869. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]
202.Donaldson DD, Whitters MJ, Fitz LJ, Neben TY, Finnerty H, Henderson SL, O’Hara RM, Beier DR, Turner KJ, Wood CR, Collins M. The murine IL-13 receptor α2: Molecular cloning, characterization, and comparison with murine IL-13 receptor α1. J Immunol [Internet] 1998;161:2317–2324. Available from: http://www.jimmunol.org/content/161/5/2317. [cited 2015 Aug 6] [PubMed] [Google Scholar]
203.Zheng T, Liu W, Oh S-Y, Zhu Z, Hu B, Homer RJ, Cohn L, Grusby MJ, Elias JA. IL-13 receptor α2 selectively inhibits IL-13-induced responses in the murine lung. J Immunol [Internet] 2008;180:522–529. doi: 10.4049/jimmunol.180.1.522. Available from: http://www.jimmunol.org/content/180/1/522. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]
204.Sironi M, Sciacca FL, Matteucci C, Conni M, Vecchi A, Bernasconi S, Minty A, Caput D, Ferrara P, Colotta F. Regulation of endothelial and mesothelial cell function by interleukin-13: selective induction of vascular cell adhesion molecule-1 and amplification of interleukin-6 production. Blood. 1994;84:1913–1921. [PubMed] [Google Scholar]
205.Rifas L, Cheng S-L. IL-13 regulates vascular cell adhesion molecule-1 expression in human osteoblasts. J Cell Biochem. 2003;89:213–219. doi: 10.1002/jcb.10531. [DOI] [PubMed] [Google Scholar]
206.Purwar R, Kraus M, Werfel T, Wittmann M. Modulation of keratinocyte-derived MMP-9 by IL-13: A possible role for the pathogenesis of epidermal inflammation. J Invest Dermatol [Internet] 2007;128:59–66. doi: 10.1038/sj.jid.5700940. Available from: http://www.nature.com/jid/journal/v128/n1/full/5700940a.html. [cited 2015 Aug 19] [DOI] [PubMed] [Google Scholar]
207.Hecker M, Zasłona Z, Kwapiszewska G, Niess G, Zakrzewicz A, Hergenreider E, Wilhelm J, Marsh LM, Sedding D, Klepetko W, Lohmeyer J, Dimmeler S, Seeger W, Weissmann N, Schermuly RT, Kneidinger N, Eickelberg O, Morty RE. Dysregulation of the IL-13 receptor system. A novel pathomechanism in pulmonary arterial hypertension. Am J Respir Crit Care Med [Internet] 2010;182:805–818. doi: 10.1164/rccm.200909-1367OC. Available from: http://www.atsjournals.org/doi/full/10.1164/rccm.200909-1367OC. [cited 2015 Aug 7] [DOI] [PubMed] [Google Scholar]
208.Christmann RB, Hayes E, Pendergrass S, Padilla C, Farina G, Affandi AJ, Whitfield ML, Farber HW, Lafyatis R. Interferon and alternative activation of monocyte/macrophages in systemic sclerosis–associated pulmonary arterial hypertension. Arthritis Rheum [Internet] 2011;63:1718–1728. doi: 10.1002/art.30318. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030759/ [cited 2015 Aug 9] [DOI] [PMC free article] [PubMed] [Google Scholar]
209.Cho W-K, Lee C-M, Kang M-J, Huang Y, Giordano FJ, Lee PJ, Trow TK, Homer RJ, Sessa WC, Elias JA, Lee CG. IL-13 receptor α2-arginase 2 pathway mediates IL-13-induced pulmonary hypertension. Am J Physiol - Lung Cell Mol Physiol [Internet] 2013;304:L112–L124. doi: 10.1152/ajplung.00101.2012. Available from: http://ajplung.physiology.org/content/304/2/L112. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]
210.Kumar R, Mickael C, Chabon J, Gebreab L, Rutebemberwa A, Rodriguez Garcia A, Koyanagi DE, Sanders L, Gandjeva A, Kearns MT, Barthel L, Janssen WJ, Mauad T, Bandeira A, Schmidt E, Tuder RM, Graham BB. The causal role of IL-4 and IL-13 in Schistosoma mansoni pulmonary hypertension. Am J Respir Crit Care Med [Internet] 2015 doi: 10.1164/rccm.201410-1820OC. Available from: http://www.atsjournals.org/doi/abs/10.1164/rccm.201410-1820OC. [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]
211.Chabon JJ, Gebreab L, Kumar R, Debella E, Tanaka T, Koyanagi D, Rodriguez Garcia A, Sanders L, Perez M, Tuder RM, Graham BB. Role of vascular endothelial growth factor signaling in Schistosoma-induced experimental pulmonary hypertension. Pulm Circ [Internet] 2014;4:289–299. doi: 10.1086/675992. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070790/ [cited 2015 Apr 3] [DOI] [PMC free article] [PubMed] [Google Scholar]
212.Graham BB, Chabon J, Gebreab L, Poole J, Debella E, Davis L, Tanaka T, Sanders L, Dropcho N, Bandeira A, Vandivier RW, Champion HC, Butrous G, Wang X-J, Wynn TA, Tuder RM. Transforming growth factor-β signaling promotes pulmonary hypertension caused by Schistosoma mansoni. Circulation [Internet] 2013;128:1354–1364. doi: 10.1161/CIRCULATIONAHA.113.003072. Available from: http://circ.ahajournals.org/content/128/12/1354. [cited 2013 Dec 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
213.Graham BB, Kumar R. Schistosomiasis and the pulmonary vasculature (2013 Grover Conference series) Pulmonary Circulation [Internet] 2014;4:353–362. doi: 10.1086/675983. Available from: http://www.jstor.org/stable/10.1086/675983 . [DOI] [PMC free article] [PubMed] [Google Scholar]
214.Kaviratne M, Hesse M, Leusink M, Cheever AW, Davies SJ, McKerrow JH, Wakefield LM, Letterio JJ, Wynn TA. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-β independent. J Immunol [Internet] 2004;173:4020–4029. doi: 10.4049/jimmunol.173.6.4020. Available from: http://www.jimmunol.org/content/173/6/4020. [cited 2015 Aug 9] [DOI] [PubMed] [Google Scholar]
215.Xu W, Kaneko FT, Zheng S, Comhair SAA, Janocha AJ, Goggans T, Thunnissen FBJM, Farver C, Hazen SL, Jennings C, Dweik RA, Arroliga AC, Erzurum SC. Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J Off Publ Fed Am Soc Exp Biol. 2004;18:1746–1748. doi: 10.1096/fj.04-2317fje. [DOI] [PubMed] [Google Scholar]
216.Xia Y, Dawson VL, Dawson TM, Snyder SH, Zweier JL. Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci. 1996;93:6770–6774. doi: 10.1073/pnas.93.13.6770. [DOI] [PMC free article] [PubMed] [Google Scholar]
217.Tabima DM, Frizzell S, Gladwin MT. Reactive oxygen and nitrogen species in pulmonary hypertension. Free Radic Biol Med [Internet] 2012;52:1970–1986. doi: 10.1016/j.freeradbiomed.2012.02.041. Available from: http://www.sciencedirect.com/science/article/pii/S0891584912001451. [cited 2018 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
218.Durante W, Johnson FK, Johnson RA. Arginase: A critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol [Internet] 2007;34:906–911. doi: 10.1111/j.1440-1681.2007.04638.x. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1440-1681.2007.04638.x. [cited 2018 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
219.Jr SMM. Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol [Internet] 2009;157:922–930. doi: 10.1111/j.1476-5381.2009.00278.x. Available from: https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1476-5381.2009.00278.x. [cited 2018 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
220.Cho W-K. Interleukin-13-mediated mechanisms of pulmonary vascular remodeling. Grantome [Internet] Available from: http://grantome.com/grant/NIH/K08-HL121183-01A1. [cited 2015 Aug 9] [Google Scholar]
221.Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol [Internet] 2014;6:a016295. doi: 10.1101/cshperspect.a016295. Available from: http://cshperspectives.cshlp.org/content/6/10/a016295. [cited 2015 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]
222.Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res [Internet] 2009;10:236–244. doi: 10.1186/1465-9921-10-6. Available from: http://www.biomedcentral.com/content/pdf/1465-9921-10-6.pdf. [cited 2015 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]
223.Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci [Internet] 2012;122:143–159. doi: 10.1042/CS20110340. Available from: http://www.clinsci.org/content/122/4/143. [cited 2018 Aug 19] [DOI] [PubMed] [Google Scholar]
224.Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest [Internet] 2011;121:3375–3383. doi: 10.1172/JCI57158. Available from: http://www.jci.org/articles/view/57158. [cited 2018 Aug 19] [DOI] [PMC free article] [PubMed] [Google Scholar]
225.Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol [Internet] 2015;16:448–457. doi: 10.1038/ni.3153. Available from: https://www.nature.com/articles/ni.3153. [cited 2018 Aug 19] [DOI] [PubMed] [Google Scholar]
226.Diehl S, Chow C-W, Weiss L, Palmetshofer A, Twardzik T, Rounds L, Serfling E, Davis RJ, Anguita J, Rincón M. Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation. J Exp Med [Internet] 2002;196:39–49. doi: 10.1084/jem.20020026. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194007/ [cited 2018 Aug 19] [DOI] [PMC free article] [PubMed] [Google Scholar]
227.Rincón M, Anguita J, Nakamura T, Fikrig E, Flavell RA. Interleukin (IL)-6 directs the differentiation of IL-4–producing CD4+ T cells. J Exp Med [Internet] 1997;185:461–470. doi: 10.1084/jem.185.3.461. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196041/ [cited 2018 Aug 19] [DOI] [PMC free article] [PubMed] [Google Scholar]
228.Diehl S, Anguita J, Hoffmeyer A, Zapton T, Ihle JN, Fikrig E, Rincón M. Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity [Internet] 2000;13:805–815. doi: 10.1016/s1074-7613(00)00078-9. Available from: https://www.cell.com/immunity/abstract/S1074-7613(00)00078-9. [cited 2018 Aug 19] [DOI] [PubMed] [Google Scholar]
229.Kobayashi T, Tanaka K, Fujita T, Umezawa H, Amano H, Yoshioka K, Naito Y, Hatano M, Kimura S, Tatsumi K, Kasuya Y. Bidirectional role of IL-6 signal in pathogenesis of lung fibrosis. Respir Res [Internet] 2015;16:99. doi: 10.1186/s12931-015-0261-z. Available from: https://respiratory-research.com/content/16/1/99/abstract. [cited 2015 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]
230.Maston LD, Jones DT, Giermakowska W, Resta TC, Ramiro-Diaz J, Howard TA, Jernigan NL, Herbert L, Maurice AA, Gonzalez Bosc LV. Interleukin-6 trans-signaling contributes to chronic hypoxia-induced pulmonary hypertension. Pulm Circ [Internet] 2018;8:204589401878073. doi: 10.1177/2045894018780734. Available from: https://journals.sagepub.com/doi/10.1177/2045894018780734. [cited 2018 Aug 17] [DOI] [PMC free article] [PubMed] [Google Scholar]
231.Tamura Y, Phan C, Tu L, Hiress ML, Thuillet R, Jutant E-M, Fadel E, Savale L, Huertas A, Humbert M, Guignabert C. Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. J Clin Invest [Internet] 2018;128:1956–1970. doi: 10.1172/JCI96462. Available from: https://www.jci.org/articles/view/96462. [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]
232.Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res [Internet] 2009;104:236–244. doi: 10.1161/CIRCRESAHA.108.182014. Available from: http://circres.ahajournals.org/content/104/2/236. [cited 2015 Aug 20] [DOI] [PMC free article] [PubMed] [Google Scholar]
233.Davies RJ, Holmes AM, Deighton J, Long L, Yang X, Barker L, Walker C, Budd DC, Upton PD, Morrell NW. BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol-Lung Cell Mol Physiol [Internet] 2012;302:L604–L615. doi: 10.1152/ajplung.00309.2011. Available from: https://www.physiology.org/doi/full/10.1152/ajplung.00309.2011. [cited 2018 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]
234.Hagen M, Fagan K, Steudel W, Carr M, Lane K, Rodman DM, West J. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol-Lung Cell Mol Physiol [Internet] 2007;292:L1473–L1479. doi: 10.1152/ajplung.00197.2006. Available from: https://www.physiology.org/doi/abs/10.1152/ajplung.00197.2006. [cited 2018 Aug 20] [DOI] [PubMed] [Google Scholar]
235.Miyata M, Sakuma F, Yoshimura A, Ishikawa H, Nishimaki T, Kasukawa R. Pulmonary hypertension in rats, role of lnterleukin-6. Int Arch Allergy Immunol [Internet] 1995;108:287–291. doi: 10.1159/000237166. Available from: http://www.karger.com/doi/10.1159/000237166. [cited 2015 Aug 21] [DOI] [PubMed] [Google Scholar]
236.Price LC, Wort SJ, Perros F, Dorfmüller P, Huertas A, Montani D, Cohen-Kaminsky S, Humbert M. Inflammation in pulmonary arterial hypertension. Chest [Internet] 2012;141:210–221. doi: 10.1378/chest.11-0793. Available from: http://chestjournal.chestpubs.org/content/141/1/210. [cited 2012 Jun 14] [DOI] [PubMed] [Google Scholar]
237.Matura LA, Ventetuolo CE, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Pinder D, Archer-Chicko C, Bagiella E, Roberts KE, Tracy RP, Hassoun PM, Girgis RE, Kawut SM. Interleukin-6 and tumor necrosis factor-α are associated with quality of life-related symptoms in pulmonary arterial hypertension. Ann Am Thorac Soc. 2015;12:370–375. doi: 10.1513/AnnalsATS.201410-463OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
238.Angeli V, Faveeuw C, Delerive P, Fontaine J, Barriera Y, Franchimont N, Staels B, Capron M, Trottein F. Schistosoma mansoni induces the synthesis of IL-6 in pulmonary microvascular endothelial cells: role of IL-6 in the control of lung eosinophilia during infection. Eur J Immunol [Internet]. 2001;31:2751–2761. doi: 10.1002/1521-4141(200109)31:9<2751::aid-immu2751>3.0.co;2-4. Available from: http://onlinelibrary.wiley.com/doi/10.1002/1521-4141(200109)31:9<2751::AID-IMMU2751>3.0.CO;2-4/abstract. [cited 2015 Aug 21] [DOI] [PubMed] [Google Scholar]
239.Graham BB, Chabon J, Kumar R, Kolosionek E, Gebreab L, Debella E, Edwards M, Diener K, Shade T, Bifeng G, Bandeira A, Butrous G, Jones K, Geraci M, Tuder RM. Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension. Am J Respir Cell Mol Biol [Internet] 2013;49:951–959. doi: 10.1165/rcmb.2012-0532OC. Available from: http://www.atsjournals.org/doi/abs/10.1165/rcmb.2012-0532OC#.Uq7DArS3CQA. [cited 2013 Dec 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
240.Ganeshan K, Bryce PJ. Regulatory T cells enhance mast cell production of IL-6 via surface-bound TGFβ. J Immunol Baltim Md 1950 [Internet] 2012;188:594–603. doi: 10.4049/jimmunol.1102389. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253181/ [cited 2018 Aug 22] [DOI] [PMC free article] [PubMed] [Google Scholar]
241.Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmüller P, Humbert M, Guignabert C. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation. 2014;129:1586–1597. doi: 10.1161/CIRCULATIONAHA.113.007469. [DOI] [PubMed] [Google Scholar]
242.Zabini D, Granton E, Hu Y, Miranda MZ, Weichelt U, Breuils Bonnet S, Bonnet S, Morrell NW, Connelly KA, Provencher S, Ghanim B, Klepetko W, Olschewski A, Kapus A, Kuebler WM. Loss of SMAD3 promotes vascular remodeling in pulmonary arterial hypertension via MRTF disinhibition. Am J Respir Crit Care Med [Internet] 2017;197:244–260. doi: 10.1164/rccm.201702-0386OC. Available from: https://www.atsjournals.org/doi/10.1164/rccm.201702-0386OC. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]
243.Breitling S, Hui Z, Zabini D, Hu Y, Hoffmann J, Goldenberg NM, Tabuchi A, Buelow R, Dos Santos C, Kuebler WM. The mast cell–B cell axis in lung vascular remodeling and pulmonary hypertension. Am J Physiol-Lung Cell Mol Physiol [Internet] 2017;312:L710–L721. doi: 10.1152/ajplung.00311.2016. Available from: https://www.physiology.org/doi/abs/10.1152/ajplung.00311.2016. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]
244.Hashimoto-Kataoka T, Hosen N, Sonobe T, Arita Y, Yasui T, Masaki T, Minami M, Inagaki T, Miyagawa S, Sawa Y, Murakami M, Kumanogoh A, Yamauchi-Takihara K, Okumura M, Kishimoto T, Komuro I, Shirai M, Sakata Y, Nakaoka Y. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci [Internet] 2015;112:e2677–E2686. doi: 10.1073/pnas.1424774112. Available from: http://www.pnas.org/content/112/20/E2677. [cited 2015 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]
245.Shi Y, Massagué J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell x[Internet] 2003;113:685–700. doi: 10.1016/s0092-8674(03)00432-x. Available from: http://www.sciencedirect.com/science/article/pii/S009286740300432X. [cited 2015 Aug 17] [DOI] [PubMed] [Google Scholar]
246.Feng X-H, Derynck R. Specificity and versatility in TGF-β signaling through smads. Annu Rev Cell Dev Biol [Internet] 2005;21:659–693. doi: 10.1146/annurev.cellbio.21.022404.142018. Available from: [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]
247.Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther. 2006;8:S3. doi: 10.1186/ar1917. [DOI] [PMC free article] [PubMed] [Google Scholar]
248.Zaiman AL, Podowski M, Medicherla S, Gordy K, Xu F, Zhen L, Shimoda LA, Neptune E, Higgins L, Murphy A, Chakravarty S, Protter A, Sehgal PB, Champion HC, Tuder RM. Role of the TGF-β/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med. 2008;177:896–905. doi: 10.1164/rccm.200707-1083OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
249.Wilks AF, Harpur AG. Cytokine signal transduction and the JAK family of protein tyrosine kinases. BioEssays [Internet] 1994;16:313–320. doi: 10.1002/bies.950160505. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/bies.950160505. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]
250.Guo X, Wang X-F. Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res [Internet] 2009;19:71–88. doi: 10.1038/cr.2008.302. Available from: https://www.nature.com/articles/cr2008302. [cited 2018 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]
251.Doetschman T, Barnett JV, Runyan RB, Camenisch TD, Heimark RL, Granzier HL, Conway SJ, Azhar M. Transforming growth factor beta signaling in adult cardiovascular diseases and repair. Cell Tissue Res [Internet] 2011;347:203–223. doi: 10.1007/s00441-011-1241-3. Available from: http://link.springer.com/article/10.1007/s00441-011-1241-3. [cited 2015 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
252.Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov [Internet] 2012;11:790–811. doi: 10.1038/nrd3810. Available from: http://www.nature.com/nrd/journal/v11/n10/abs/nrd3810.html. [cited 2015 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
253.Richter A, Yeager ME, Zaiman A, Cool CD, Voelkel NF, Tuder RM. Impaired transforming growth factor-β signaling in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med [Internet] 2004;170:1340–1348. doi: 10.1164/rccm.200311-1602OC. Available from: http://www.atsjournals.org/doi/full/10.1164/rccm.200311-1602OC#.UpEXM-K3CQA. [cited 2013 Nov 23] [DOI] [PubMed] [Google Scholar]
254.Zakrzewicz A, Kouri FM, Nejman B, Kwapiszewska G, Hecker M, Sandu R, Dony E, Seeger W, Schermuly RT, Eickelberg O, Morty RE. The transforming growth factor-β/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension. Eur Respir J [Internet] 2007;29:1094–1104. doi: 10.1183/09031936.00138206. Available from: http://erj.ersjournals.com/content/29/6/1094. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]
255.Yanagisawa K, Osada H, Masuda A, Kondo M, Saito T, Yatabe Y, Takagi K, Takahashi T, Takahashi T. Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells. Oncogene [Internet] 1998;17:1743–1747. doi: 10.1038/sj.onc.1202052. Available from: https://www.nature.com/articles/1202052. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]
256.Vaillancourt M, Ruffenach G, Meloche J, Bonnet S. Adaptation and remodelling of the pulmonary circulation in pulmonary hypertension. Can J Cardiol. 2015;31:407–415. doi: 10.1016/j.cjca.2014.10.023. [DOI] [PubMed] [Google Scholar]
257.Farkas L, Kolb MRJ. A switch in TGF-β signaling explains contradictory findings in pulmonary arterial hypertension. Am J Respir Crit Care Med [Internet] 2017;197:157–159. doi: 10.1164/rccm.201708-1741ED. Available from: https://www.atsjournals.org/doi/full/10.1164/rccm.201708-1741ED. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]
258.Tuder RM, Archer SL, Dorfmüller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol [Internet] 2013;62:D4–D12. doi: 10.1016/j.jacc.2013.10.025. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0735109713058683. [cited 2014 Apr 6] [DOI] [PMC free article] [PubMed] [Google Scholar]
259.Vlugt LEPM van der, Labuda LA, Ozir-Fazalalikhan A, Lievers E, Gloudemans AK, Liu K-Y, Barr TA, Sparwasser T, Boon L, Ngoa UA, Feugap EN, Adegnika AA, Kremsner PG, Gray D, Yazdanbakhsh M, Smits HH. Schistosomes induce regulatory features in human and mouse CD1dhi B cells: Inhibition of allergic inflammation by IL-10 and regulatory T cells. PLOS ONE [Internet] 2012;7:e30883. doi: 10.1371/journal.pone.0030883. Available from: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030883. [cited 2018 Aug 23] [DOI] [PMC free article] [PubMed] [Google Scholar]
260.Hesse M, Piccirillo CA, Belkaid Y, Prufer J, Mentink-Kane M, Leusink M, Cheever AW, Shevach EM, Wynn TA. The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J Immunol Baltim Md 1950. 2004;172:3157–3166. doi: 10.4049/jimmunol.172.5.3157. [DOI] [PubMed] [Google Scholar]
261.Hoffmann KF, Cheever AW, Wynn TA. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J Immunol Baltim Md 1950. 2000;164:6406–6416. doi: 10.4049/jimmunol.164.12.6406. [DOI] [PubMed] [Google Scholar]
262.Ito T, Okada T, Miyashita H, Nomoto T, Nonaka-Sarukawa M, Uchibori R, Maeda Y, Urabe M, Mizukami H, Kume A, et al. Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats. Circ Res [Internet] 2007;101:734–741. doi: 10.1161/CIRCRESAHA.107.153023. Available from: http://circres.ahajournals.org/content/101/7/734.short. [cited 2015 Aug 21] [DOI] [PubMed] [Google Scholar]
263.Vergadi E, Chang MS, Lee C, Liang OD, Liu X, Fernandez-Gonzalez A, Mitsialis SA, Kourembanas S. Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. Circulation [Internet] 2011;123:1986–1995. doi: 10.1161/CIRCULATIONAHA.110.978627. Available from: http://circ.ahajournals.org/content/123/18/1986. [cited 2015 Aug 20] [DOI] [PMC free article] [PubMed] [Google Scholar]
264.Groth A, Vrugt B, Brock M, Speich R, Ulrich S, Huber LC. Inflammatory cytokines in pulmonary hypertension. Respir Res [Internet] 2014;15:47. doi: 10.1186/1465-9921-15-47. Available from: https://respiratory-research.com/content/15/1/47/abstract. [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]
265.Sabin EA, Kopf MA, Pearce EJ. Schistosoma mansoni egg-induced early IL-4 production is dependent upon IL-5 and eosinophils. J Exp Med. 1996;184:1871–1878. doi: 10.1084/jem.184.5.1871. [DOI] [PMC free article] [PubMed] [Google Scholar]
266.Paiva LA, C, Bandeira-Melo C, Bozza PT, El-Cheikh MC, Silva PM, Borojevic R, Perez SAC. Hepatic myofibroblasts derived from Schistosoma mansoni-infected mice are a source of IL-5 and eotaxin: controls of eosinophil populations in vitro. Parasit Vectors [Internet] 2015;8:577. doi: 10.1186/s13071-015-1197-3. Available from: [cited 2018 Aug 23] [DOI] [PMC free article] [PubMed] [Google Scholar]
