Respiratory pharmacology

The review articles in this issue of Current Opinion in Pharmacology cover a broad array of novel experimental therapeutic strategies that we anticipate will illuminate future therapies and improve the treatment of lung disease. A particular theme shared by many of the new agents under investigation is that of the innate host response, with particular attention being paid to the prevention or treatment of inflammation, edema and pathogenic tissue remodelling. Although specific lung diseases were not the primary focus of this series, asthma, acute lung injury and pulmonary fibrosis stand out as candidate disorders for many new emerging experimental therapies. Interestingly, upon reviewing these topics, it becomes clear that many therapies targeting the host response against insult are shared across a spectrum of disorders, thereby providing opportunities to treat multiple disorders with single agents. With this state of the art series comes optimism that novel agents targeting endogenous pathways involved in the innate host response could lead to improved options when treating these problematic disorders.

Firstly, emerging new research on diet and obesity as factors in lung disease is described. This area of research should also promote the discovery of additional pharmacological strategies to manipulate pulmonary injury and inflammation. Shore specifically reviews the intriguing influence of obesity and associated endocrine factors, such as leptin, on airway hyperreactivity in experimental models. She also discusses the current state of clinical research into the link between obesity and asthma, which strongly suggests that treatment of obese asthmatics should include a weight loss program. It is anticipated that further understanding of the mechanistic basis for the relationship between obesity and asthma will lead to additional therapeutic strategies in this susceptible population. To emphasise the importance of dietary regulation in lung disease, Zalewski provides an update on zinc and its critical role in maintaining airway defence against inflammatory challenges. Although zinc supplements are readily available to consumers as ‘cold remedies’, little is known about their efficacy and the mechanism by which they work. In this concise yet comprehensive review, Zalewski highlights substantial evidence demonstrating that zinc deficiency enhances oxidative damage, inflammation and cellular death of the airway epithelium. Clinical evidence underscoring the important role of dietary zinc and its potential ability in deficient patients to augment pathogenesis in asthma and cystic fibrosis is also presented. The author stresses that, although much is known about the basic biological roles of zinc, far less is known about the relevance of zinc homeostasis in human health and disease, particularly that relating to the lung. Furthermore, as zinc supplementation is safe and relatively inexpensive, more consideration should be given to such experimental strategies for the management of patients with diseased airways, particularly those with zinc deficiency. The challenge will be to develop non-invasive techniques that accurately and reproducibly monitor functional zinc levels to guide therapy.

Angiotensin II and peroxisome proliferator-activated receptors (PPARs), highlighted below, might also be connected with diet and obesity. Endogenous small molecules that are involved in the host response to stress are reviewed by several authors in this issue. Brinkmann and Baumruker review sphingosine-1-phosphate, which is known to regulate T cell recruitment, pulmonary vascular development, lung endothelial and epithelial barrier function, airway remodelling and asthma. Caruso, Holgate and Polosa review the current status of the endogenous agent adenosine in chronic obstructive pulmonary disease and asthma. Levels of adenosine and its receptors are increased in several disorders, and in genetically modified mice, in association with inflammation. Thus, the authors argue that targeting of adenosine signalling pathways could help to ameliorate inflammatory sequelae in obstructive lung disease.

Carbon monoxide (CO) as a therapeutic agent? Ryter and Choi summarize the intriguing protective properties of this gas, generated endogenously by heme oxygenase, which could be beneficial in several lung diseases when administered by inhalation. The therapeutic range of CO is impressive. Inhalation of low concentrations of CO protects animals against sepsis as well as from hyperoxia-, ventilator- and ischemia/reperfusion-induced lung injury. CO also inhibits asthmatic responses in antigen-sensitized mice, and can protect against bleomycin-induced pulmonary fibrosis. Reduced production of CO might also contribute to the pathology of chronic obstructive pulmonary disease and emphysema. As a result of substantial preclinical evidence, it is anticipated that human trials will follow that could open new doors for CO as a therapeutic agent.

Cuzzocrea has reviewed the impact of a group of non-steroid nuclear hormone receptors — PPARs — on inflammatory lung disease. PPARs are activated by endogenous lipid metabolites, such as prostaglandins and fatty acids, and regulate endocrine metabolic responses. They are generally anti-inflammatory when occupied by agonists. The author describes the effectiveness of synthetic small-molecule PPAR agonists for the treatment or prevention of acute lung injury, which indicates a role for these receptors (and agonists) in suppressing pulmonary inflammation. The article also reviews work suggesting a role for PPARs in inhibiting acute lung injury, thereby preventing pulmonary fibrosis following bleomycin challenge in mice. As described above, this family of receptors might also be involved in the influence of diet on lung pathophysiology.

Kuba, Imai and Penninger provide a succinct review of the accumulating evidence that angiotensin II is a significant mediator of inflammation in the lung. The role of angiotensin II also extends into the area of obesity and diet through modulation