267.Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF, Cheever AW, Young DA, Collins M, Grusby MJ, Wynn TA. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest [Internet] 2006;116:2044–2055. doi: 10.1172/JCI27727. Available from: https://www.jci.org/articles/view/27727. [cited 2018 Aug 23] [DOI] [PMC free article] [PubMed] [Google Scholar]
268.Nady S, Shata MTM, Mohey MA, El-Shorbagy A. Protective role of IL-22 against Schistosoma mansoni soluble egg antigen-induced granuloma in vitro. Parasite Immunol [Internet] 2017;39:e12392. doi: 10.1111/pim.12392. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/pim.12392. [cited 2018 Aug 23] [DOI] [PubMed] [Google Scholar]
269.Ezz A, Gmail I, Salem F, Salama R, Nady S. Anti-IL-17 markedly inhibited the in vitro granuloma induced by Schistosoma mansoni soluble egg antigen. Int J Med Dev Ctries [Internet] 2018;38 Available from: https://www.ejmanager.com/fulltextpdf.php?mno=291092. [cited 2018 Aug 23] [Google Scholar]
270.Maston LD, Jones DT, Giermakowska W, Howard TA, Cannon JL, Wang W, Wei Y, Xuan W, Resta TC, Bosc LVG. Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension. Am J Physiol - Lung Cell Mol Physiol [Internet] 2017;312:L609–L624. doi: 10.1152/ajplung.00531.2016. Available from: http://ajplung.physiology.org/content/312/5/L609. [cited 2017 Jun 11] [DOI] [PMC free article] [PubMed] [Google Scholar]
271.Hautefort A, Girerd B, Montani D, Cohen-Kaminsky S, Price L, Lambrecht BN, Humbert M, Perros F. T-Helper 17 cell polarization in pulmonary arterial hypertension. Chest [Internet] 2015;147:1610–1620. doi: 10.1378/chest.14-1678. Available from: http://www.sciencedirect.com/science/article/pii/S0012369215372172 . [DOI] [PubMed] [Google Scholar]
272.Angelini DJ, Su Q, Yamaji-Kegan K, Fan C, Skinner JT, Poloczek A, El-Haddad H, Cheadle C, Johns RA. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling. Respir Res [Internet] 2013;14:1. doi: 10.1186/1465-9921-14-1. Available from: https://respiratory-research.com/content/14/1/1/abstract. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]
273.Yamaji-Kegan K, Takimoto E, Zhang A, Weiner NC, Meuchel LW, Berger AE, Cheadle C, Johns RA. Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. Am J Physiol - Lung Cell Mol Physiol [Internet] 2014;306:L1090–L1103. doi: 10.1152/ajplung.00279.2013. Available from: http://ajplung.physiology.org/content/306/12/L1090. [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]
274.Pesce JT, Ramalingam TR, Wilson MS, Mentink-Kane MM, Thompson RW, Cheever AW, Urban JF, Wynn TA. Retnla (Relmα/Fizz1) suppresses helminth-induced Th2-type immunity. PLoS Pathog [Internet] 2009;5 doi: 10.1371/journal.ppat.1000393. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663845/ [DOI] [PMC free article] [PubMed] [Google Scholar]
275.Wagner KF, Hellberg A-K, Balenger S, Depping R, Dodd OJ, Johns RA, Li D. Hypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha. Am J Respir Cell Mol Biol. 2004;31:276–282. doi: 10.1165/rcmb.2003-0319OC. [DOI] [PubMed] [Google Scholar]
276.Butrous G. Human immunodeficiency virus–associated pulmonary arterial hypertension considerations for pulmonary vascular diseases in the developing world. Circulation [Internet] 2015;131:1361–1370. doi: 10.1161/CIRCULATIONAHA.114.006978. Available from: http://circ.ahajournals.org/content/131/15/1361. [cited 2015 Apr 14] [DOI] [PubMed] [Google Scholar]
277.Mbabazi PS, Andan O, Fitzgerald DW, Chitsulo L, Engels D, Downs JA. Examining the relationship between urogenital schistosomiasis and HIV infection. PLoS Negl Trop Dis [Internet] 2011;5:e1396. doi: 10.1371/journal.pntd.0001396. Available from: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0001396. [cited 2018 Sep 3] [DOI] [PMC free article] [PubMed] [Google Scholar]
278.Downs JA, et al. HIV and schistosomiasis: studies in Tanzania [Internet] 2016 Available from: https://openaccess.leidenuniv.nl/handle/1887/39785 . [Google Scholar]
279.Downs JA, Dam GJ van, Changalucha JM, Corstjens PLAM, Peck RN, Dood CJ de, Bang H, Andreasen A, Kalluvya SE, Lieshout L van, Johnson WD, Fitzgerald DW. Association of schistosomiasis and HIV Infection in Tanzania. Am J Trop Med Hyg [Internet] 2012;87:868–873. doi: 10.4269/ajtmh.2012.12-0395. Available from: http://www.ajtmh.org/content/87/5/868. [cited 2015 May 21] [DOI] [PMC free article] [PubMed] [Google Scholar]
280.Colombe S, Machemba R, Mtenga B, Lutonja P, Kalluvya SE, Dood CJ de, Hoekstra PT, Dam GJ van, Corstjens PLAM, Urassa M, Changalucha JM, Todd J, Downs JA. Impact of schistosome infection on long-term HIV/AIDS outcomes. PLoS Negl Trop Dis [Internet] 2018;12:e0006613. doi: 10.1371/journal.pntd.0006613. Available from: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006613. [cited 2018 Sep 4] [DOI] [PMC free article] [PubMed] [Google Scholar]
281.Kallestrup P, Zinyama R, Gomo E, Butterworth AE, Mudenge B, Dam GJ van, Gerstoft J, Erikstrup C, Ullum H. Schistosomiasis and HIV-1 infection in rural Zimbabwe: Effect of treatment of schistosomiasis on CD4 cell count and plasma HIV-1 RNA load. J Infect Dis [Internet] 2005;192:1956–1961. doi: 10.1086/497696. Available from: http://jid.oxfordjournals.org/content/192/11/1956. [cited 2014 May 19] [DOI] [PubMed] [Google Scholar]
282.Parikh R, Scherzer R, Nitta E, MacGregor J, Leone A, Deeks S, Martin J, Donovan C, Morelli J, Ganz P, Hsue P. Asymmetric dimethylarginine levels are associated with pulmonary arterial hypertension in HIV-infected individuals. J Am Coll Cardiol [Internet] 2012;59:e1614–E1614. doi: 10.1016/S0735-1097(12)61615-5. Available from: [cited 2014 Sep 28] [DOI] [Google Scholar]
283.Parikh RV, Scherzer R, Nitta EM, Leone A, Hur S, Mistry V, Macgregor JS, Martin JN, Deeks SG, Ganz P, Hsue PY. Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection. AIDS [Internet] 2014;28:511–519. doi: 10.1097/QAD.0000000000000124. Available from: http://journals.lww.com/aidsonline/Abstract/2014/02200/Increased_levels_of_asymmetric_dimethylarginine.7.aspx. [cited 2014 Apr 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
284.Cooke JP. Asymmetrical dimethylarginine the über marker? Circulation [Internet] 2004;109:1813–1818. doi: 10.1161/01.CIR.0000126823.07732.D5. Available from: http://circ.ahajournals.org/content/109/15/1813. [cited 2014 May 21] [DOI] [PubMed] [Google Scholar]
285.Yu Y-RA, Mao L, Piantadosi CA, Gunn MD. CCR2 deficiency, dysregulation of notch signaling, and spontaneous pulmonary arterial hypertension. Am J Respir Cell Mol Biol [Internet] 2013;48:647–654. doi: 10.1165/rcmb.2012-0182OC. Available from: http://www.atsjournals.org/doi/full/10.1165/rcmb.2012-0182OC. [cited 2014 May 12] [DOI] [PMC free article] [PubMed] [Google Scholar]
286.Sanchez O, Marcos E, Perros F, Fadel E, Tu L, Humbert M, Dartevelle P, Simonneau G, Adnot S, Eddahibi S. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med [Internet] 2007;176:1041–1047. doi: 10.1164/rccm.200610-1559OC. Available from: http://www.atsjournals.org/doi/abs/10.1164/rccm.200610-1559OC. [cited 2014 May 12] [DOI] [PubMed] [Google Scholar]
287.Mazigo HD, Nuwaha F, Wilson S, Kinung’hi SM, Morona D, Waihenya R, Heukelbach J, Dunne DW. Epidemiology and interactions of human immunodeficiency virus-1 and Schistosoma mansoni in sub-Saharan Africa. Infect Poverty [Internet] 2013;2:2–11. doi: 10.1186/2049-9957-2-2. Available from: http://www.biomedcentral.com/content/pdf/2049-9957-2-2.pdf. [cited 2014 May 19] [DOI] [PMC free article] [PubMed] [Google Scholar]
288.Downs JA, Dupnik KM, Dam GJ van, Urassa M, Lutonja P, Kornelis D, Dood CJ de, Hoekstra P, Kanjala C, Isingo R, Peck RN, Lee MH, Corstjens PLAM, Todd J, Changalucha JM, Jr WDJ, Fitzgerald DW. Effects of schistosomiasis on susceptibility to HIV-1 infection and HIV-1 viral load at HIV-1 seroconversion: A nested case-control study. PLoS Negl Trop Dis [Internet] 2017;11:e0005968. doi: 10.1371/journal.pntd.0005968. Available from: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0005968. [cited 2018 Sep 3] [DOI] [PMC free article] [PubMed] [Google Scholar]
289.Efraim L, Peck RN, Kalluvya SE, Kabangila R, Mazigo HD, Mpondo B, Bang H, Todd J, Fitzgerald DW, Downs JA. Schistosomiasis and impaired response to antiretroviral therapy among HIV-infected patients in Tanzania. JAIDS J Acquir Immune Defic Syndr [Internet] 2013;62:e153–e156. doi: 10.1097/QAI.0b013e318282a1a4. Available from: http://journals.lww.com/jaids/Fulltext/2013/04150/Schistosomiasis_and_Impaired_Response_to.22.aspx. [cited 2014 May 19] [DOI] [PMC free article] [PubMed] [Google Scholar]
290.Bustinduy A, King C, Scott J, Appleton S, Sousa-Figueiredo JC, Betson M, Stothard JR. HIV and schistosomiasis co-infection in African children. Lancet Infect Dis [Internet] doi: 10.1016/S1473-3099(14)70001-5. Available from: http://www.sciencedirect.com/science/article/pii/S1473309914700015 . [DOI] [PubMed] [Google Scholar]
291.Belleli V. Les oeufs de Bilharzia haematobia dans les poumons. Unione Á Med ÁEgiz Á1. 1885:22–23. [Google Scholar]
292.Shaw AFB, Ghareeb AA. The pathogenesis of pulmonary schistosomiasis in Egypt with special reference to Ayerza’s disease. J Pathol Bacteriol [Internet] 1938;46:401–424. Available from: http://onlinelibrary.wiley.com/doi/10.1002/path.1700460302/abstract. [cited 2013 Apr 15] [Google Scholar]
293.Ward T, Butrous G, Fenwick A. The prevalence of pulmonary hypertension in schistosomiasis: A systematic review. PVRI Rev [Internet] 2011;3:12. Available from: https://www.pvrireview.org/article.asp?issn=0974-6013;year=2011;volume=3;issue=1;spage=12;epage=21;aulast=Ward. [cited 2013 Apr 15] [Google Scholar]
294.Lapa MS, Ferreira EVM, Jardim C, Martins B do C dos S, Arakaki JSO, Souza R. Clinical characteristics of pulmonary hypertension patients in two reference centers in the city of Sao Paulo. Rev Assoc Med Bras [Internet] 2006;52:139–143. doi: 10.1590/s0104-42302006000300012. Available from: http://www.scielo.br/scielo.php?pid=S0104-42302006000300012&script=sci_arttext&tlng=es. [cited 2017 Jan 15] [DOI] [PubMed] [Google Scholar]
295.Rocha RL, Pedroso ER, Rocha MO, Lambertucci JR, Greco DB, Ferreira CE. Chronic pulmonary form of schistosomiasis mansoni. Clinico-radiologic evaluation. Rev Soc Bras Med Trop [Internet] 1989;23:83–89. doi: 10.1590/s0037-86821990000200004. Available from: http://europepmc.org/abstract/med/2129521. [cited 2017 Jan 15] [DOI] [PubMed] [Google Scholar]
296.Barbosa MM, Lamounier JA, Oliveira EC, Souza MV, Marques DS, Silva AA, Lambertucci JR. Pulmonary hypertension in schistosomiasis mansoni. Trans R Soc Trop Med Hyg. 1996;90:663–665. doi: 10.1016/s0035-9203(96)90424-1. [DOI] [PubMed] [Google Scholar]
297.Bottieau E, Clerinx J, De Vega MR, Van den Enden E, Colebunders R, Van Esbroeck M, Vervoort T, Van Gompel A, Van den Ende J. Imported Katayama fever: clinical and biological features at presentation and during treatment. J Infect [Internet] 2006;52:339–345. doi: 10.1016/j.jinf.2005.07.022. Available from: http://www.sciencedirect.com/science/article/pii/S0163445305002203. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]
298.Meltzer E, Artom G, Marva E, Assous M, Rahav G, Schwartz E. Schistosomiasis among travelers: New aspects of an old disease. Emerg Infect Dis [Internet] 2006;12:1696–1700. doi: 10.3201/eid1211.060340. Available from: http://wwwnc.cdc.gov/eid/article/17/11/06-0340_article.htm. [cited 2015 Jun 25] [DOI] [PMC free article] [PubMed] [Google Scholar]
299.Ross AG, Vickers D, Olds GR, Shah SM, McManus DP. Katayama syndrome. Lancet Infect Dis [Internet] 2007;7:218–224. doi: 10.1016/S1473-3099(07)70053-1. Available from: http://www.sciencedirect.com/science/article/pii/S1473309907700531. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]
300.Ishii A, Tsuji M, Tada I. History of Katayama disease: schistosomiasis japonica in Katayama district, Hiroshima, Japan. Parasitol Int [Internet] 2003;52:313–319. doi: 10.1016/s1383-5769(03)00046-1. Available from: http://www.sciencedirect.com/science/article/pii/S1383576903000461. [cited 2015 May 3] [DOI] [PubMed] [Google Scholar]
301.Renoult AJ. Notice sur l’hématurie qu’éprouvent les Européens dans la haute Egypt et la Nubie. J Gen Médecine. 1803;17:366–370. [Google Scholar]
302.Carstens PA. The encyclopaedia of egypt during the reign of the Mehemet Ali Dynasty 1798-1952 - the people, places and events. 2014. [Google Scholar]
303.Leshem E, Maor Y, Meltzer E, Assous M, Schwartz E. Acute schistosomiasis outbreak: Clinical features and economic impact. Clin Infect Dis [Internet] 2008;47:1499–1506. doi: 10.1086/593191. Available from: http://cid.oxfordjournals.org/content/47/12/1499. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]
304.Schwartz E, Rozenman J, Perelman M. Pulmonary manifestations of early schistosome infection among nonimmune travelers. Am J Med [Internet] 2000;109:718–722. doi: 10.1016/s0002-9343(00)00619-7. Available from: http://www.sciencedirect.com/science/article/pii/S0002934300006197. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]
305.Kapoor S. Katayama syndrome in patients with schistosomiasis. Asian Pac J Trop Biomed [Internet] 2014;4:244. doi: 10.1016/S2221-1691(14)60239-2. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868797/ [cited 2015 Jun 25] [DOI] [PMC free article] [PubMed] [Google Scholar]
306.Epelboin L, Jauréguiberry S, Estève J-B, Danis M, Komajda M, Bricaire F, Caumes E. Myocarditis during acute schistosomiasis in two travelers. Am J Trop Med Hyg [Internet] 2010;82:365–367. doi: 10.4269/ajtmh.2010.09-0084. Available from: http://www.ajtmh.org/content/82/3/365. [cited 2015 Jun 25] [DOI] [PMC free article] [PubMed] [Google Scholar]
307.Meltzer E, Schwartz E. Schistosomiasis: current epidemiology and management in travelers. Curr Infect Dis Rep [Internet] 2013;15:211–215. doi: 10.1007/s11908-013-0329-1. Available from: http://link.springer.com/article/10.1007/s11908-013-0329-1. [cited 2014 Jan 11] [DOI] [PubMed] [Google Scholar]
308.Ben-Chetrit E, Lachish T, Mørch K, Atias D, Maguire C, Schwartz E. Schistosomiasis in pregnant travelers: a case series. J Travel Med [Internet] 2015;22:94–98. doi: 10.1111/jtm.12165. Available from: http://onlinelibrary.wiley.com/doi/10.1111/jtm.12165/pdf. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]
309.Hoette S, Figueiredo C, Dias B, Alves-Jr JL, Gavilanes F, Prada LF, Jasinowodolinski D, Morinaga LTK, Jardim C, Fernandes CJC, Souza R. Pulmonary artery enlargement in schistosomiasis associated pulmonary arterial hypertension. BMC Pulm Med [Internet] 2015;15:118. doi: 10.1186/s12890-015-0115-y. Available from: [cited 2017 Jan 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
310.Abo-Salem ES, Ramadan MM. A huge thrombosed pulmonary artery aneurysm without pulmonary hypertension in a patient with hepatosplenic schistosomiasis. Am J Case Rep [Internet] 2015;16:140–145. doi: 10.12659/AJCR.892451. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356186/ [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]
311.Santarém OL de A, Cleva R de, Sasaya FM, Assumpção MS de, Furtado MS, Barbato AJG, Herman P. Left ventricular dilation and pulmonary vasodilatation after surgical shunt for treatment of pre-sinusoidal portal hypertension. PLOS ONE [Internet] 2016;11:e0154011. doi: 10.1371/journal.pone.0154011. Available from: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154011. [cited 2017 Jan 16] [DOI] [PMC free article] [PubMed] [Google Scholar]
312.Gavilanes F, Piloto B, Fernandes CJC. Giant pulmonary artery aneurysm in a patient with schistosomiasis-associated pulmonary arterial hypertension. J Bras Pneumol. 2018;44:167–167. doi: 10.1590/S1806-37562018000000098. [DOI] [PMC free article] [PubMed] [Google Scholar]
313.Corrêa R de A, Silva LC dos S, Rezende CJ, Bernardes RC, Prata TA, Silva HL. Pulmonary hypertension and pulmonary artery dissection. J Bras Pneumol [Internet] 2013;39:238–241. doi: 10.1590/S1806-37132013000200016. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S1806-37132013000200238&lng=en&nrm=iso&tlng=en. [cited 2018 Aug 25] [DOI] [PMC free article] [PubMed] [Google Scholar]
314.Guimaraes AC. Situacao atual dos conhecimentos sobre o envolvimento cardiopulmonar na esquistossomose mansonica. Arq Bras Cardiol [Internet] 1982 Available from: http://agris.fao.org/agris-search/search.do;jsessionid=E48F06768A694AEC49D2BE0FAB22A853?request_locale=en&recordID=US201302173481&sourceQuery=&query=&sortField=&sortOrder=&agrovocString=&advQuery=&centerString=&enableField= [cited 2018 Aug 26] [PubMed] [Google Scholar]
315.Ferreira RCS, Domingues ALC, Bandeira AP, Markman Filho B, Albuqerque Filho ES, Correiade de Araújo ACC, Batista LJB, Markman M, Campelo ARL. Prevalence of pulmonary hypertension in patients with Schistosomal liver fibrosis. Ann Trop Med Parasitol. 2009;103:129–143. doi: 10.1179/136485909X398168. [DOI] [PubMed] [Google Scholar]
316.dos Santos Fernandes CJC, Jardim CVP, Hovnanian A, Hoette S, Dias BA, Souza S, Humbert M, Souza R. Survival in schistosomiasis - associated pulmonary arterial hypertension. J Am Coll Cardiol [Internet] 2010;56:715–720. doi: 10.1016/j.jacc.2010.03.065. Available from: http://content.onlinejacc.org/cgi/content/abstract/56/9/715. [cited 2012 Jun 14] [DOI] [PubMed] [Google Scholar]
317.Kinkel H-F, Dittrich S, Bäumer B, Weitzel T. Evaluation of eight serological tests for diagnosis of imported schistosomiasis. Clin Vaccine Immunol [Internet] 2012;19:948–953. doi: 10.1128/CVI.05680-11. Available from: http://cvi.asm.org/content/19/6/948. [cited 2014 Jan 11] [DOI] [PMC free article] [PubMed] [Google Scholar]
318.Hovnanian A, Hoette S, Fernandes CJC, Jardim C, Souza R. Schistosomiasis associated pulmonary hypertension. Int J Clin Pract. 2010;64:25–28. doi: 10.1111/j.1742-1241.2009.02234.x. [DOI] [PubMed] [Google Scholar]
319.Fernandes CJCD, Jardim CV, Hovnanian A, Hoette S, Morinaga LK, Souza R. Schistosomiasis and pulmonary hypertension. Expert Rev Respir Med. 2011;5:675–681. doi: 10.1586/ers.11.58. [DOI] [PubMed] [Google Scholar]
320.de Amorim Correa R, Moreira MVSC, da Silva Saraiva JM, Mancuzo EV, dos Santos Silva LC, Lambertucci JR. Treatment of schistosomiasis-associated pulmonary hypertension. J Bras Pneumol [Internet] 2011;37:272–276. doi: 10.1590/s1806-37132011000200018. Available from: http://www.scielo.br/pdf/jbpneu/v37n2/en_v37n2a18.pdf. [cited 2013 Apr 25] [DOI] [PubMed] [Google Scholar]
321.Loureiro R, Mendes A, Bandeira A, Cartaxo H, de Sa D. Circulation. 2004. Oral sildenafil improves functional status and cardiopulmonary hemodynamics in patients with severe pulmonary hypertension secondary to chronic pulmonary schistosomiasis: a cardiac magnetic resonance study; pp. 572–572. [Google Scholar]
322.Fernandes CJCS, Dias BA, Jardim CVP, Hovnanian A, Hoette S, Morinaga LK, Souza S, Suesada M, Breda AP, Souza R. The role of target therapies in schistosomiasis - associated pulmonary arterial hypertension. Chest [Internet] 2012;141:923–928. doi: 10.1378/chest.11-0483. Available from: http://chestjournal.chestpubs.org/content/141/4/923. [cited 2012 Jun 14] [DOI] [PubMed] [Google Scholar]
323.Bandeira A, Mendes A, Santos-Filho P, Sa D, Loureiro R. Circulation. 2004. Clinical efficacy of oral sildenafil in severe pulmonary hypertension in patients with chronic pulmonary schistosomiasis; pp. 296–296. [Google Scholar]
324.Fernandes CJC, Piloto B, Castro M, Oleas FG, Alves JL, Prada LFL, Jardim C, Souza R. Survival of patients with schistosomiasis-associated pulmonary arterial hypertension in the modern management era. Eur Respir J [Internet] 2018;51:1800307. doi: 10.1183/13993003.00307-2018. Available from: https://erj.ersjournals.com/content/51/6/1800307. [cited 2018 Aug 25] [DOI] [PubMed] [Google Scholar]
325.Salvador-Recatalà V, Greenberg RM. Calcium channels of schistosomes: unresolved questions and unexpected answers. Wiley Interdiscip Rev Membr Transp Signal [Internet] 2012;1:85–93. doi: 10.1002/wmts.19. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278165/ [cited 2018 Aug 31] [DOI] [PMC free article] [PubMed] [Google Scholar]
326.Crosby A, Jones FM, Kolosionek E, Southwood M, Purvis I, Soon E, Butrous G, Dunne DW, Morrelp NW. Praziquantel reverses pulmonary hypertension and vascular remodeling in murine schistosomiasis. Am J Respir Crit Care Med [Internet] 2011;184:467–473. doi: 10.1164/rccm.201101-0146OC. Available from: http://cat.inist.fr/?aModele=afficheN&cpsidt=24441614. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]
327.Huang Y, Xu Y, Yu C, Li H, Yin X, Wang T, Wang W, Liang Y. Effect of praziquantel prolonged administration on granuloma formation around Schistosoma japonicum eggs in lung of sensitized mice. Parasitol Res [Internet] 2011;109:1453. doi: 10.1007/s00436-011-2485-2. Available from: [cited 2018 Aug 26] [DOI] [PubMed] [Google Scholar]
328.Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension*. Chest [Internet] 2006;130:545–552. doi: 10.1378/chest.130.2.545. Available from: http://chestjournal.chestpubs.org/content/130/2/545. [cited 2012 Apr 18] [DOI] [PubMed] [Google Scholar]
329.Johnson SR, Mehta S, Granton JT. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur Respir J. 2006;28:999–1004. doi: 10.1183/09031936.06.00015206. [DOI] [PubMed] [Google Scholar]
330.de Cleva R, Herman P, D’albuquerque LAC, Pugliese V, Santarem OL, Saad WA. Pre-and postoperative systemic hemodynamic evaluation in patients subjected to esophagogastric devascularization plus splenectomy and distal splenorenal shunt: a comparative study in schistomomal portal hypertension. World J Gastroenterol WJG [Internet] 2007;13:5471. doi: 10.3748/wjg.v13.i41.5471. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4171281/ [cited 2017 Jun 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-1] 1.Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis [Internet] 2006;6:411–425. doi: 10.1016/S1473-3099(06)70521-7. Available from: http://www.sciencedirect.com/science/article/pii/S1473309906705217. [cited 2014 Jan 11] [DOI] [PubMed] [Google Scholar]

[ref-2] 2.Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet [Internet] 2013;380:2163–2196. doi: 10.1016/S0140-6736(12)61729-2. Available from: http://www.sciencedirect.com/science/article/pii/S0140673612617292. [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-3] 3.Colley DG, Bustinduy AL, Secor WE, King CH. Human schistosomiasis. The Lancet [Internet] 2014;383:2253–2264. doi: 10.1016/S0140-6736(13)61949-2. Available from: http://www.sciencedirect.com/science/article/pii/S0140673613619492. [cited 2015 May 3] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-4] 4.Littlewood DTJ, Webster BL. Schistosoma. CRC Press; 2017. Origins and evolutionary radiation of Schistosoma; pp. 9–16. [Google Scholar]

[ref-5] 5.Robotham JL. Schistosomal cor pulmonale: A fluke in the fas lane? Respiration [Internet] 2003;70:569–571. doi: 10.1159/000075199. Available from: https://www.karger.com/Article/FullText/75199. [cited 2018 Aug 24] [DOI] [PubMed] [Google Scholar]

[ref-6] 6.Ross AGP, Bartley PB, Sleigh AC, Olds GR, Li Y, Williams GM, McManus DP. Schistosomiasis. N Engl J Med [Internet] 2002;346:1212–1220. doi: 10.1056/NEJMra012396. Available from: http://www.nejm.org/doi/full/10.1056/NEJMra012396. [cited 2014 Jan 11] [DOI] [PubMed] [Google Scholar]

[ref-7] 7.Bustinduy AL, Parraga IM, Thomas CL, Mungai PL, Mutuku F, Muchiri EM, Kitron U, King CH. Impact of polyparasitic infections on anemia and undernutrition among kenyan children living in a Schistosoma haematobium-endemic area. Am J Trop Med Hyg [Internet] 2013;88:433–440. doi: 10.4269/ajtmh.12-0552. Available from: http://www.ajtmh.org/content/88/3/433. [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-8] 8.Mott KE, Desjeux P, Moncayo A, Ranque P, De Raadt P. Parasitic diseases and urban development. Bull World Health Organ [Internet] 1990;68:691. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2393177/ [cited 2015 May 21] [PMC free article] [PubMed] [Google Scholar]

[ref-9] 9.Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. The Lancet [Internet] 368:1106–1118. doi: 10.1016/S0140-6736(06)69440-3. Available from: http://www.sciencedirect.com/science/article/pii/S0140673606694403 , 23 [cited 2014 Jan 11] [DOI] [PubMed] [Google Scholar]

[ref-10] 10.van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, Habbema JDF, Engels D. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop [Internet] 2003;86:125–139. doi: 10.1016/s0001-706x(03)00029-9. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X03000299 . [DOI] [PubMed] [Google Scholar]

[ref-11] 11.Mutengo MM, Mduluza T, Kelly P, Mwansa JCL, Kwenda G, Musonda P, Chipeta J. Low IL-6, IL-10, and TNF-α and high IL-13 cytokine levels are associated with severe hepatic fibrosis in Schistosoma mansoni chronically exposed individuals. J Parasitol Res [Internet] 2018 doi: 10.1155/2018/9754060. Available from: https://www.hindawi.com/journals/jpr/2018/9754060/ [cited 2018 Aug 23] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-12] 12.Engels D, Chitsulo L, Montresor A, Savioli L. The global epidemiological situation of schistosomiasis and new approaches to control and research. Acta Trop [Internet] 2002;82:139–146. doi: 10.1016/s0001-706x(02)00045-1. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X02000451. [cited 2014 Jan 11] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-13] 13.Alan Fenwick OBE, Fleming FM, Blair L. Control of schistosomiasis. Schistosoma Biol Pathol Control. 2017:440. [Google Scholar]

[ref-14] 14.El-Khoby T, Galal N, Fenwick A, Barakat R, El-Hawey A, Nooman Z, Habib M, Abdel-Wahab F, Gabr NS, Hammam HM, Hussein MH, Mikhail NN, Cline BL, Strickl GT. The epidemiology of schistosomiasis in Egypt: summary findings in nine governorates. Am J Trop Med Hyg [Internet] 2000;62:88–99. doi: 10.4269/ajtmh.2000.62.88. Available from: http://www.ajtmh.org/content/journals/10.4269/ajtmh.2000.62.88. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]

[ref-15] 15.Fenwick A, Savioli L, Engels D, Bergquist NR, Todd MH. Drugs for the control of parasitic diseases: current status and development in schistosomiasis. Trends Parasitol. 2003;19:509–515. doi: 10.1016/j.pt.2003.09.005. [DOI] [PubMed] [Google Scholar]

[ref-16] 16.Doenhoff MJ, Cioli D, Utzinger J. Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis [Internet] 2008;21:659–667. doi: 10.1097/QCO.0b013e328318978f. Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00001432-200812000-00013. [cited 2015 May 21] [DOI] [PubMed] [Google Scholar]

[ref-17] 17.Utzinger J, Xiao S-H, Tanner M, Keiser J. Artemisinins for schistosomiasis and beyond. Curr Opin Investig Drugs Lond Engl 2000. 2007;8:105–116. [PubMed] [Google Scholar]

[ref-18] 18.Cioli D, Pica-Mattoccia L, Basso A, Guidi A. Schistosomiasis control: praziquantel forever? Mol Biochem Parasitol [Internet] 2014;195:23–29. doi: 10.1016/j.molbiopara.2014.06.002. Available from: http://www.sciencedirect.com/science/article/pii/S0166685114000759. [cited 2015 Jul 31] [DOI] [PubMed] [Google Scholar]

[ref-19] 19.Ricciardi A, Ndao M. Still hope for schistosomiasis vaccine. Hum Vaccines Immunother [Internet] 2015;0:00–00. doi: 10.1080/21645515.2015.1059981. Available from: [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-20] 20.Grimes JE, Croll D, Harrison WE, Utzinger J, Freeman MC, Templeton MR. The roles of water, sanitation and hygiene in reducing schistosomiasis: A review. Parasit Vectors. 2015;8 doi: 10.1186/s13071-015-0766-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-21] 21.Utzinger J, N’Goran EK, Caffrey CR, Keiser J. From innovation to application: Social–ecological context, diagnostics, drugs and integrated control of schistosomiasis. Acta Trop [Internet] 2011;120(Supplement 1):S121–S137. doi: 10.1016/j.actatropica.2010.08.020. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X10002330. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]

[ref-22] 22.Rollinson D, Knopp S, Levitz S, Stothard JR, Tchuem Tchuenté L-A, Garba A, Mohammed KA, Schur N, Person B, Colley DG, Utzinger J. Time to set the agenda for schistosomiasis elimination. Acta Trop [Internet] 2013;128:423–440. doi: 10.1016/j.actatropica.2012.04.013. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X1200191X. [cited 2014 Apr 11] [DOI] [PubMed] [Google Scholar]

[ref-23] 23.Abdel-Wahab MF, El-Sahly A, Zakaria S, Strickland GT, El-Kady N, Ahmed L. Changing pattern of schistosomiasis in egypt 1935-79. The Lancet [Internet] 1979;314:242–244. doi: 10.1016/s0140-6736(79)90249-6. Available from: http://www.sciencedirect.com/science/article/pii/S0140673679902496. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]

[ref-24] 24.Abdel-Wahab MF, Yosery A, Narooz S, Esmat G, Hak SE, Nasif S, Strickl GT. Is Schistosoma mansoni replacing Schistosoma haematobium in the fayoum? Am J Trop Med Hyg [Internet] 1993;49:697–700. doi: 10.4269/ajtmh.1993.49.697. Available from: http://www.ajtmh.org/content/journals/10.4269/ajtmh.1993.49.697. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]

[ref-25] 25.Michelson MK, Azziz FA, Gamil FM, Wahid AA, Richards FO, Juranek DD, Habib MA, Spencer HC. Recent trends in the prevalence and distribution of schistosomiasis in the Nile Delta region. Am J Trop Med Hyg [Internet] 1993;49:76–87. doi: 10.4269/ajtmh.1993.49.76. Available from: http://www.ajtmh.org/content/journals/10.4269/ajtmh.1993.49.76. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]

[ref-26] 26.Talaat M, El-Ayyat A, Sayed HA, Miller FD. Emergence of Schistosoma mansoni infection in upper Egypt: the Giza governorate. Am J Trop Med Hyg [Internet] 1999;60:822–826. doi: 10.4269/ajtmh.1999.60.822. Available from: https://www.ajtmh.org/content/journals/10.4269/ajtmh.1999.60.822. [cited 2018 Sep 4] [DOI] [PubMed] [Google Scholar]

[ref-27] 27.Ross AG, Li Y, Williams GM, Jiang Z, McManus DP. Dam worms. Biol Lond Engl. 2001;48:121–124. [PubMed] [Google Scholar]

[ref-28] 28.Li YS, Sleigh AC, Ross AG, Williams GM, Tanner M, McManus DP. Epidemiology of Schistosoma japonicum in China: morbidity and strategies for control in the Dongting Lake region. Int J Parasitol. 2000;30:273–281. doi: 10.1016/s0020-7519(99)00201-5. [DOI] [PubMed] [Google Scholar]

[ref-29] 29.McManus DP, Gray DJ, Li Y, Feng Z, Williams GM, Stewart D, Rey-Ladino J, Ross AG. Schistosomiasis in the People’s Republic of China: the era of the Three Gorges Dam. Clin Microbiol Rev. 2010;23:442–466. doi: 10.1128/CMR.00044-09. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-30] 30.McManus DP, Gray DJ, Ross AG, Williams GM, He H-B, Li Y-S. Schistosomiasis research in the dongting lake region and its impact on local and national treatment and control in China. PLoS Negl Trop Dis. 2011;5:e1053. doi: 10.1371/journal.pntd.0001053. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-31] 31.Schistosomiasis: number of people receiving preventive chemotherapy in 2012. Relevé Épidémiologique Hebd Sect Hygiène Secrétariat Société Nations Wkly Epidemiol Rec Health Sect Secr Leag Nations. 2014;89:21–28. [PubMed] [Google Scholar]

[ref-32] 32.Deelder AM, Miller RL, Jonge ND, Krijger FW. Detection of schistosome antigen in mummies. The Lancet [Internet] 1990;335:724–725. doi: 10.1016/0140-6736(90)90838-v. Available from: https://www.thelancet.com/journals/lancet/article/PII0140-6736(90)90838-V/abstract. [cited 2018 Aug 27] [DOI] [PubMed] [Google Scholar]

[ref-33] 33.Miller RL, Armelagos GJ, Ikram S, De Jonge N, Krijger FW, Deelder AM, et al. Palaeoepidemiology of Schistosoma infection in mummies. BMJ [Internet] 1992;304:555–556. doi: 10.1136/bmj.304.6826.555. Available from: http://www.bmj.com/content/bmj/304/6826/555.full.pdf. [cited 2015 Jun 13] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-34] 34.Bella SD, Riccardi N, Giacobbe DR, Luzzati R. History of schistosomiasis (bilharziasis) in humans: from Egyptian medical papyri to molecular biology on mummies. Pathog Glob Health [Internet] 2018;0:1–6. doi: 10.1080/20477724.2018.1495357. Available from: [cited 2018 Aug 27] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-35] 35.Eltawil KM, Plassmann M. Theodor maximillian Bilharz (1825-1862): the discoverer of schistosomiasis. Int J Parasitol Res. 2011;3:17. [Google Scholar]

[ref-36] 36.Jamieson BGM. Schistosoma: Biology, pathology and control. CRC Press; 2017. [Google Scholar]

[ref-37] 37.Gobert GN, Schulte L, KJones M. Tegument and external features of Schistosoma (with particular reference to ultrastructure) Schistosoma Biol Pathol Control. 2017;213 [Google Scholar]

[ref-38] 38.Barrett J. Forty years of helminth biochemistry. Parasitology [Internet] 2009;136:1633–1642. doi: 10.1017/S003118200900568X. Available from: http://journals.cambridge.org/article_S003118200900568X. [cited 2015 May 20] [DOI] [PubMed] [Google Scholar]

[ref-39] 39.Huang SC-C, Freitas TC, Amiel E, Everts B, Pearce EL, Lok JB, Pearce EJ. Fatty acid oxidation is essential for egg production by the parasitic flatworm Schistosoma mansoni. PLoS Pathog [Internet] 2012;8:e1002996. doi: 10.1371/journal.ppat.1002996. Available from: [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-40] 40.Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE. Helminth parasites –masters of regulation. Immunol Rev [Internet] 2004;201:89–116. doi: 10.1111/j.0105-2896.2004.00191.x. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.0105-2896.2004.00191.x. [cited 2018 Aug 28] [DOI] [PubMed] [Google Scholar]

[ref-41] 41.Allen JE, Maizels RM. Diversity and dialogue in immunity to helminths. Nat Rev Immunol [Internet] 2011;11:375–388. doi: 10.1038/nri2992. Available from: http://www.nature.com/nri/journal/v11/n6/full/nri2992.html. [cited 2017 Jun 12] [DOI] [PubMed] [Google Scholar]

[ref-42] 42.Schmid-Hempel P. Immune defence, parasite evasion strategies and their relevance for ‘macroscopic phenomena’ such as virulence. Philos Trans R Soc Lond B Biol Sci [Internet] 2009;364:85–98. doi: 10.1098/rstb.2008.0157. Available from: http://rstb.royalsocietypublishing.org/content/364/1513/85. [cited 2018 Aug 28] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-43] 43.Rollinson D, Webster JP, Webster B, Nyakaana S, Jørgensen A, Stothard JR. Genetic diversity of schistosomes and snails: implications for control. Parasitology [Internet] 2009;136:1801–1811. doi: 10.1017/S0031182009990412. Available from: http://journals.cambridge.org/article_S0031182009990412. [cited 2015 May 20] [DOI] [PubMed] [Google Scholar]

[ref-44] 44.Anderson TJC, LoVerde PT, Le Clec’h W, Chevalier FD. Genetic crosses and linkage mapping in Schistosome parasites. Trends Parasitol [Internet] 2018 doi: 10.1016/j.pt.2018.08.001. Available from: http://www.sciencedirect.com/science/article/pii/S1471492218301533. [cited 2018 Aug 28] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-45] 45.Gower CM, Gouvras AN, Lamberton PHL, Deol A, Shrivastava J, Mutombo PN, Mbuh JV, Norton AJ, Webster BL, Stothard JR, Garba A, Lamine MS, Kariuki C, Lange CN, Mkoji GM, Kabatereine NB, Gabrielli AF, Rudge JW, Fenwick A, Sacko M, Dembelé R, Lwambo NJS, Tchuem Tchuenté L-A, Rollinson D, Webster JP. Population genetic structure of Schistosoma mansoni and Schistosoma haematobium from across six sub-Saharan African countries: implications for epidemiology, evolution and control. Acta Trop [Internet] 2013;128:261–274. doi: 10.1016/j.actatropica.2012.09.014. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X12003336. [cited 2015 May 20] [DOI] [PubMed] [Google Scholar]

[ref-46] 46.Zerlotini A, Aguiar ERGR, Yu F, Xu H, Li Y, Young ND, Gasser RB, Protasio AV, Berriman M, Roos DS, Kissinger JC, Oliveira G. SchistoDB: an updated genome resource for the three key schistosomes of humans. Nucleic Acids Res [Internet] 2012 doi: 10.1093/nar/gks1087. gks1087. Available from: http://nar.oxfordjournals.org/content/early/2012/11/16/nar.gks1087. [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-47] 47.Chen M. Assessment of morbidity due to Schistosoma japonicum infection in China. Infect Dis Poverty [Internet] 2014;3:6. doi: 10.1186/2049-9957-3-6. Available from: https://www.idpjournal.com/content/3/1/6/abstract. [cited 2015 May 20] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-48] 48.Jamieson B, Haas W. Miracidium of Schistosoma. Schistosoma Biol Pathol Control. 2017;77 [Google Scholar]

[ref-49] 49.Chia-Tung Pan S. The fine structure of the miracidium of Schistosoma mansoni. J Invertebr Pathol [Internet] 1980;36:307–372. doi: 10.1016/0022-2011(80)90040-3. Available from: https://www.cabdirect.org/cabdirect/abstract/19800879091. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]

[ref-50] 50.Théron BGA, Yoshino TP. Schistosoma. CRC Press; 2017. Schistosoma sporocysts; pp. 126–156. [Google Scholar]

[ref-51] 51.Kašnỳ M, Haas W, Jamieson BG, Horák P. Cercaria of Schistosoma. Schistosoma Biol Pathol Control. 2017;149 [Google Scholar]

[ref-52] 52.Gryseels B. Schistosomiasis. Infect Dis Clin North Am [Internet] 2012;26:383–397. doi: 10.1016/j.idc.2012.03.004. Available from: http://www.sciencedirect.com/science/article/pii/S089155201200013X. [cited 2015 May 21] [DOI] [PubMed] [Google Scholar]

[ref-53] 53.Graefe G, Hohorst W, Dräger H. Forked tail of the cercaria of Schistosoma mansoni—a rowing device. Nature [Internet] 1967;215:207–208. doi: 10.1038/215207a0. Available from: https://www.nature.com/articles/215207a0. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]

[ref-54] 54.Haas W. Physiological analyses of host-finding behaviour in trematode cercariae: adaptations for transmission success. Parasitology [Internet] 1994;109:S15–S29. doi: 10.1017/s003118200008505x. Available from: https://www.cambridge.org/core/journals/parasitology/article/physiological-analyses-of-hostfinding-behaviour-in-trematode-cercariae-adaptations-for-transmission-success/E3B9752C932E3B29D00D4E1046FF3DCE. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]

[ref-55] 55.Gobert G. Schistosoma: Biology, pathology and control. CRC Press; 2017. Nawaratna.Sujeevi. Schistosomula; pp. 184–212. [Google Scholar]

[ref-56] 56.Wilson RA. The saga of schistosome migration and attrition. Parasitology [Internet] 2009;136:1581–1592. doi: 10.1017/S0031182009005708. Available from: https://www.cambridge.org/core/journals/parasitology/article/saga-of-schistosome-migration-and-attrition/70AC43F6399DC161E22443E0C2D9C545. [cited 2018 Sep 3] [DOI] [PubMed] [Google Scholar]

[ref-57] 57.Gobert GN, Chai M, McManus DP. Biology of the schistosome lung-stage schistosomulum. Parasitology [Internet] 2007;134:453–460. doi: 10.1017/S0031182006001648. Available from: http://journals.cambridge.org/article_S0031182006001648 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-58] 58.Wilson MS, Mentink-Kane MM, Pesce JT, Ramalingam TR, Thompson R, Wynn TA. Immunopathology of schistosomiasis. Immunol Cell Biol [Internet] 2007;85:148–154. doi: 10.1038/sj.icb.7100014. Available from: http://www.nature.com/icb/journal/v85/n2/abs/7100014a.html. [cited 2013 Apr 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-59] 59.Pearce EJ. Priming of the immune response by schistosome eggs. Parasite Immunol [Internet] 2005;27:265–270. doi: 10.1111/j.1365-3024.2005.00765.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3024.2005.00765.x/abstract. [cited 2015 May 21] [DOI] [PubMed] [Google Scholar]

[ref-60] 60.Grzych JM, Pearce E, Cheever A, Caulada ZA, Caspar P, Heiny S, Lewis F, Sher A. Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis mansoni. J Immunol [Internet] 1991;146:1322–1327. Available from: http://www.jimmunol.org/content/146/4/1322. [cited 2015 May 21] [PubMed] [Google Scholar]

[ref-61] 61.Almadi MA, Aljebreen AM, Sanai FM, Marcus V, AlMeghaiseeb ES, Ghosh S. New insights into gastrointestinal and hepatic granulomatous disorders. Nat Rev Gastroenterol Hepatol [Internet] 2011;8:455–466. doi: 10.1038/nrgastro.2011.115. Available from: http://www.nature.com/nrgastro/journal/v8/n8/full/nrgastro.2011.115.html. [cited 2015 Jul 2] [DOI] [PubMed] [Google Scholar]

[ref-62] 62.Hirata, Takushima M, Kage M, Fukuma T. Comparative analysis of hepatic, pulmonary, and intestinal granuloma formation around freshly laid Schistosoma japonicum eggs in mice. Parasitol Res. 1993;79 doi: 10.1007/BF00932188. [DOI] [PubMed] [Google Scholar]

[ref-63] 63.Warren, Boros DL, Hang LM, Mahmoud AA. The Schistosoma japonicum egg granuloma. Am J Pathol. 1975;80 [PMC free article] [PubMed] [Google Scholar]

[ref-64] 64.Peterson WP, Lichtenberg F von. Studies on granuloma formation. IV in vivo antigenicity of schistosome egg antigen in lung tissue. J Immunol [Internet] 1965;95:959–965. Available from: http://www.jimmunol.org/content/95/5/959. [cited 2015 Jun 25] [PubMed] [Google Scholar]

[ref-65] 65.von LF, Je B. Pulmonary cell reactions in natural and acquired host resistance to Schistosoma mansoni. Am J Trop Med Hyg [Internet] 1980;29:1286–1300. doi: 10.4269/ajtmh.1980.29.1286. Available from: http://europepmc.org/abstract/med/7446820. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]

[ref-66] 66.Silveira-Lemos D, Teixeira-Carvalho A, Martins-Filho OA, Oliveira LFA, Costa-Silva MF, Matoso LF, de Souza LJ, Gazzinelli A, Corrêa-Oliveira R. Eosinophil activation status, cytokines and liver fibrosis in Schistosoma mansoni infected patients. Acta Trop [Internet] 2008;108:150–159. doi: 10.1016/j.actatropica.2008.04.006. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X08000892. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]

[ref-67] 67.Wynn TA, Thompson RW, Cheever AW, Mentink-Kane MM. Immunopathogenesis of schistosomiasis. Immunol Rev [Internet] 2004;201:156–167. doi: 10.1111/j.0105-2896.2004.00176.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.0105-2896.2004.00176.x/abstract. [cited 2015 May 21] [DOI] [PubMed] [Google Scholar]

[ref-68] 68.Andrade ZA, Santana TS. Angiogenesis and schistosomiasis. Mem Inst Oswaldo Cruz [Internet] 2010;105:436–439. doi: 10.1590/s0074-02762010000400013. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S0074-02762010000400013&lng=en&nrm=iso&tlng=en. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]

[ref-69] 69.Warren The pathogenesis of “clay-pipe stem cirrhosis” in mice with chronic schistosomiasis mansoni, with a note on the longevity of the schistosomes. Am J Pathol. 1966;49:477–489. [PMC free article] [PubMed] [Google Scholar]

[ref-70] 70.Symmers W. Note on a new form of liver cirrhosis due to the presence of the eggs of Bilharzia haematobia. J Pathol Bacteriol. 1904;9:237–239. [Google Scholar]

[ref-71] 71.Grimaud, Borojevic R, Borojevic R, Borojevic R. Chronic human schistosomiasis mansoni. Pathology of the Disse’s space. Lab Invest. 1977;36 [PubMed] [Google Scholar]

[ref-72] 72.Grimaud, Borojevic R, Borojevic R, Borojevic R. Portal fibrosis: intrahepatic portal vein pathology in chronic human schistosomiasis mansoni. J Submicrosc Cytol. 1986;18:783–793. [PubMed] [Google Scholar]

[ref-73] 73.Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM. Schistosomiasis-associated pulmonary hypertension. Chest. 2010;137:20S–29S. doi: 10.1378/chest.10-0048. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-74] 74.Cheever, Andrade ZA, Andrade ZA, Andrade ZA. Pathological lesions associated with Schistosoma mansoni infection in man. Trans R Soc Trop Med Hyg. 1967;61:626–639. doi: 10.1016/0035-9203(67)90125-3. [DOI] [PubMed] [Google Scholar]

[ref-75] 75.Andrade, Cheever AW, Cheever AW, Cheever AW. Characterization of the murine model of Schistosomal hepatic periportal fibrosis. Int J Exp Pathol. 1993;74:195–202. [PMC free article] [PubMed] [Google Scholar]

[ref-76] 76.Lichtenberg F von. Portal Hypertension and schistosomiasis*. Ann N Y Acad Sci [Internet] 1970;170:100–114. Available from: https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.1970.tb37006.x. [cited 2018 Aug 29] [Google Scholar]

[ref-77] 77.Nel CJC, Honiball PJ, Wyk V, K FA. Portal hypertension in schistosomiasis. S Afr J Surg [Internet] 1974;12:233–9. Available from: https://www.cabdirect.org/cabdirect/abstract/19752901254. [cited 2018 Aug 29] [PubMed] [Google Scholar]

[ref-78] 78.Elbaz T, Esmat G. Hepatic and intestinal schistosomiasis: Review. J Adv Res [Internet] 2013;4:445–452. doi: 10.1016/j.jare.2012.12.001. Available from: http://www.sciencedirect.com/science/article/pii/S2090123212001087. [cited 2018 Aug 29] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-79] 79.Andrade ZA, Baptista AP, Santana TS. Remodeling of hepatic vascular changes after specific chemotherapy of Schistosomal periportal fibrosis. Mem Inst Oswaldo Cruz [Internet] 2006;101:267–272. doi: 10.1590/s0074-02762006000900041. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S0074-02762006000900041&lng=en&nrm=iso&tlng=en. [cited 2018 Aug 26] [DOI] [PubMed] [Google Scholar]

[ref-80] 80.Andrade ZA. Extracellular matrix degradation in parasitic diseases. Braz J Med Biol Res Rev Bras Pesqui Medicas E Biol [Internet] 1994;27:2273–2281. Available from: http://europepmc.org/abstract/med/7787811. [cited 2018 Aug 29] [PubMed] [Google Scholar]

[ref-81] 81.Cleva R, Herman P, Pugliese V, Zilberstein B, Saad W-A, Gama-Rodrigues J-J. Fathal pulmonary hypertension after distal splenorenal shunt in Schistosomal portal hypertension. World J Gastroenterol. 2004;10:1836–1837. doi: 10.3748/wjg.v10.i12.1836. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-82] 82.Andrade ZA, Andrade SG, et al. Pathogenesis of schistosomal pulmonary arteritis. Am J Trop Med Hyg [Internet] 1970;19:305–10. doi: 10.4269/ajtmh.1970.19.305. Available from: http://www.cabdirect.org/abstracts/19702902421.html. [cited 2015 Jul 31] [DOI] [PubMed] [Google Scholar]

[ref-83] 83.Bourée, Piveteau J, Gerbal JL, Halpen G. Pulmonary arterial hypertension due to bilharziasis. Apropos of a case due to Schistosoma haematobium having been cured by praziquantel. Bull Soc Pathol Exot. 1990;83:66–71. [PubMed] [Google Scholar]

[ref-84] 84.Wünschmann, Ribas E, Ribas E, Ribas E. Chronic cor pulmonale due to granulomatous and obliterating pulmonary arteritis caused by schistosomiasis. Zentralbl Allg Pathol. 1989;135:241–247. [PubMed] [Google Scholar]

[ref-85] 85.Ibrahim M, Girgis B. Bilharzial cor pulmonale. A clinico-pathological report of 50 cases. J Trop Med Hyg [Internet] 1960;63:55–8. Available from: https://www.cabdirect.org/cabdirect/abstract/19602901362. [cited 2018 Aug 31] [PubMed] [Google Scholar]

[ref-86] 86.Gelfand M. Cor-pulmonale and cardio-pulmonary schistosomiasis. Trans R Soc Trop Med Hyg [Internet] 1957;51:533–540. doi: 10.1016/0035-9203(57)90043-3. Available from: https://www.surgpath.theclinics.com/article/0035-9203(57)90043-3/abstract. [cited 2018 Aug 31] [DOI] [PubMed] [Google Scholar]

[ref-87] 87.Almeida, Andrade ZA, Andrade ZA, Andrade ZA. Effect of chemotherapy on experimental pulmonary schistosomiasis. Am J Trop Med Hyg. 1983;32:1049–1054. doi: 10.4269/ajtmh.1983.32.1049. [DOI] [PubMed] [Google Scholar]

[ref-88] 88.Sadigursky, Andrade ZA, Andrade ZA, Andrade ZA. Pulmonary changes in Schistosomal cor pulmonale. Am J Trop Med Hyg. 1982;31:779–784. doi: 10.4269/ajtmh.1982.31.779. [DOI] [PubMed] [Google Scholar]

[ref-89] 89.Vidal MR, Barbosa Jr AA, Andrade ZA. Experimental pulmonary schistosomiasis: lack of morphological evidence of modulation in Schistosomal pulmonary granulomas. Rev Inst Med Trop São Paulo [Internet] 1993;35:423–429. doi: 10.1590/s0036-46651993000500007. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S0036-46651993000500007&lng=en&nrm=iso&tlng=pt. [cited 2018 Aug 29] [DOI] [PubMed] [Google Scholar]

[ref-90] 90.Kolosionek E, King J, Rollinson D, Schermuly RT, Grimminger F, Graham BB, Morrell N, Butrous G. Schistosomiasis causes remodeling of pulmonary vessels in the lung in a heterogeneous localized manner: Detailed study. Pulm Circ [Internet] 2013;3:356–362. doi: 10.4103/2045-8932.114764. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757830/ [cited 2013 Dec 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-91] 91.Warren Experimental pulmonary schistosomiasis. Trans R Soc Trop Med Hyg. 1964;58:228–33. doi: 10.1016/0035-9203(64)90034-3. [DOI] [PubMed] [Google Scholar]

[ref-92] 92.Crosby A, Jones FM, Southwood M, Stewart S, Schermuly R, Butrous G, Dunne DW, Morrell NW. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am J Respir Crit Care Med [Internet] 2009;181:279–288. doi: 10.1164/rccm.200903-0355OC. Available from: http://cat.inist.fr/?aModele=afficheN&cpsidt=22362871. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]

[ref-93] 93.Mauad T, Pozzan G, Lanças T, Overbeek MJ, Souza R, Jardim C, Dolhnikoff M, Mello G, Pires-Neto RC, Bernardi F del C, Grünberg K. Immunopathological aspects of schistosomiasis-associated pulmonary arterial hypertension. J Infect [Internet] 2014;68:90–98. doi: 10.1016/j.jinf.2013.08.004. Available from: http://www.sciencedirect.com/science/article/pii/S0163445313002363. [cited 2013 Dec 16] [DOI] [PubMed] [Google Scholar]

[ref-94] 94.Lapa M, Dias B, Jardim C, Fernandes CJC, Dourado PMM, Figueiredo M, Farias A, Tsutsui J, Terra-Filho M, Humbert M, Souza R. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation [Internet] 2009;119:1518–1523. doi: 10.1161/CIRCULATIONAHA.108.803221. Available from: http://circ.ahajournals.org/content/119/11/1518. [cited 2012 Jun 14] [DOI] [PubMed] [Google Scholar]

[ref-95] 95.Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation [Internet] 2004;109:159–165. doi: 10.1161/01.CIR.0000102381.57477.50. Available from: http://circ.ahajournals.org/content/109/2/159. [cited 2014 May 12] [DOI] [PubMed] [Google Scholar]

[ref-96] 96.Rieder F, Kessler SP, West GA, Bhilocha S, De LM, Sadler TM, Gopalan B, Stylianou E, Fiocchi C. Inflammation-induced endothelial-to-mesenchymal transition: A novel mechanism of intestinal fibrosis. Am J Pathol. 2011;179:2660–2673. doi: 10.1016/j.ajpath.2011.07.042. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-97] 97.Good RB, Gilbane AJ, Trinder SL, Denton CP, Coghlan G, Abraham DJ, Holmes AM. Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. Am J Pathol [Internet] 2015;185:1850–1858. doi: 10.1016/j.ajpath.2015.03.019. Available from: http://www.sciencedirect.com/science/article/pii/S0002944015002102 . [DOI] [PubMed] [Google Scholar]

[ref-98] 98.Graham B, Bandeira A, Butrous G, Chabon J, Espinheira L, Tuder R. Significant intrapulmonary Schistosoma egg antigens are not present in schistosomiasis-associated pulmonary hypertension. Pulm Circ [Internet] 2011;1:456. doi: 10.4103/2045-8932.93544. Available from: https://www.pulmonarycirculation.org/text.asp?2011/1/4/456/93544. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-99] 99.Cavalcanti, Tompson G, Tompson G, Barbosa FS. Pulmonary hypertension in schistosomiasis. Br Heart J. 1962;24:363–371. doi: 10.1136/hrt.24.3.363. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-100] 100.Shaw A, Ghareeb AA, Ghareeb AA, Ghareeb AA. The pathogenesis of pulmonary schistosomiasis in Egypt with special reference to Ayerza’s disease. J Pathol Bacteriol. 1938;46:401–424. [Google Scholar]

[ref-101] 101.Jaffe The anatomical pathology and pathogenesis of Bilharziasis mansoni in Venezuela. Trop Bull. 1949;49:269. [Google Scholar]

[ref-102] 102.Magalhaes Filho Pulmonary lesions in mice experimentally infected with Schistosoma mansoni. Am J Trop Med Hyg. 1959;8:527–35. doi: 10.4269/ajtmh.1959.8.527. [DOI] [PubMed] [Google Scholar]

[ref-103] 103.Doss H. Pulmonary circulation and respiratory function: a symposium held at Queen’s College 1956.

[ref-104] 104.Lambertucci JR, Serufo JC, Gerspacher-Lara R, Rayes AA, Teixeira R, Nobre V, Antunes CM. Schistosoma mansoni: assessment of morbidity before and after control. Acta Trop [Internet] 2000;77:101–109. doi: 10.1016/s0001-706x(00)00124-8. Available from: http://www.sciencedirect.com/science/article/pii/S0001706X00001248. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]

[ref-105] 105.de Cleva R, Herman P, Pugliese V, Zilberstein B, Saad WA, Gama-Rodrigues JJ. Fatal pulmonary hypertension after distal splenorenal shunt in Schistosomal portal hypertension. World J Gastroenterol WJG [Internet] 2004;10:1836–1837. doi: 10.3748/wjg.v10.i12.1836. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572282/ [cited 2018 Aug 26] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-106] 106.de Cleva R, Herman P, Pugliese V, Zilberstein B, Saad WA, Rodrigues JJ, Laudanna AA. Prevalence of pulmonary hypertension in patients with hepatosplenic Mansonic schistosomiasis –prospective study. Hepatogastroenterology [Internet] 2002;50:2028–2030. Available from: http://europepmc.org/abstract/med/14696458 . [PubMed] [Google Scholar]

[ref-107] 107.Donovan CL, Marcovitz PA, Punch JD, Bach DS, Brown KA, Lucey MR, Armstrong WF. Two-dimensional and dobutamine stress echocardiography in the preoperative assessment of patients with end-stage liver disease prior to orthotopic liver transplantation. Transplantation [Internet] 1996;61:1180–1188. doi: 10.1097/00007890-199604270-00011. Available from: http://journals.lww.com/transplantjournal/Abstract/1996/04270/TWO_DIMENSIONAL_AND_DOBUTAMINE_STRESS.11.aspx . [DOI] [PubMed] [Google Scholar]

[ref-108] 108.Ali Z, Kosanovic D, Kolosionek E, Schermuly RT, Graham BB, Mathie A, Butrous G. Enhanced inflammatory cell profiles in schistosomiasis-induced pulmonary vascular remodeling. Pulm Circ. 2017;7:244–252. doi: 10.1086/690687. Available from: [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-109] 109.Butrous G. Pulmonary vascular diseases secondary to schistosomiasis. Adv Pulm Hypertens [Internet] 2017;15:144–148. Available from: http://advancesinph.org/doi/abs/10.21693/1933-088X-15.3.144 . [Google Scholar]

[ref-110] 110.Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM. Schistosomiasis-associated pulmonary hypertension: Pulmonary vascular disease: the global perspective. CHEST J [Internet] 2010;137:20S–29S. doi: 10.1378/chest.10-0048. Available from: [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-111] 111.Graham BB, Mentink-Kane MM, El-Haddad H, Purnell S, Zhang L, Zaiman A, Redente EF, Riches DWH, Hassoun PM, Bandeira A, Champion HC, Butrous G, Wynn TA, Tuder RM. Schistosomiasis-induced experimental pulmonary hypertension: Role of interleukin-13 signaling. Am J Pathol [Internet] 2010;177:1549–1561. doi: 10.2353/ajpath.2010.100063. Available from: http://www.sciencedirect.com/science/article/pii/S0002944010602052. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-112] 112.Kolosionek E, Graham BB, Tuder RM, Butrous G. Pulmonary vascular disease associated with parasitic infection—the role of schistosomiasis. Clin Microbiol Infect [Internet] 2011;17:15–24. doi: 10.1111/j.1469-0691.2010.03308.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2010.03308.x/abstract. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-113] 113.Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J [Internet] 2003;22:358–363. doi: 10.1183/09031936.03.00038903. Available from: http://erj.ersjournals.com/content/22/2/358. [cited 2015 Jun 24] [DOI] [PubMed] [Google Scholar]

[ref-114] 114.Hassoun PM, Mouthon L, Barberà JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitl ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX-J, Humbert M. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol [Internet] 2009;54:S10–S19. doi: 10.1016/j.jacc.2009.04.006. Available from: [DOI] [PubMed] [Google Scholar]

[ref-115] 115.Kherbeck N, Tamby MC, Bussone G, Dib H, Perros F, Humbert M, Mouthon L. The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension. Clin Rev Allergy Immunol [Internet] 2013;44:31–38. doi: 10.1007/s12016-011-8265-z. Available from: http://link.springer.com/article/10.1007/s12016-011-8265-z. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]

[ref-116] 116.Meyrick B, Perkett EA, Brigham KL. Inflammation and models of chronic pulmonary hypertension. Am Rev Respir Dis [Internet] 1987;136:765–767. doi: 10.1164/ajrccm/136.3.765. Available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccm/136.3.765. [cited 2014 Apr 19] [DOI] [PubMed] [Google Scholar]

[ref-117] 117.Phillips SM, DiConza JJ, Gold JA, Reid WA. Schistosomiasis in the congenitally athymic (nude) mouse. J Immunol [Internet] 1977;118:594–599. Available from: http://www.jimmunol.org/content/118/2/594. [cited 2017 May 27] [PubMed] [Google Scholar]

[ref-118] 118.Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, Walker C, Budd DC, Pepke-Zaba J, Morrell NW. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation [Internet] 2010;122:920–927. doi: 10.1161/CIRCULATIONAHA.109.933762. Available from: http://circ.ahajournals.org/content/122/9/920. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]

[ref-119] 119.Schlosser K, Taha M, Deng Y, Jiang B, McIntyre LA, Mei SH, Stewart DJ. Lack of elevation in plasma levels of pro-inflammatory cytokines in common rodent models of pulmonary arterial hypertension: questions of construct validity for human patients. Pulm Circ [Internet] 2017 doi: 10.1177/2045893217705878. 2045893217705878. Available from: [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-120] 120.Saunders BM, Britton WJ. Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol [Internet] 2007;85:103–111. doi: 10.1038/sj.icb.7100027. Available from: http://www.nature.com/icb/journal/v85/n2/full/7100027a.html. [cited 2015 Jul 2] [DOI] [PubMed] [Google Scholar]

[ref-121] 121.Chuah C, Jones MK, Burke ML, McManus DP, Gobert GN. Cellular and chemokine-mediated regulation in schistosome-induced hepatic pathology. Trends Parasitol [Internet] 2014;30:141–150. doi: 10.1016/j.pt.2013.12.009. Available from: http://www.sciencedirect.com/science/article/pii/S1471492213002158. [cited 2015 Jul 1] [DOI] [PubMed] [Google Scholar]

[ref-122] 122.Hurst MH, Willingham AL, Lindberg R. Tissue responses in experimental schistosomiasis japonica in the pig: a histopathologic study of different stages of single low- or high-dose infections. Am J Trop Med Hyg [Internet] 2000;62:45–56. doi: 10.4269/ajtmh.2000.62.45. Available from: http://www.ajtmh.org/content/62/1/45. [cited 2015 Jul 1] [DOI] [PubMed] [Google Scholar]

[ref-123] 123.Hurst MH, Willingham AL, Lindberg R. Experimental schistosomiasis japonica in the pig: immunohistology of the hepatic egg granuloma. Parasite Immunol [Internet] 2002;24:151–159. doi: 10.1046/j.1365-3024.2002.00448.x. Available from: http://onlinelibrary.wiley.com/doi/10.1046/j.1365-3024.2002.00448.x/abstract. [cited 2015 Jul 1] [DOI] [PubMed] [Google Scholar]

[ref-124] 124.Burke ML, Jones MK, Gobert GN, Li YS, Ellis MK, McManus DP. Immunopathogenesis of human schistosomiasis. Parasite Immunol [Internet] 2009;31:163–176. doi: 10.1111/j.1365-3024.2009.01098.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3024.2009.01098.x/abstract. [cited 2013 Apr 21] [DOI] [PubMed] [Google Scholar]

[ref-125] 125.Lenzi HL, Romanha W de S, Santos RZ dos, Rosas A, Mota EM, Manso PPA, Caputo LFG, Pelajo-Machado M. Four whole-istic aspects of schistosome granuloma biology: fractal arrangement, internal regulation, autopoietic component and closure. Mem Inst Oswaldo Cruz [Internet] 2006;101:219–231. doi: 10.1590/s0074-02762006000900034. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S0074-02762006000900034&lng=en&nrm=iso&tlng=en. [cited 2015 Jul 2] [DOI] [PubMed] [Google Scholar]

[ref-126] 126.Secor WE. Immunology of human schistosomiasis: off the beaten path. Parasite Immunol [Internet] 2005;27:309–316. doi: 10.1111/j.1365-3024.2005.00778.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3024.2005.00778.x/abstract. [cited 2015 Jul 30] [DOI] [PubMed] [Google Scholar]

[ref-127] 127.Boros D. The role of cytokines in the formation of the schistosome egg granuloma. Immunobiology. 1994;191:441–450. doi: 10.1016/S0171-2985(11)80450-X. [DOI] [PubMed] [Google Scholar]

[ref-128] 128.Chiu B-C, Freeman CM, Stolberg VR, Komuniecki E, Lincoln PM, Kunkel SL, Chensue SW. Cytokine–chemokine networks in experimental mycobacterial and Schistosomal pulmonary granuloma formation. Am J Respir Cell Mol Biol [Internet] 2003;29:106–116. doi: 10.1165/rcmb.2002-0241OC. Available from: http://www.atsjournals.org/doi/abs/10.1165/rcmb.2002-0241OC. [cited 2015 Jul 30] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-129] 129.Kaplan MH, Whitfield JR, Boros DL, Grusby MJ. Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. J Immunol [Internet] 1998;160:1850–1856. Available from: http://www.jimmunol.org/content/160/4/1850. [cited 2015 Jun 25] [PubMed] [Google Scholar]

[ref-130] 130.Reiman R, Thompson R, Feng C, Hari D, Knight R, Cheever A, Rosenberg H, Wynn T. Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity. Infect Immun. 2006;74 doi: 10.1128/IAI.74.3.1471-1479.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-131] 131.Fallon PG, Smith P, Dunne DW. Type 1 and type 2 cytokine-producing mouse CD4+ and CD8+ T cells in acute Schistosoma mansoni infection. Eur J Immunol [Internet] 1998;28:1408–1416. doi: 10.1002/(SICI)1521-4141(199804)28:04<1408::AID-IMMU1408>3.0.CO;2-H. Available from: http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1521-4141(199804)28:04<1408::AID-IMMU1408>3.0.CO;2-H/abstract. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]

[ref-132] 132.Pearce EJ, MacDonald AS. The immunobiology of schistosomiasis. Nat Rev Immunol [Internet] 2002;2:499–511. doi: 10.1038/nri843. Available from: http://www.nature.com/nri/journal/v2/n7/full/nri843.html. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]

[ref-133] 133.Stavitsky AB. Regulation of granulomatous inflammation in experimental models of schistosomiasis. Infect Immun [Internet] 2004;72:1–12. doi: 10.1128/IAI.72.1.1-12.2004. Available from: http://iai.asm.org/content/72/1/1. [cited 2017 May 28] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-134] 134.Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation. 2008;118:1758–1766. doi: 10.1161/CIRCULATIONAHA.107.727289. [DOI] [PubMed] [Google Scholar]

[ref-135] 135.Boros, Pelley RP, Warren KS, Warren KS. Spontaneous modulation of granulomatous hypersensitivity in schistosomiasis mansoni. J Immunol. 1975;114 [PubMed] [Google Scholar]

[ref-136] 136.Wen X, He L, Chi Y, Zhou S, Hoellwarth J, Zhang C, Zhu J, Wu C, Dhesi S, Wang X, Liu F, Su C. Dynamics of Th17 cells and their role in Schistosoma japonicum infection in C57BL/6 mice. PLoS Negl Trop Dis [Internet] 2011;5:e1399. doi: 10.1371/journal.pntd.0001399. Available from: [cited 2015 Jul 30] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-137] 137.Shainheit MG, Lasocki KW, Finger E, Larkin BM, Smith PM, Sharpe AH, Dinarello CA, Rutitzky LI, Stadecker MJ. The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1β. J Immunol [Internet] 2011;187:5328–5335. doi: 10.4049/jimmunol.1101445. Available from: http://www.jimmunol.org/content/187/10/5328. [cited 2015 Jul 30] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-138] 138.Rutitzky L, Lopes da Rosa J, Stadecker M, Stadecker M. Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17. J Immunol. 2005;175 doi: 10.4049/jimmunol.175.6.3920. [DOI] [PubMed] [Google Scholar]

[ref-139] 139.Ji F, Liu Z, Cao J, Li N, Liu Z, Zuo J, Chen Y, Wang X, Sun J. B cell response is required for granuloma formation in the early infection of Schistosoma japonicum. PLoS ONE [Internet] 2008;3:e1724. doi: 10.1371/journal.pone.0001724. Available from: http://dx.plos.org/10.1371/journal.pone.0001724. [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-140] 140.Fairfax KC, Amiel E, King IL, Freitas TC, Mohrs M, Pearce EJ. IL-10R blockade during chronic schistosomiasis mansoni results in the loss of B cells from the liver and the development of severe pulmonary disease. PLoS Pathog [Internet] 2012;8:e1002490. doi: 10.1371/journal.ppat.1002490. Available from: [cited 2012 Jun 14] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-141] 141.Colley, Garcia AA, Lambertucci JR, Parra JC, Katz N, Rocha RS, Gazzinelli G. Immune responses during human schistosomiasis. XII. Differential responsiveness in patients with hepatosplenic disease. Am J Trop Med Hyg. 1986;35:793–802. [PubMed] [Google Scholar]

[ref-142] 142.Tweardy, Osman GS, El Kholy A, Ellner JJ. Abnormalities of immunosuppression in patients with hepatosplenic schistosomiasis mansoni. Trans Assoc Am Physicians. 1983;96:392–400. [PubMed] [Google Scholar]

[ref-143] 143.Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science [Internet] 2003;299:1057–1061. Available from: http://www.sciencemag.org/content/299/5609/1057. [cited 2015 Jul 31] [PubMed] [Google Scholar]

[ref-144] 144.Rumbley CA, Sugaya H, Zekavat SA, Perrin PJ, Phillips SM. Elimination of lymphocytes, but not eosinophils, by Fas-mediated apoptosis in murine schistosomiasis. Am J Trop Med Hyg. 2001;65:442–449. doi: 10.4269/ajtmh.2001.65.442. [DOI] [PubMed] [Google Scholar]

[ref-145] 145.Carneiro-Santos P, Martins-Filho O, Alves-Oliveira LF, Silveira AM, Coura-Filho P, Viana IR, Wilson RA, Correa-Oliveira R. Apoptosis: a mechanism of immunoregulation during human schistosomiasis mansoni. Parasite Immunol. 2000;22:267–277. doi: 10.1046/j.1365-3024.2000.00294.x. [DOI] [PubMed] [Google Scholar]

[ref-146] 146.Lundy SK, Lerman SP, Boros DL. Soluble egg antigen-stimulated T helper lymphocyte apoptosis and evidence for cell death mediated by FasL(+) T and B cells during murine Schistosoma mansoni infection. Infect Immun. 2001;69:271–280. doi: 10.1128/IAI.69.1.271-280.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-147] 147.Lundy SK, Lukacs NW. Chronic schistosome infection leads to modulation of granuloma formation and systemic immune suppression. Front Immunol [Internet] 2013;4 doi: 10.3389/fimmu.2013.00039. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576626/ [cited 2015 May 3] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-148] 148.Wajant H. The Fas signaling pathway: More than a paradigm. Science [Internet] 2002;296:1635–1636. doi: 10.1126/science.1071553. Available from: http://science.sciencemag.org/content/296/5573/1635. [cited 2017 Jun 10] [DOI] [PubMed] [Google Scholar]

[ref-149] 149.Siegel RM, Chan FK-M, Chun HJ, Lenardo MJ. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat Immunol [Internet] 2000;1:469–474. doi: 10.1038/82712. Available from: https://www.nature.com/articles/ni1200_469. [cited 2018 Aug 24] [DOI] [PubMed] [Google Scholar]

[ref-150] 150.Krammer PH. CD95’s deadly mission in the immune system [Internet] Nature. 2000 doi: 10.1038/35037728. Available from: https://www.nature.com/articles/35037728. [cited 2018 Aug 24] [DOI] [PubMed] [Google Scholar]

[ref-151] 151.Salama M, El-Kholy G, El-Haleem SA, Elzamarany E, Freikha MA, Elwan N, El-Masry M, Al-Bacil A, Elhendy A. Serum soluble Fas in patients with Schistosomal cor pulmonale. Respiration [Internet] 2003;70:574–578. doi: 10.1159/000075201. Available from: http://www.karger.com/Article/Abstract/75201. [cited 2017 May 29] [DOI] [PubMed] [Google Scholar]

[ref-152] 152.Kayagaki N, Kawasaki A, Ebata T, Ohmoto H, Ikeda S, Inoue S, Yoshino K, Okumura K, Yagita H. Metalloproteinase-mediated release of human Fas ligand. J Exp Med [Internet] 1995;182:1777–1783. doi: 10.1084/jem.182.6.1777. Available from: http://jem.rupress.org/content/182/6/1777. [cited 2018 Aug 25] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-153] 153.Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med [Internet] 1995;151:1628–1631. doi: 10.1164/ajrccm.151.5.7735624. Available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccm.151.5.7735624 . [DOI] [PubMed] [Google Scholar]

[ref-154] 154.Hajjar DP, Gotto Jr AM. Biological relevance of inflammation and oxidative stress in the pathogenesis of arterial diseases. Am J Pathol [Internet] 2013;182:1474–1481. doi: 10.1016/j.ajpath.2013.01.010. Available from: http://www.sciencedirect.com/science/article/pii/S0002944013000941 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-155] 155.Dinarello CA. Biology of interleukin- 1. FEBS Lett. 1988 [PubMed] [Google Scholar]

[ref-156] 156.Voelkel NF, Tuder RM, Bridges J, Arend WP. Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am J Respir Cell Mol Biol [Internet] 1994;11:664–675. doi: 10.1165/ajrcmb.11.6.7946395. Available from: http://www.atsjournals.org/doi/abs/10.1165/ajrcmb.11.6.7946395 . [DOI] [PubMed] [Google Scholar]

[ref-157] 157.Xu X-Q, Jing Z-C. High-altitude pulmonary hypertension. Eur Respir Rev [Internet] 2009;18:13–17. doi: 10.1183/09059180.00011104. Available from: http://err.ersjournals.com/content/18/111/13. [cited 2012 Jun 15] [DOI] [PubMed] [Google Scholar]

[ref-158] 158.Friedlander RM, Gagliardini V, Rotello RJ, Yuan J. Functional role of interleukin 1β (IL-1β) in IL-1β-converting enzyme-mediated apoptosis. J Exp Med. 1996;184:717–724. doi: 10.1084/jem.184.2.717. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-159] 159.Cracowski J-L, Chabot F, Labarère J, Faure P, Degano B, Schwebel C, Chaouat A, Reynaud-Gaubert M, Cracowski C, Sitbon O, Yaici A, Simonneau G, Humbert M. Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension. Eur Respir J [Internet] 2014;43:915–917. doi: 10.1183/09031936.00151313. Available from: http://erj.ersjournals.com/content/43/3/915. [cited 2017 May 28] [DOI] [PubMed] [Google Scholar]

[ref-160] 160.Verghese MW, McConnell RT, Strickl AB, Gooding RC, Stimpson SA, Yarnall DP, Taylor JD, Furdon PJ. Differential regulation of human monocyte-derived TNF alpha and IL-1β by type IV cAMP-phosphodiesterase (cAMP-PDE) inhibitors. J Pharmacol Exp Ther [Internet] 1995;272:1313–1320. Available from: http://jpet.aspetjournals.org/content/272/3/1313. [cited 2017 May 28] [PubMed] [Google Scholar]

[ref-161] 161.Kaliński P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol [Internet] 1997;159:28–35. Available from: http://www.jimmunol.org/content/159/1/28. [cited 2018 Aug 5] [PubMed] [Google Scholar]

[ref-162] 162.Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science [Internet] 1993;260:547–549. doi: 10.1126/science.8097338. Available from: http://science.sciencemag.org/content/260/5107/547. [cited 2018 Aug 5] [DOI] [PubMed] [Google Scholar]

[ref-163] 163.Wynn TA, Eltoum I, Oswald IP, Cheever AW, Sher A. Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med [Internet] 1994;179:1551–1561. doi: 10.1084/jem.179.5.1551. Available from: http://jem.rupress.org/content/179/5/1551. [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-164] 164.Oswald IP, Caspar P, Jankovic D, Wynn TA, Pearce EJ, Sher A. IL-12 inhibits Th2 cytokine responses induced by eggs of Schistosoma mansoni. J Immunol [Internet] 1994;153:1707–1713. Available from: http://www.jimmunol.org/content/153/4/1707. [cited 2018 Aug 5] [PubMed] [Google Scholar]

[ref-165] 165.Wynn TA, Cheever AW, Jankovic D, Poindexter RW, Caspar P, Lewis FA, Sher A. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature [Internet] 1995;376:594–596. doi: 10.1038/376594a0. Available from: http://www.nature.com/nature/journal/v376/n6541/abs/376594a0.html. [cited 2013 Apr 21] [DOI] [PubMed] [Google Scholar]

[ref-166] 166.Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O’Shea JJ. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev [Internet] 2004;202:139–156. doi: 10.1111/j.0105-2896.2004.00211.x. Available from: http://doi.wiley.com/10.1111/j.0105-2896.2004.00211.x. [cited 2018 Aug 5] [DOI] [PubMed] [Google Scholar]

[ref-167] 167.Cytokine responses to Schistosoma haematobium in a Zimbabwean population: contrasting profiles for IFN-γ, IL-4, IL-5 and IL-10 with age. — BMC Infectious Diseases — Full Text [Internet] doi: 10.1186/1471-2334-7-139. Available from: https://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-7-139. [cited 2018 Sep 3] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-168] 168.El-Kady IM, Lotfy M, Badra G, El-Masry S, Waked I. Interleukin (IL)-4, IL-10, IL-18 and IFN-gamma cytokines pattern in patients with combined hepatitis C virus and Schistosoma mansoni infections. Scand J Immunol. 2005;61:87–91. doi: 10.1111/j.0300-9475.2005.01529.x. [DOI] [PubMed] [Google Scholar]

[ref-169] 169.Andert SE, Griesmacher A, Zuckermann A, Müller MM. Neopterin release from human endothelial cells is triggered by interferon-gamma. Clin Exp Immunol [Internet] 1992;88:555–558. doi: 10.1111/j.1365-2249.1992.tb06486.x. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2249.1992.tb06486.x. [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-170] 170.Schoedon G, Troppmair J, Adolf G, Huber C, Niederwieser A. Interferon-γ enhances biosynthesis of pterins in peripheral blood mononuclear cells by induction of GTP-cyclohydrolase I activity. J Interferon Res [Internet] 1986;6:697–703. doi: 10.1089/jir.1986.6.697. Available from: https://www.liebertpub.com/doi/abs/10.1089/jir.1986.6.697. [cited 2018 Aug 5] [DOI] [PubMed] [Google Scholar]

[ref-171] 171.Gordon S. Alternative activation of macrophages. Nat Rev Immunol [Internet] 2003;3:23–35. doi: 10.1038/nri978. Available from: https://www.nature.com/articles/nri978. [cited 2018 Aug 5] [DOI] [PubMed] [Google Scholar]

[ref-172] 172.Gallegos AM, Heijst JWJ van, Samstein M, Su X, Pamer EG, Glickman MS. A gamma interferon independent mechanism of CD4 T cell mediated control of M. tuberculosis Infection in vivo. PLOS Pathog [Internet] 2011;7:e1002052. doi: 10.1371/journal.ppat.1002052. Available from: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1002052. [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-173] 173.Lombardi A, Cantini G, Piscitelli E, Gelmini S, Francalanci M, Mello T, Ceni E, Varano G, Forti G, Rotondi M, Galli A, Serio M, Luconi M. A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-alpha and interferon-gamma inflammatory effects in human endothelial cells. Arterioscler Thromb Vasc Biol. 2008;28:718–724. doi: 10.1161/ATVBAHA.107.160713. [DOI] [PubMed] [Google Scholar]

[ref-174] 174.Wort SJ, Woods M, Warner TD, Evans TW, Mitchell JA. Cyclooxygenase-2 acts as an endogenous brake on endothelin-1 release by human pulmonary artery smooth muscle cells: Implications for pulmonary hypertension. Mol Pharmacol [Internet] 2002;62:1147–1153. doi: 10.1124/mol.62.5.1147. Available from: http://molpharm.aspetjournals.org/content/62/5/1147. [cited 2018 Sep 3] [DOI] [PubMed] [Google Scholar]

[ref-175] 175.George PM, Oliver E, Dorfmuller P, Dubois OD, Reed DM, Kirkby NS, Mohamed NA, Perros F, Antigny F, Fadel E, Schreiber BE, Holmes AM, Southwood M, Hagan G, Wort SJ, Bartlett N, Morrell NW, Coghlan JG, Humbert M, Zhao L, Mitchell JA. Evidence for the involvement of type I interferon in pulmonary arterial hypertension. Circ Res [Internet] 2014;114:677–688. doi: 10.1161/CIRCRESAHA.114.302221. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006084/ [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-176] 176.Fujita M, Shannon JM, Irvin CG, Fagan KA, Cool C, Augustin A, Mason RJ. Overexpression of tumor necrosis factor-α produces an increase in lung volumes and pulmonary hypertension. Am J Physiol - Lung Cell Mol Physiol [Internet] 2001;280:L39–L49. doi: 10.1152/ajplung.2001.280.1.L39. Available from: http://ajplung.physiology.org/content/280/1/L39. [cited 2017 May 28] [DOI] [PubMed] [Google Scholar]

[ref-177] 177.Hurst LA, Dunmore BJ, Long L, Crosby A, Al-Lamki R, Deighton J, Southwood M, Yang X, Nikolic MZ, Herrera B, Inman GJ, Bradley JR, Rana AA, Upton PD, Morrell NW. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nat Commun [Internet] 2017;8:14079. doi: 10.1038/ncomms14079. Available from: https://www.nature.com/ncomms/2017/170113/ncomms14079/full/ncomms14079.html. [cited 2017 May 28] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-178] 178.Sutendra G, Dromparis P, Bonnet S, Haromy A, McMurtry MS, Bleackley RC, Michelakis ED. Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension. J Mol Med [Internet] 2011;89:771. doi: 10.1007/s00109-011-0762-2. Available from: http://link.springer.com/article/10.1007/s00109-011-0762-2 . [DOI] [PubMed] [Google Scholar]

[ref-179] 179.Jiang H, Harris MB, Rothman P. IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol [Internet] 2000;105:1063–1070. doi: 10.1067/mai.2000.107604. Available from: http://www.jacionline.org/article/S0091-6749(00)70038-8/fulltext. [cited 2017 May 29] [DOI] [PubMed] [Google Scholar]

[ref-180] 180.Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nat Med [Internet] 2006;12:99–106. doi: 10.1038/nm1332. Available from: http://www.nature.com/nm/journal/v12/n1/full/nm1332.html. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]

[ref-181] 181.Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol. 1999;17:701–738. doi: 10.1146/annurev.immunol.17.1.701. [DOI] [PubMed] [Google Scholar]

[ref-182] 182.Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol [Internet] 2008;9:310–318. doi: 10.1038/ni1558. Available from: http://www.nature.com/ni/journal/v9/n3/full/ni1558.html. [cited 2015 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-183] 183.Mowen KA, Glimcher LH. Signaling pathways in Th2 development. Immunol Rev [Internet] 2004;202:203–222. doi: 10.1111/j.0105-2896.2004.00209.x. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.0105-2896.2004.00209.x/abstract. [cited 2015 Aug 5] [DOI] [PubMed] [Google Scholar]

[ref-184] 184.Oh K, Shen T, Le Gros G, Min B. Induction of Th2 type immunity in a mouse system reveals a novel immunoregulatory role of basophils. Blood. 2007;109:2921–2927. doi: 10.1182/blood-2006-07-037739. [DOI] [PubMed] [Google Scholar]

[ref-185] 185.Vazquez MI, Catalan-Dibene J, Zlotnik A. B cells responses and cytokine production are regulated by their immune microenvironment. Cytokine [Internet] 2015;74:318–326. doi: 10.1016/j.cyto.2015.02.007. Available from: http://www.sciencedirect.com/science/article/pii/S1043466615000666. [cited 2015 Aug 6] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-186] 186.Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD. Interleukin-4 and interleukin-13 signaling connections maps. Science. 2003;300:1527–1528. doi: 10.1126/science.1085458. [DOI] [PubMed] [Google Scholar]

[ref-187] 187.Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S. Essential role of Stat6 in IL-4 signalling. Nature [Internet] 1996;380:627–630. doi: 10.1038/380627a0. Available from: http://www.nature.com/nature/journal/v380/n6575/abs/380627a0.html. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]

[ref-188] 188.Paul WE. Interleukin 4: signalling mechanisms and control of T cell differentiation. Ciba Found Symp. 1997;204:208–216. doi: 10.1002/9780470515280.ch14. discussion 216-219. [DOI] [PubMed] [Google Scholar]

[ref-189] 189.Wedemeyer J, Tsai M, Galli SJ. Roles of mast cells and basophils in innate and acquired immunity. Curr Opin Immunol [Internet] 2000;12:624–631. doi: 10.1016/s0952-7915(00)00154-0. Available from: http://www.sciencedirect.com/science/article/pii/S0952791500001540. [cited 2015 Aug 5] [DOI] [PubMed] [Google Scholar]

[ref-190] 190.Luzina IG, Keegan AD, Heller NM, Rook GAW, Shea-Donohue T, Atamas SP. Regulation of inflammation by interleukin-4: a review of “alternatives”. J Leukoc Biol [Internet] 2012;92:753–764. doi: 10.1189/jlb.0412214. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441310/ [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-191] 191.Cheever AW, Williams ME, Wynn TA, Finkelman FD, Seder RA, Cox TM, Hieny S, Caspar P, Sher A. Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis. J Immunol Baltim Md 1950. 1994;153:753–759. [PubMed] [Google Scholar]

[ref-192] 192.Vannella KM, Barron L, Borthwick LA, Kindrachuk KN, Narasimhan PB, Hart KM, Thompson RW, White S, Cheever AW, Ramalingam TR, Wynn TA. Incomplete Deletion of IL-4Rα by LysMCre reveals distinct subsets of M2 macrophages controlling inflammation and fibrosis in chronic schistosomiasis. PLoS Pathog [Internet] 2014;10:e1004372. doi: 10.1371/journal.ppat.1004372. Available from: [cited 2015 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-193] 193.Daley E, Emson C, Guignabert C, Malefyt R de W, Louten J, Kurup VP, Hogaboam C, Taraseviciene-Stewart L, Voelkel NF, Rabinovitch M, Grunig E, Grunig G. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med [Internet] 2008;205:361–372. doi: 10.1084/jem.20071008. Available from: http://jem.rupress.org/content/205/2/361. [cited 2015 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-194] 194.Taraseviciene-Stewart L, Nicolls MR, Kraskauskas D, Scerbavicius R, Burns N, Cool C, Wood K, Parr JE, Boackle SA, Voelkel NF. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med [Internet] 2007;175:1280–1289. doi: 10.1164/rccm.200608-1189OC. Available from: http://www.atsjournals.org/doi/abs/10.1164/rccm.200608-1189OC. [cited 2015 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-195] 195.Yamaji-Kegan K, Su Q, Angelini DJ, Myers AC, Cheadle C, Johns RA. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) increases lung inflammation and activates pulmonary microvascular endothelial cells via an IL-4–dependent mechanism. J Immunol [Internet] 2010;185:5539–5548. doi: 10.4049/jimmunol.0904021. Available from: http://www.jimmunol.org/content/185/9/5539. [cited 2013 Apr 21] [DOI] [PubMed] [Google Scholar]

[ref-196] 196.Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, McKenzie ANJ. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol. 2012;129:191–198.e1–4. doi: 10.1016/j.jaci.2011.09.041. [DOI] [PubMed] [Google Scholar]

[ref-197] 197.Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TKA, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie ANJ. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature [Internet] 2010;464:1367–1370. doi: 10.1038/nature08900. Available from: http://www.nature.com/nature/journal/v464/n7293/full/nature08900.html#ref5. [cited 2015 Aug 6] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-198] 198.Wynn T. Cellular and molecular mechanisms of fibrosis. J Pathol [Internet] 2008;214:199–210. doi: 10.1002/path.2277. Available from: http://onlinelibrary.wiley.com/doi/10.1002/path.2277/abstract. [cited 2015 Aug 7] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-199] 199.Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2–dominated inflammatory response. J Clin Invest [Internet] 1999;104:777. doi: 10.1172/JCI7325. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC408441/ [cited 2015 Aug 7] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-200] 200.Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD. Interleukin-13: Central mediator of allergic asthma. Science [Internet] 1998;282:2258–2261. doi: 10.1126/science.282.5397.2258. Available from: http://www.sciencemag.org/content/282/5397/2258. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]

[ref-201] 201.Zurawski SM, Chomarat P, Djossou O, Bidaud C, McKenzie ANJ, Miossec P, Banchereau J, Zurawski G. The primary binding subunit of the human interleukin-4 receptor is also a component of the interleukin-13 receptor. J Biol Chem [Internet] 1995;270:13869–13878. doi: 10.1074/jbc.270.23.13869. Available from: http://www.jbc.org/content/270/23/13869. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]

[ref-202] 202.Donaldson DD, Whitters MJ, Fitz LJ, Neben TY, Finnerty H, Henderson SL, O’Hara RM, Beier DR, Turner KJ, Wood CR, Collins M. The murine IL-13 receptor α2: Molecular cloning, characterization, and comparison with murine IL-13 receptor α1. J Immunol [Internet] 1998;161:2317–2324. Available from: http://www.jimmunol.org/content/161/5/2317. [cited 2015 Aug 6] [PubMed] [Google Scholar]

[ref-203] 203.Zheng T, Liu W, Oh S-Y, Zhu Z, Hu B, Homer RJ, Cohn L, Grusby MJ, Elias JA. IL-13 receptor α2 selectively inhibits IL-13-induced responses in the murine lung. J Immunol [Internet] 2008;180:522–529. doi: 10.4049/jimmunol.180.1.522. Available from: http://www.jimmunol.org/content/180/1/522. [cited 2015 Aug 6] [DOI] [PubMed] [Google Scholar]

[ref-204] 204.Sironi M, Sciacca FL, Matteucci C, Conni M, Vecchi A, Bernasconi S, Minty A, Caput D, Ferrara P, Colotta F. Regulation of endothelial and mesothelial cell function by interleukin-13: selective induction of vascular cell adhesion molecule-1 and amplification of interleukin-6 production. Blood. 1994;84:1913–1921. [PubMed] [Google Scholar]

[ref-205] 205.Rifas L, Cheng S-L. IL-13 regulates vascular cell adhesion molecule-1 expression in human osteoblasts. J Cell Biochem. 2003;89:213–219. doi: 10.1002/jcb.10531. [DOI] [PubMed] [Google Scholar]

[ref-206] 206.Purwar R, Kraus M, Werfel T, Wittmann M. Modulation of keratinocyte-derived MMP-9 by IL-13: A possible role for the pathogenesis of epidermal inflammation. J Invest Dermatol [Internet] 2007;128:59–66. doi: 10.1038/sj.jid.5700940. Available from: http://www.nature.com/jid/journal/v128/n1/full/5700940a.html. [cited 2015 Aug 19] [DOI] [PubMed] [Google Scholar]

[ref-207] 207.Hecker M, Zasłona Z, Kwapiszewska G, Niess G, Zakrzewicz A, Hergenreider E, Wilhelm J, Marsh LM, Sedding D, Klepetko W, Lohmeyer J, Dimmeler S, Seeger W, Weissmann N, Schermuly RT, Kneidinger N, Eickelberg O, Morty RE. Dysregulation of the IL-13 receptor system. A novel pathomechanism in pulmonary arterial hypertension. Am J Respir Crit Care Med [Internet] 2010;182:805–818. doi: 10.1164/rccm.200909-1367OC. Available from: http://www.atsjournals.org/doi/full/10.1164/rccm.200909-1367OC. [cited 2015 Aug 7] [DOI] [PubMed] [Google Scholar]

[ref-208] 208.Christmann RB, Hayes E, Pendergrass S, Padilla C, Farina G, Affandi AJ, Whitfield ML, Farber HW, Lafyatis R. Interferon and alternative activation of monocyte/macrophages in systemic sclerosis–associated pulmonary arterial hypertension. Arthritis Rheum [Internet] 2011;63:1718–1728. doi: 10.1002/art.30318. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030759/ [cited 2015 Aug 9] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-209] 209.Cho W-K, Lee C-M, Kang M-J, Huang Y, Giordano FJ, Lee PJ, Trow TK, Homer RJ, Sessa WC, Elias JA, Lee CG. IL-13 receptor α2-arginase 2 pathway mediates IL-13-induced pulmonary hypertension. Am J Physiol - Lung Cell Mol Physiol [Internet] 2013;304:L112–L124. doi: 10.1152/ajplung.00101.2012. Available from: http://ajplung.physiology.org/content/304/2/L112. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-210] 210.Kumar R, Mickael C, Chabon J, Gebreab L, Rutebemberwa A, Rodriguez Garcia A, Koyanagi DE, Sanders L, Gandjeva A, Kearns MT, Barthel L, Janssen WJ, Mauad T, Bandeira A, Schmidt E, Tuder RM, Graham BB. The causal role of IL-4 and IL-13 in Schistosoma mansoni pulmonary hypertension. Am J Respir Crit Care Med [Internet] 2015 doi: 10.1164/rccm.201410-1820OC. Available from: http://www.atsjournals.org/doi/abs/10.1164/rccm.201410-1820OC. [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-211] 211.Chabon JJ, Gebreab L, Kumar R, Debella E, Tanaka T, Koyanagi D, Rodriguez Garcia A, Sanders L, Perez M, Tuder RM, Graham BB. Role of vascular endothelial growth factor signaling in Schistosoma-induced experimental pulmonary hypertension. Pulm Circ [Internet] 2014;4:289–299. doi: 10.1086/675992. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070790/ [cited 2015 Apr 3] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-212] 212.Graham BB, Chabon J, Gebreab L, Poole J, Debella E, Davis L, Tanaka T, Sanders L, Dropcho N, Bandeira A, Vandivier RW, Champion HC, Butrous G, Wang X-J, Wynn TA, Tuder RM. Transforming growth factor-β signaling promotes pulmonary hypertension caused by Schistosoma mansoni. Circulation [Internet] 2013;128:1354–1364. doi: 10.1161/CIRCULATIONAHA.113.003072. Available from: http://circ.ahajournals.org/content/128/12/1354. [cited 2013 Dec 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-213] 213.Graham BB, Kumar R. Schistosomiasis and the pulmonary vasculature (2013 Grover Conference series) Pulmonary Circulation [Internet] 2014;4:353–362. doi: 10.1086/675983. Available from: http://www.jstor.org/stable/10.1086/675983 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-214] 214.Kaviratne M, Hesse M, Leusink M, Cheever AW, Davies SJ, McKerrow JH, Wakefield LM, Letterio JJ, Wynn TA. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-β independent. J Immunol [Internet] 2004;173:4020–4029. doi: 10.4049/jimmunol.173.6.4020. Available from: http://www.jimmunol.org/content/173/6/4020. [cited 2015 Aug 9] [DOI] [PubMed] [Google Scholar]

[ref-215] 215.Xu W, Kaneko FT, Zheng S, Comhair SAA, Janocha AJ, Goggans T, Thunnissen FBJM, Farver C, Hazen SL, Jennings C, Dweik RA, Arroliga AC, Erzurum SC. Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J Off Publ Fed Am Soc Exp Biol. 2004;18:1746–1748. doi: 10.1096/fj.04-2317fje. [DOI] [PubMed] [Google Scholar]

[ref-216] 216.Xia Y, Dawson VL, Dawson TM, Snyder SH, Zweier JL. Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci. 1996;93:6770–6774. doi: 10.1073/pnas.93.13.6770. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-217] 217.Tabima DM, Frizzell S, Gladwin MT. Reactive oxygen and nitrogen species in pulmonary hypertension. Free Radic Biol Med [Internet] 2012;52:1970–1986. doi: 10.1016/j.freeradbiomed.2012.02.041. Available from: http://www.sciencedirect.com/science/article/pii/S0891584912001451. [cited 2018 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-218] 218.Durante W, Johnson FK, Johnson RA. Arginase: A critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol [Internet] 2007;34:906–911. doi: 10.1111/j.1440-1681.2007.04638.x. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1440-1681.2007.04638.x. [cited 2018 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-219] 219.Jr SMM. Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol [Internet] 2009;157:922–930. doi: 10.1111/j.1476-5381.2009.00278.x. Available from: https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1476-5381.2009.00278.x. [cited 2018 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-220] 220.Cho W-K. Interleukin-13-mediated mechanisms of pulmonary vascular remodeling. Grantome [Internet] Available from: http://grantome.com/grant/NIH/K08-HL121183-01A1. [cited 2015 Aug 9] [Google Scholar]

[ref-221] 221.Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol [Internet] 2014;6:a016295. doi: 10.1101/cshperspect.a016295. Available from: http://cshperspectives.cshlp.org/content/6/10/a016295. [cited 2015 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-222] 222.Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res [Internet] 2009;10:236–244. doi: 10.1186/1465-9921-10-6. Available from: http://www.biomedcentral.com/content/pdf/1465-9921-10-6.pdf. [cited 2015 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-223] 223.Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci [Internet] 2012;122:143–159. doi: 10.1042/CS20110340. Available from: http://www.clinsci.org/content/122/4/143. [cited 2018 Aug 19] [DOI] [PubMed] [Google Scholar]

[ref-224] 224.Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest [Internet] 2011;121:3375–3383. doi: 10.1172/JCI57158. Available from: http://www.jci.org/articles/view/57158. [cited 2018 Aug 19] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-225] 225.Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol [Internet] 2015;16:448–457. doi: 10.1038/ni.3153. Available from: https://www.nature.com/articles/ni.3153. [cited 2018 Aug 19] [DOI] [PubMed] [Google Scholar]

[ref-226] 226.Diehl S, Chow C-W, Weiss L, Palmetshofer A, Twardzik T, Rounds L, Serfling E, Davis RJ, Anguita J, Rincón M. Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation. J Exp Med [Internet] 2002;196:39–49. doi: 10.1084/jem.20020026. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194007/ [cited 2018 Aug 19] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-227] 227.Rincón M, Anguita J, Nakamura T, Fikrig E, Flavell RA. Interleukin (IL)-6 directs the differentiation of IL-4–producing CD4+ T cells. J Exp Med [Internet] 1997;185:461–470. doi: 10.1084/jem.185.3.461. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196041/ [cited 2018 Aug 19] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-228] 228.Diehl S, Anguita J, Hoffmeyer A, Zapton T, Ihle JN, Fikrig E, Rincón M. Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity [Internet] 2000;13:805–815. doi: 10.1016/s1074-7613(00)00078-9. Available from: https://www.cell.com/immunity/abstract/S1074-7613(00)00078-9. [cited 2018 Aug 19] [DOI] [PubMed] [Google Scholar]

[ref-229] 229.Kobayashi T, Tanaka K, Fujita T, Umezawa H, Amano H, Yoshioka K, Naito Y, Hatano M, Kimura S, Tatsumi K, Kasuya Y. Bidirectional role of IL-6 signal in pathogenesis of lung fibrosis. Respir Res [Internet] 2015;16:99. doi: 10.1186/s12931-015-0261-z. Available from: https://respiratory-research.com/content/16/1/99/abstract. [cited 2015 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-230] 230.Maston LD, Jones DT, Giermakowska W, Resta TC, Ramiro-Diaz J, Howard TA, Jernigan NL, Herbert L, Maurice AA, Gonzalez Bosc LV. Interleukin-6 trans-signaling contributes to chronic hypoxia-induced pulmonary hypertension. Pulm Circ [Internet] 2018;8:204589401878073. doi: 10.1177/2045894018780734. Available from: https://journals.sagepub.com/doi/10.1177/2045894018780734. [cited 2018 Aug 17] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-231] 231.Tamura Y, Phan C, Tu L, Hiress ML, Thuillet R, Jutant E-M, Fadel E, Savale L, Huertas A, Humbert M, Guignabert C. Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. J Clin Invest [Internet] 2018;128:1956–1970. doi: 10.1172/JCI96462. Available from: https://www.jci.org/articles/view/96462. [cited 2018 Aug 5] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-232] 232.Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res [Internet] 2009;104:236–244. doi: 10.1161/CIRCRESAHA.108.182014. Available from: http://circres.ahajournals.org/content/104/2/236. [cited 2015 Aug 20] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-233] 233.Davies RJ, Holmes AM, Deighton J, Long L, Yang X, Barker L, Walker C, Budd DC, Upton PD, Morrell NW. BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol-Lung Cell Mol Physiol [Internet] 2012;302:L604–L615. doi: 10.1152/ajplung.00309.2011. Available from: https://www.physiology.org/doi/full/10.1152/ajplung.00309.2011. [cited 2018 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-234] 234.Hagen M, Fagan K, Steudel W, Carr M, Lane K, Rodman DM, West J. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol-Lung Cell Mol Physiol [Internet] 2007;292:L1473–L1479. doi: 10.1152/ajplung.00197.2006. Available from: https://www.physiology.org/doi/abs/10.1152/ajplung.00197.2006. [cited 2018 Aug 20] [DOI] [PubMed] [Google Scholar]

[ref-235] 235.Miyata M, Sakuma F, Yoshimura A, Ishikawa H, Nishimaki T, Kasukawa R. Pulmonary hypertension in rats, role of lnterleukin-6. Int Arch Allergy Immunol [Internet] 1995;108:287–291. doi: 10.1159/000237166. Available from: http://www.karger.com/doi/10.1159/000237166. [cited 2015 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-236] 236.Price LC, Wort SJ, Perros F, Dorfmüller P, Huertas A, Montani D, Cohen-Kaminsky S, Humbert M. Inflammation in pulmonary arterial hypertension. Chest [Internet] 2012;141:210–221. doi: 10.1378/chest.11-0793. Available from: http://chestjournal.chestpubs.org/content/141/1/210. [cited 2012 Jun 14] [DOI] [PubMed] [Google Scholar]

[ref-237] 237.Matura LA, Ventetuolo CE, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Pinder D, Archer-Chicko C, Bagiella E, Roberts KE, Tracy RP, Hassoun PM, Girgis RE, Kawut SM. Interleukin-6 and tumor necrosis factor-α are associated with quality of life-related symptoms in pulmonary arterial hypertension. Ann Am Thorac Soc. 2015;12:370–375. doi: 10.1513/AnnalsATS.201410-463OC. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-238] 238.Angeli V, Faveeuw C, Delerive P, Fontaine J, Barriera Y, Franchimont N, Staels B, Capron M, Trottein F. Schistosoma mansoni induces the synthesis of IL-6 in pulmonary microvascular endothelial cells: role of IL-6 in the control of lung eosinophilia during infection. Eur J Immunol [Internet]. 2001;31:2751–2761. doi: 10.1002/1521-4141(200109)31:9<2751::aid-immu2751>3.0.co;2-4. Available from: http://onlinelibrary.wiley.com/doi/10.1002/1521-4141(200109)31:9<2751::AID-IMMU2751>3.0.CO;2-4/abstract. [cited 2015 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-239] 239.Graham BB, Chabon J, Kumar R, Kolosionek E, Gebreab L, Debella E, Edwards M, Diener K, Shade T, Bifeng G, Bandeira A, Butrous G, Jones K, Geraci M, Tuder RM. Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension. Am J Respir Cell Mol Biol [Internet] 2013;49:951–959. doi: 10.1165/rcmb.2012-0532OC. Available from: http://www.atsjournals.org/doi/abs/10.1165/rcmb.2012-0532OC#.Uq7DArS3CQA. [cited 2013 Dec 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-240] 240.Ganeshan K, Bryce PJ. Regulatory T cells enhance mast cell production of IL-6 via surface-bound TGFβ. J Immunol Baltim Md 1950 [Internet] 2012;188:594–603. doi: 10.4049/jimmunol.1102389. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253181/ [cited 2018 Aug 22] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-241] 241.Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmüller P, Humbert M, Guignabert C. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation. 2014;129:1586–1597. doi: 10.1161/CIRCULATIONAHA.113.007469. [DOI] [PubMed] [Google Scholar]

[ref-242] 242.Zabini D, Granton E, Hu Y, Miranda MZ, Weichelt U, Breuils Bonnet S, Bonnet S, Morrell NW, Connelly KA, Provencher S, Ghanim B, Klepetko W, Olschewski A, Kapus A, Kuebler WM. Loss of SMAD3 promotes vascular remodeling in pulmonary arterial hypertension via MRTF disinhibition. Am J Respir Crit Care Med [Internet] 2017;197:244–260. doi: 10.1164/rccm.201702-0386OC. Available from: https://www.atsjournals.org/doi/10.1164/rccm.201702-0386OC. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-243] 243.Breitling S, Hui Z, Zabini D, Hu Y, Hoffmann J, Goldenberg NM, Tabuchi A, Buelow R, Dos Santos C, Kuebler WM. The mast cell–B cell axis in lung vascular remodeling and pulmonary hypertension. Am J Physiol-Lung Cell Mol Physiol [Internet] 2017;312:L710–L721. doi: 10.1152/ajplung.00311.2016. Available from: https://www.physiology.org/doi/abs/10.1152/ajplung.00311.2016. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-244] 244.Hashimoto-Kataoka T, Hosen N, Sonobe T, Arita Y, Yasui T, Masaki T, Minami M, Inagaki T, Miyagawa S, Sawa Y, Murakami M, Kumanogoh A, Yamauchi-Takihara K, Okumura M, Kishimoto T, Komuro I, Shirai M, Sakata Y, Nakaoka Y. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci [Internet] 2015;112:e2677–E2686. doi: 10.1073/pnas.1424774112. Available from: http://www.pnas.org/content/112/20/E2677. [cited 2015 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-245] 245.Shi Y, Massagué J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell x[Internet] 2003;113:685–700. doi: 10.1016/s0092-8674(03)00432-x. Available from: http://www.sciencedirect.com/science/article/pii/S009286740300432X. [cited 2015 Aug 17] [DOI] [PubMed] [Google Scholar]

[ref-246] 246.Feng X-H, Derynck R. Specificity and versatility in TGF-β signaling through smads. Annu Rev Cell Dev Biol [Internet] 2005;21:659–693. doi: 10.1146/annurev.cellbio.21.022404.142018. Available from: [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-247] 247.Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther. 2006;8:S3. doi: 10.1186/ar1917. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-248] 248.Zaiman AL, Podowski M, Medicherla S, Gordy K, Xu F, Zhen L, Shimoda LA, Neptune E, Higgins L, Murphy A, Chakravarty S, Protter A, Sehgal PB, Champion HC, Tuder RM. Role of the TGF-β/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med. 2008;177:896–905. doi: 10.1164/rccm.200707-1083OC. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-249] 249.Wilks AF, Harpur AG. Cytokine signal transduction and the JAK family of protein tyrosine kinases. BioEssays [Internet] 1994;16:313–320. doi: 10.1002/bies.950160505. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/bies.950160505. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-250] 250.Guo X, Wang X-F. Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res [Internet] 2009;19:71–88. doi: 10.1038/cr.2008.302. Available from: https://www.nature.com/articles/cr2008302. [cited 2018 Aug 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-251] 251.Doetschman T, Barnett JV, Runyan RB, Camenisch TD, Heimark RL, Granzier HL, Conway SJ, Azhar M. Transforming growth factor beta signaling in adult cardiovascular diseases and repair. Cell Tissue Res [Internet] 2011;347:203–223. doi: 10.1007/s00441-011-1241-3. Available from: http://link.springer.com/article/10.1007/s00441-011-1241-3. [cited 2015 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-252] 252.Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov [Internet] 2012;11:790–811. doi: 10.1038/nrd3810. Available from: http://www.nature.com/nrd/journal/v11/n10/abs/nrd3810.html. [cited 2015 Aug 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-253] 253.Richter A, Yeager ME, Zaiman A, Cool CD, Voelkel NF, Tuder RM. Impaired transforming growth factor-β signaling in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med [Internet] 2004;170:1340–1348. doi: 10.1164/rccm.200311-1602OC. Available from: http://www.atsjournals.org/doi/full/10.1164/rccm.200311-1602OC#.UpEXM-K3CQA. [cited 2013 Nov 23] [DOI] [PubMed] [Google Scholar]

[ref-254] 254.Zakrzewicz A, Kouri FM, Nejman B, Kwapiszewska G, Hecker M, Sandu R, Dony E, Seeger W, Schermuly RT, Eickelberg O, Morty RE. The transforming growth factor-β/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension. Eur Respir J [Internet] 2007;29:1094–1104. doi: 10.1183/09031936.00138206. Available from: http://erj.ersjournals.com/content/29/6/1094. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-255] 255.Yanagisawa K, Osada H, Masuda A, Kondo M, Saito T, Yatabe Y, Takagi K, Takahashi T, Takahashi T. Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells. Oncogene [Internet] 1998;17:1743–1747. doi: 10.1038/sj.onc.1202052. Available from: https://www.nature.com/articles/1202052. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-256] 256.Vaillancourt M, Ruffenach G, Meloche J, Bonnet S. Adaptation and remodelling of the pulmonary circulation in pulmonary hypertension. Can J Cardiol. 2015;31:407–415. doi: 10.1016/j.cjca.2014.10.023. [DOI] [PubMed] [Google Scholar]

[ref-257] 257.Farkas L, Kolb MRJ. A switch in TGF-β signaling explains contradictory findings in pulmonary arterial hypertension. Am J Respir Crit Care Med [Internet] 2017;197:157–159. doi: 10.1164/rccm.201708-1741ED. Available from: https://www.atsjournals.org/doi/full/10.1164/rccm.201708-1741ED. [cited 2018 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-258] 258.Tuder RM, Archer SL, Dorfmüller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol [Internet] 2013;62:D4–D12. doi: 10.1016/j.jacc.2013.10.025. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0735109713058683. [cited 2014 Apr 6] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-259] 259.Vlugt LEPM van der, Labuda LA, Ozir-Fazalalikhan A, Lievers E, Gloudemans AK, Liu K-Y, Barr TA, Sparwasser T, Boon L, Ngoa UA, Feugap EN, Adegnika AA, Kremsner PG, Gray D, Yazdanbakhsh M, Smits HH. Schistosomes induce regulatory features in human and mouse CD1dhi B cells: Inhibition of allergic inflammation by IL-10 and regulatory T cells. PLOS ONE [Internet] 2012;7:e30883. doi: 10.1371/journal.pone.0030883. Available from: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030883. [cited 2018 Aug 23] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-260] 260.Hesse M, Piccirillo CA, Belkaid Y, Prufer J, Mentink-Kane M, Leusink M, Cheever AW, Shevach EM, Wynn TA. The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J Immunol Baltim Md 1950. 2004;172:3157–3166. doi: 10.4049/jimmunol.172.5.3157. [DOI] [PubMed] [Google Scholar]

[ref-261] 261.Hoffmann KF, Cheever AW, Wynn TA. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J Immunol Baltim Md 1950. 2000;164:6406–6416. doi: 10.4049/jimmunol.164.12.6406. [DOI] [PubMed] [Google Scholar]

[ref-262] 262.Ito T, Okada T, Miyashita H, Nomoto T, Nonaka-Sarukawa M, Uchibori R, Maeda Y, Urabe M, Mizukami H, Kume A, et al. Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats. Circ Res [Internet] 2007;101:734–741. doi: 10.1161/CIRCRESAHA.107.153023. Available from: http://circres.ahajournals.org/content/101/7/734.short. [cited 2015 Aug 21] [DOI] [PubMed] [Google Scholar]

[ref-263] 263.Vergadi E, Chang MS, Lee C, Liang OD, Liu X, Fernandez-Gonzalez A, Mitsialis SA, Kourembanas S. Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. Circulation [Internet] 2011;123:1986–1995. doi: 10.1161/CIRCULATIONAHA.110.978627. Available from: http://circ.ahajournals.org/content/123/18/1986. [cited 2015 Aug 20] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-264] 264.Groth A, Vrugt B, Brock M, Speich R, Ulrich S, Huber LC. Inflammatory cytokines in pulmonary hypertension. Respir Res [Internet] 2014;15:47. doi: 10.1186/1465-9921-15-47. Available from: https://respiratory-research.com/content/15/1/47/abstract. [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-265] 265.Sabin EA, Kopf MA, Pearce EJ. Schistosoma mansoni egg-induced early IL-4 production is dependent upon IL-5 and eosinophils. J Exp Med. 1996;184:1871–1878. doi: 10.1084/jem.184.5.1871. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-266] 266.Paiva LA, C, Bandeira-Melo C, Bozza PT, El-Cheikh MC, Silva PM, Borojevic R, Perez SAC. Hepatic myofibroblasts derived from Schistosoma mansoni-infected mice are a source of IL-5 and eotaxin: controls of eosinophil populations in vitro. Parasit Vectors [Internet] 2015;8:577. doi: 10.1186/s13071-015-1197-3. Available from: [cited 2018 Aug 23] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-267] 267.Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF, Cheever AW, Young DA, Collins M, Grusby MJ, Wynn TA. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest [Internet] 2006;116:2044–2055. doi: 10.1172/JCI27727. Available from: https://www.jci.org/articles/view/27727. [cited 2018 Aug 23] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-268] 268.Nady S, Shata MTM, Mohey MA, El-Shorbagy A. Protective role of IL-22 against Schistosoma mansoni soluble egg antigen-induced granuloma in vitro. Parasite Immunol [Internet] 2017;39:e12392. doi: 10.1111/pim.12392. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/pim.12392. [cited 2018 Aug 23] [DOI] [PubMed] [Google Scholar]

[ref-269] 269.Ezz A, Gmail I, Salem F, Salama R, Nady S. Anti-IL-17 markedly inhibited the in vitro granuloma induced by Schistosoma mansoni soluble egg antigen. Int J Med Dev Ctries [Internet] 2018;38 Available from: https://www.ejmanager.com/fulltextpdf.php?mno=291092. [cited 2018 Aug 23] [Google Scholar]

[ref-270] 270.Maston LD, Jones DT, Giermakowska W, Howard TA, Cannon JL, Wang W, Wei Y, Xuan W, Resta TC, Bosc LVG. Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension. Am J Physiol - Lung Cell Mol Physiol [Internet] 2017;312:L609–L624. doi: 10.1152/ajplung.00531.2016. Available from: http://ajplung.physiology.org/content/312/5/L609. [cited 2017 Jun 11] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-271] 271.Hautefort A, Girerd B, Montani D, Cohen-Kaminsky S, Price L, Lambrecht BN, Humbert M, Perros F. T-Helper 17 cell polarization in pulmonary arterial hypertension. Chest [Internet] 2015;147:1610–1620. doi: 10.1378/chest.14-1678. Available from: http://www.sciencedirect.com/science/article/pii/S0012369215372172 . [DOI] [PubMed] [Google Scholar]

[ref-272] 272.Angelini DJ, Su Q, Yamaji-Kegan K, Fan C, Skinner JT, Poloczek A, El-Haddad H, Cheadle C, Johns RA. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling. Respir Res [Internet] 2013;14:1. doi: 10.1186/1465-9921-14-1. Available from: https://respiratory-research.com/content/14/1/1/abstract. [cited 2013 Apr 15] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-273] 273.Yamaji-Kegan K, Takimoto E, Zhang A, Weiner NC, Meuchel LW, Berger AE, Cheadle C, Johns RA. Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. Am J Physiol - Lung Cell Mol Physiol [Internet] 2014;306:L1090–L1103. doi: 10.1152/ajplung.00279.2013. Available from: http://ajplung.physiology.org/content/306/12/L1090. [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-274] 274.Pesce JT, Ramalingam TR, Wilson MS, Mentink-Kane MM, Thompson RW, Cheever AW, Urban JF, Wynn TA. Retnla (Relmα/Fizz1) suppresses helminth-induced Th2-type immunity. PLoS Pathog [Internet] 2009;5 doi: 10.1371/journal.ppat.1000393. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663845/ [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-275] 275.Wagner KF, Hellberg A-K, Balenger S, Depping R, Dodd OJ, Johns RA, Li D. Hypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha. Am J Respir Cell Mol Biol. 2004;31:276–282. doi: 10.1165/rcmb.2003-0319OC. [DOI] [PubMed] [Google Scholar]

[ref-276] 276.Butrous G. Human immunodeficiency virus–associated pulmonary arterial hypertension considerations for pulmonary vascular diseases in the developing world. Circulation [Internet] 2015;131:1361–1370. doi: 10.1161/CIRCULATIONAHA.114.006978. Available from: http://circ.ahajournals.org/content/131/15/1361. [cited 2015 Apr 14] [DOI] [PubMed] [Google Scholar]

[ref-277] 277.Mbabazi PS, Andan O, Fitzgerald DW, Chitsulo L, Engels D, Downs JA. Examining the relationship between urogenital schistosomiasis and HIV infection. PLoS Negl Trop Dis [Internet] 2011;5:e1396. doi: 10.1371/journal.pntd.0001396. Available from: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0001396. [cited 2018 Sep 3] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-278] 278.Downs JA, et al. HIV and schistosomiasis: studies in Tanzania [Internet] 2016 Available from: https://openaccess.leidenuniv.nl/handle/1887/39785 . [Google Scholar]

[ref-279] 279.Downs JA, Dam GJ van, Changalucha JM, Corstjens PLAM, Peck RN, Dood CJ de, Bang H, Andreasen A, Kalluvya SE, Lieshout L van, Johnson WD, Fitzgerald DW. Association of schistosomiasis and HIV Infection in Tanzania. Am J Trop Med Hyg [Internet] 2012;87:868–873. doi: 10.4269/ajtmh.2012.12-0395. Available from: http://www.ajtmh.org/content/87/5/868. [cited 2015 May 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-280] 280.Colombe S, Machemba R, Mtenga B, Lutonja P, Kalluvya SE, Dood CJ de, Hoekstra PT, Dam GJ van, Corstjens PLAM, Urassa M, Changalucha JM, Todd J, Downs JA. Impact of schistosome infection on long-term HIV/AIDS outcomes. PLoS Negl Trop Dis [Internet] 2018;12:e0006613. doi: 10.1371/journal.pntd.0006613. Available from: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006613. [cited 2018 Sep 4] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-281] 281.Kallestrup P, Zinyama R, Gomo E, Butterworth AE, Mudenge B, Dam GJ van, Gerstoft J, Erikstrup C, Ullum H. Schistosomiasis and HIV-1 infection in rural Zimbabwe: Effect of treatment of schistosomiasis on CD4 cell count and plasma HIV-1 RNA load. J Infect Dis [Internet] 2005;192:1956–1961. doi: 10.1086/497696. Available from: http://jid.oxfordjournals.org/content/192/11/1956. [cited 2014 May 19] [DOI] [PubMed] [Google Scholar]

[ref-282] 282.Parikh R, Scherzer R, Nitta E, MacGregor J, Leone A, Deeks S, Martin J, Donovan C, Morelli J, Ganz P, Hsue P. Asymmetric dimethylarginine levels are associated with pulmonary arterial hypertension in HIV-infected individuals. J Am Coll Cardiol [Internet] 2012;59:e1614–E1614. doi: 10.1016/S0735-1097(12)61615-5. Available from: [cited 2014 Sep 28] [DOI] [Google Scholar]

[ref-283] 283.Parikh RV, Scherzer R, Nitta EM, Leone A, Hur S, Mistry V, Macgregor JS, Martin JN, Deeks SG, Ganz P, Hsue PY. Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection. AIDS [Internet] 2014;28:511–519. doi: 10.1097/QAD.0000000000000124. Available from: http://journals.lww.com/aidsonline/Abstract/2014/02200/Increased_levels_of_asymmetric_dimethylarginine.7.aspx. [cited 2014 Apr 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-284] 284.Cooke JP. Asymmetrical dimethylarginine the über marker? Circulation [Internet] 2004;109:1813–1818. doi: 10.1161/01.CIR.0000126823.07732.D5. Available from: http://circ.ahajournals.org/content/109/15/1813. [cited 2014 May 21] [DOI] [PubMed] [Google Scholar]

[ref-285] 285.Yu Y-RA, Mao L, Piantadosi CA, Gunn MD. CCR2 deficiency, dysregulation of notch signaling, and spontaneous pulmonary arterial hypertension. Am J Respir Cell Mol Biol [Internet] 2013;48:647–654. doi: 10.1165/rcmb.2012-0182OC. Available from: http://www.atsjournals.org/doi/full/10.1165/rcmb.2012-0182OC. [cited 2014 May 12] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-286] 286.Sanchez O, Marcos E, Perros F, Fadel E, Tu L, Humbert M, Dartevelle P, Simonneau G, Adnot S, Eddahibi S. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med [Internet] 2007;176:1041–1047. doi: 10.1164/rccm.200610-1559OC. Available from: http://www.atsjournals.org/doi/abs/10.1164/rccm.200610-1559OC. [cited 2014 May 12] [DOI] [PubMed] [Google Scholar]

[ref-287] 287.Mazigo HD, Nuwaha F, Wilson S, Kinung’hi SM, Morona D, Waihenya R, Heukelbach J, Dunne DW. Epidemiology and interactions of human immunodeficiency virus-1 and Schistosoma mansoni in sub-Saharan Africa. Infect Poverty [Internet] 2013;2:2–11. doi: 10.1186/2049-9957-2-2. Available from: http://www.biomedcentral.com/content/pdf/2049-9957-2-2.pdf. [cited 2014 May 19] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-288] 288.Downs JA, Dupnik KM, Dam GJ van, Urassa M, Lutonja P, Kornelis D, Dood CJ de, Hoekstra P, Kanjala C, Isingo R, Peck RN, Lee MH, Corstjens PLAM, Todd J, Changalucha JM, Jr WDJ, Fitzgerald DW. Effects of schistosomiasis on susceptibility to HIV-1 infection and HIV-1 viral load at HIV-1 seroconversion: A nested case-control study. PLoS Negl Trop Dis [Internet] 2017;11:e0005968. doi: 10.1371/journal.pntd.0005968. Available from: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0005968. [cited 2018 Sep 3] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-289] 289.Efraim L, Peck RN, Kalluvya SE, Kabangila R, Mazigo HD, Mpondo B, Bang H, Todd J, Fitzgerald DW, Downs JA. Schistosomiasis and impaired response to antiretroviral therapy among HIV-infected patients in Tanzania. JAIDS J Acquir Immune Defic Syndr [Internet] 2013;62:e153–e156. doi: 10.1097/QAI.0b013e318282a1a4. Available from: http://journals.lww.com/jaids/Fulltext/2013/04150/Schistosomiasis_and_Impaired_Response_to.22.aspx. [cited 2014 May 19] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-290] 290.Bustinduy A, King C, Scott J, Appleton S, Sousa-Figueiredo JC, Betson M, Stothard JR. HIV and schistosomiasis co-infection in African children. Lancet Infect Dis [Internet] doi: 10.1016/S1473-3099(14)70001-5. Available from: http://www.sciencedirect.com/science/article/pii/S1473309914700015 . [DOI] [PubMed] [Google Scholar]

[ref-291] 291.Belleli V. Les oeufs de Bilharzia haematobia dans les poumons. Unione Á Med ÁEgiz Á1. 1885:22–23. [Google Scholar]

[ref-292] 292.Shaw AFB, Ghareeb AA. The pathogenesis of pulmonary schistosomiasis in Egypt with special reference to Ayerza’s disease. J Pathol Bacteriol [Internet] 1938;46:401–424. Available from: http://onlinelibrary.wiley.com/doi/10.1002/path.1700460302/abstract. [cited 2013 Apr 15] [Google Scholar]

[ref-293] 293.Ward T, Butrous G, Fenwick A. The prevalence of pulmonary hypertension in schistosomiasis: A systematic review. PVRI Rev [Internet] 2011;3:12. Available from: https://www.pvrireview.org/article.asp?issn=0974-6013;year=2011;volume=3;issue=1;spage=12;epage=21;aulast=Ward. [cited 2013 Apr 15] [Google Scholar]

[ref-294] 294.Lapa MS, Ferreira EVM, Jardim C, Martins B do C dos S, Arakaki JSO, Souza R. Clinical characteristics of pulmonary hypertension patients in two reference centers in the city of Sao Paulo. Rev Assoc Med Bras [Internet] 2006;52:139–143. doi: 10.1590/s0104-42302006000300012. Available from: http://www.scielo.br/scielo.php?pid=S0104-42302006000300012&script=sci_arttext&tlng=es. [cited 2017 Jan 15] [DOI] [PubMed] [Google Scholar]

[ref-295] 295.Rocha RL, Pedroso ER, Rocha MO, Lambertucci JR, Greco DB, Ferreira CE. Chronic pulmonary form of schistosomiasis mansoni. Clinico-radiologic evaluation. Rev Soc Bras Med Trop [Internet] 1989;23:83–89. doi: 10.1590/s0037-86821990000200004. Available from: http://europepmc.org/abstract/med/2129521. [cited 2017 Jan 15] [DOI] [PubMed] [Google Scholar]

[ref-296] 296.Barbosa MM, Lamounier JA, Oliveira EC, Souza MV, Marques DS, Silva AA, Lambertucci JR. Pulmonary hypertension in schistosomiasis mansoni. Trans R Soc Trop Med Hyg. 1996;90:663–665. doi: 10.1016/s0035-9203(96)90424-1. [DOI] [PubMed] [Google Scholar]

[ref-297] 297.Bottieau E, Clerinx J, De Vega MR, Van den Enden E, Colebunders R, Van Esbroeck M, Vervoort T, Van Gompel A, Van den Ende J. Imported Katayama fever: clinical and biological features at presentation and during treatment. J Infect [Internet] 2006;52:339–345. doi: 10.1016/j.jinf.2005.07.022. Available from: http://www.sciencedirect.com/science/article/pii/S0163445305002203. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]

[ref-298] 298.Meltzer E, Artom G, Marva E, Assous M, Rahav G, Schwartz E. Schistosomiasis among travelers: New aspects of an old disease. Emerg Infect Dis [Internet] 2006;12:1696–1700. doi: 10.3201/eid1211.060340. Available from: http://wwwnc.cdc.gov/eid/article/17/11/06-0340_article.htm. [cited 2015 Jun 25] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-299] 299.Ross AG, Vickers D, Olds GR, Shah SM, McManus DP. Katayama syndrome. Lancet Infect Dis [Internet] 2007;7:218–224. doi: 10.1016/S1473-3099(07)70053-1. Available from: http://www.sciencedirect.com/science/article/pii/S1473309907700531. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]

[ref-300] 300.Ishii A, Tsuji M, Tada I. History of Katayama disease: schistosomiasis japonica in Katayama district, Hiroshima, Japan. Parasitol Int [Internet] 2003;52:313–319. doi: 10.1016/s1383-5769(03)00046-1. Available from: http://www.sciencedirect.com/science/article/pii/S1383576903000461. [cited 2015 May 3] [DOI] [PubMed] [Google Scholar]

[ref-301] 301.Renoult AJ. Notice sur l’hématurie qu’éprouvent les Européens dans la haute Egypt et la Nubie. J Gen Médecine. 1803;17:366–370. [Google Scholar]

[ref-302] 302.Carstens PA. The encyclopaedia of egypt during the reign of the Mehemet Ali Dynasty 1798-1952 - the people, places and events. 2014. [Google Scholar]

[ref-303] 303.Leshem E, Maor Y, Meltzer E, Assous M, Schwartz E. Acute schistosomiasis outbreak: Clinical features and economic impact. Clin Infect Dis [Internet] 2008;47:1499–1506. doi: 10.1086/593191. Available from: http://cid.oxfordjournals.org/content/47/12/1499. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]

[ref-304] 304.Schwartz E, Rozenman J, Perelman M. Pulmonary manifestations of early schistosome infection among nonimmune travelers. Am J Med [Internet] 2000;109:718–722. doi: 10.1016/s0002-9343(00)00619-7. Available from: http://www.sciencedirect.com/science/article/pii/S0002934300006197. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]

[ref-305] 305.Kapoor S. Katayama syndrome in patients with schistosomiasis. Asian Pac J Trop Biomed [Internet] 2014;4:244. doi: 10.1016/S2221-1691(14)60239-2. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868797/ [cited 2015 Jun 25] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-306] 306.Epelboin L, Jauréguiberry S, Estève J-B, Danis M, Komajda M, Bricaire F, Caumes E. Myocarditis during acute schistosomiasis in two travelers. Am J Trop Med Hyg [Internet] 2010;82:365–367. doi: 10.4269/ajtmh.2010.09-0084. Available from: http://www.ajtmh.org/content/82/3/365. [cited 2015 Jun 25] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-307] 307.Meltzer E, Schwartz E. Schistosomiasis: current epidemiology and management in travelers. Curr Infect Dis Rep [Internet] 2013;15:211–215. doi: 10.1007/s11908-013-0329-1. Available from: http://link.springer.com/article/10.1007/s11908-013-0329-1. [cited 2014 Jan 11] [DOI] [PubMed] [Google Scholar]

[ref-308] 308.Ben-Chetrit E, Lachish T, Mørch K, Atias D, Maguire C, Schwartz E. Schistosomiasis in pregnant travelers: a case series. J Travel Med [Internet] 2015;22:94–98. doi: 10.1111/jtm.12165. Available from: http://onlinelibrary.wiley.com/doi/10.1111/jtm.12165/pdf. [cited 2015 Jun 25] [DOI] [PubMed] [Google Scholar]

[ref-309] 309.Hoette S, Figueiredo C, Dias B, Alves-Jr JL, Gavilanes F, Prada LF, Jasinowodolinski D, Morinaga LTK, Jardim C, Fernandes CJC, Souza R. Pulmonary artery enlargement in schistosomiasis associated pulmonary arterial hypertension. BMC Pulm Med [Internet] 2015;15:118. doi: 10.1186/s12890-015-0115-y. Available from: [cited 2017 Jan 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-310] 310.Abo-Salem ES, Ramadan MM. A huge thrombosed pulmonary artery aneurysm without pulmonary hypertension in a patient with hepatosplenic schistosomiasis. Am J Case Rep [Internet] 2015;16:140–145. doi: 10.12659/AJCR.892451. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356186/ [cited 2015 Jul 31] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-311] 311.Santarém OL de A, Cleva R de, Sasaya FM, Assumpção MS de, Furtado MS, Barbato AJG, Herman P. Left ventricular dilation and pulmonary vasodilatation after surgical shunt for treatment of pre-sinusoidal portal hypertension. PLOS ONE [Internet] 2016;11:e0154011. doi: 10.1371/journal.pone.0154011. Available from: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154011. [cited 2017 Jan 16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-312] 312.Gavilanes F, Piloto B, Fernandes CJC. Giant pulmonary artery aneurysm in a patient with schistosomiasis-associated pulmonary arterial hypertension. J Bras Pneumol. 2018;44:167–167. doi: 10.1590/S1806-37562018000000098. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-313] 313.Corrêa R de A, Silva LC dos S, Rezende CJ, Bernardes RC, Prata TA, Silva HL. Pulmonary hypertension and pulmonary artery dissection. J Bras Pneumol [Internet] 2013;39:238–241. doi: 10.1590/S1806-37132013000200016. Available from: http://www.scielo.br/scielo.php?script=sci_abstract&pid=S1806-37132013000200238&lng=en&nrm=iso&tlng=en. [cited 2018 Aug 25] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-314] 314.Guimaraes AC. Situacao atual dos conhecimentos sobre o envolvimento cardiopulmonar na esquistossomose mansonica. Arq Bras Cardiol [Internet] 1982 Available from: http://agris.fao.org/agris-search/search.do;jsessionid=E48F06768A694AEC49D2BE0FAB22A853?request_locale=en&recordID=US201302173481&sourceQuery=&query=&sortField=&sortOrder=&agrovocString=&advQuery=&centerString=&enableField= [cited 2018 Aug 26] [PubMed] [Google Scholar]

[ref-315] 315.Ferreira RCS, Domingues ALC, Bandeira AP, Markman Filho B, Albuqerque Filho ES, Correiade de Araújo ACC, Batista LJB, Markman M, Campelo ARL. Prevalence of pulmonary hypertension in patients with Schistosomal liver fibrosis. Ann Trop Med Parasitol. 2009;103:129–143. doi: 10.1179/136485909X398168. [DOI] [PubMed] [Google Scholar]

[ref-316] 316.dos Santos Fernandes CJC, Jardim CVP, Hovnanian A, Hoette S, Dias BA, Souza S, Humbert M, Souza R. Survival in schistosomiasis - associated pulmonary arterial hypertension. J Am Coll Cardiol [Internet] 2010;56:715–720. doi: 10.1016/j.jacc.2010.03.065. Available from: http://content.onlinejacc.org/cgi/content/abstract/56/9/715. [cited 2012 Jun 14] [DOI] [PubMed] [Google Scholar]

[ref-317] 317.Kinkel H-F, Dittrich S, Bäumer B, Weitzel T. Evaluation of eight serological tests for diagnosis of imported schistosomiasis. Clin Vaccine Immunol [Internet] 2012;19:948–953. doi: 10.1128/CVI.05680-11. Available from: http://cvi.asm.org/content/19/6/948. [cited 2014 Jan 11] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-318] 318.Hovnanian A, Hoette S, Fernandes CJC, Jardim C, Souza R. Schistosomiasis associated pulmonary hypertension. Int J Clin Pract. 2010;64:25–28. doi: 10.1111/j.1742-1241.2009.02234.x. [DOI] [PubMed] [Google Scholar]

[ref-319] 319.Fernandes CJCD, Jardim CV, Hovnanian A, Hoette S, Morinaga LK, Souza R. Schistosomiasis and pulmonary hypertension. Expert Rev Respir Med. 2011;5:675–681. doi: 10.1586/ers.11.58. [DOI] [PubMed] [Google Scholar]

[ref-320] 320.de Amorim Correa R, Moreira MVSC, da Silva Saraiva JM, Mancuzo EV, dos Santos Silva LC, Lambertucci JR. Treatment of schistosomiasis-associated pulmonary hypertension. J Bras Pneumol [Internet] 2011;37:272–276. doi: 10.1590/s1806-37132011000200018. Available from: http://www.scielo.br/pdf/jbpneu/v37n2/en_v37n2a18.pdf. [cited 2013 Apr 25] [DOI] [PubMed] [Google Scholar]

[ref-321] 321.Loureiro R, Mendes A, Bandeira A, Cartaxo H, de Sa D. Circulation. 2004. Oral sildenafil improves functional status and cardiopulmonary hemodynamics in patients with severe pulmonary hypertension secondary to chronic pulmonary schistosomiasis: a cardiac magnetic resonance study; pp. 572–572. [Google Scholar]

[ref-322] 322.Fernandes CJCS, Dias BA, Jardim CVP, Hovnanian A, Hoette S, Morinaga LK, Souza S, Suesada M, Breda AP, Souza R. The role of target therapies in schistosomiasis - associated pulmonary arterial hypertension. Chest [Internet] 2012;141:923–928. doi: 10.1378/chest.11-0483. Available from: http://chestjournal.chestpubs.org/content/141/4/923. [cited 2012 Jun 14] [DOI] [PubMed] [Google Scholar]

[ref-323] 323.Bandeira A, Mendes A, Santos-Filho P, Sa D, Loureiro R. Circulation. 2004. Clinical efficacy of oral sildenafil in severe pulmonary hypertension in patients with chronic pulmonary schistosomiasis; pp. 296–296. [Google Scholar]

[ref-324] 324.Fernandes CJC, Piloto B, Castro M, Oleas FG, Alves JL, Prada LFL, Jardim C, Souza R. Survival of patients with schistosomiasis-associated pulmonary arterial hypertension in the modern management era. Eur Respir J [Internet] 2018;51:1800307. doi: 10.1183/13993003.00307-2018. Available from: https://erj.ersjournals.com/content/51/6/1800307. [cited 2018 Aug 25] [DOI] [PubMed] [Google Scholar]

[ref-325] 325.Salvador-Recatalà V, Greenberg RM. Calcium channels of schistosomes: unresolved questions and unexpected answers. Wiley Interdiscip Rev Membr Transp Signal [Internet] 2012;1:85–93. doi: 10.1002/wmts.19. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278165/ [cited 2018 Aug 31] [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref-326] 326.Crosby A, Jones FM, Kolosionek E, Southwood M, Purvis I, Soon E, Butrous G, Dunne DW, Morrelp NW. Praziquantel reverses pulmonary hypertension and vascular remodeling in murine schistosomiasis. Am J Respir Crit Care Med [Internet] 2011;184:467–473. doi: 10.1164/rccm.201101-0146OC. Available from: http://cat.inist.fr/?aModele=afficheN&cpsidt=24441614. [cited 2013 Apr 15] [DOI] [PubMed] [Google Scholar]

[ref-327] 327.Huang Y, Xu Y, Yu C, Li H, Yin X, Wang T, Wang W, Liang Y. Effect of praziquantel prolonged administration on granuloma formation around Schistosoma japonicum eggs in lung of sensitized mice. Parasitol Res [Internet] 2011;109:1453. doi: 10.1007/s00436-011-2485-2. Available from: [cited 2018 Aug 26] [DOI] [PubMed] [Google Scholar]

[ref-328] 328.Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension*. Chest [Internet] 2006;130:545–552. doi: 10.1378/chest.130.2.545. Available from: http://chestjournal.chestpubs.org/content/130/2/545. [cited 2012 Apr 18] [DOI] [PubMed] [Google Scholar]

[ref-329] 329.Johnson SR, Mehta S, Granton JT. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur Respir J. 2006;28:999–1004. doi: 10.1183/09031936.06.00015206. [DOI] [PubMed] [Google Scholar]

[ref-330] 330.de Cleva R, Herman P, D’albuquerque LAC, Pugliese V, Santarem OL, Saad WA. Pre-and postoperative systemic hemodynamic evaluation in patients subjected to esophagogastric devascularization plus splenectomy and distal splenorenal shunt: a comparative study in schistomomal portal hypertension. World J Gastroenterol WJG [Internet] 2007;13:5471. doi: 10.3748/wjg.v13.i41.5471. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4171281/ [cited 2017 Jun 21] [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Schistosome infection and its effect on pulmonary circulation

Ghazwan Butrous

Abstract

Introduction

Figure 1. A world map showing the geographical distribution of Schistosomiasis with its approximate prevalence.

Discovery of Schistosomiasis

Figure 2. Infographic history of discovery of schistosomiasis from ancient time till the commencement of the 20th century.

The Parasite

The Different Forms of the Parasite and its Life Cycle

Figure 3. Schistosoma life cycle.

Figure 4. Eggs from the main three human Schistosoma parasite, showing the size and the location of the spine (red arrows) which is one of the main species differentiators.

Pathological Effects of Schistosome Infection

Figure 5. Schematic representation showing the development and cellular composition (right panel) of the granuloma around the Schistosoma eggs.

Hepatic Pathology

Lung Pathology

Figure 6. Schistosomiasis induced granuloma in the lung (mouse model 12 weeks after infection with Schistosoma cercaria).

Figure 7. The mouse model of 12 weeks after infection with Schistosoma cercaria, showed that more than two third of the mouse could be infected with eggs and presence of granulomas (left panel).

Immunology and inflammatory role on the pathogenesis of pulmonary hypertension due to schistosomiasis

Figure 8. The upper panel shows a hypothetical diagram of a simplified chronological sequence of the T helper cells after the tissue is exposed to schistosome eggs.

Th-1 proinflammatory mediators

Interleukin-1

Interleukin 12

Interferon-gamma

Tumour necrosis factor

Th-2 proinflammatory mediators

Interleukin 4

Interleukin 13

Figure 9. Diagrammatic representations of IL-4 and IL13 showing the interaction of IL-13 and IL-4.

BOX 1.

BOX 2.

Interleukin 6

Figure 10. Current understanding of the role of IL-6 and its interaction with TGF-β in the pathogenesis of schistosomiasis pulmonary vascular pathology.

Transforming growth factor β

Vascular endothelial growth factor

Interleukin 10

Interleukin 5

Interleukin -21

BOX 3.

Interleukin 17

Resistin-like molecule α

The Role of Co-Infection

The Prevalence of Pulmonary Hypertension Secondary to Schistosomiasis

Figure 11. Number of studies (cumulative) assessing prevalence by year, showing a relative gap in research in pulmonary hypertension due to schistosomiasis from 1982 to 1995 and an increase since 1995 (from 293).

Acute Pulmonary Schistosomiasis (Katayama Syndrome)

The Clinical Presentations of Pulmonary Hypertension Secondary to Schistosomiasis

Figure 12. A chest radiograph of a 52-year old man with pulmonary hypertension due to schistosomiasis.

Figure 13. CT scan of patient with pulmonary hypertension due to schistosomiasis.

Treatment of Schistosomiasis Associated with Pulmonary Arterial Hypertension

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases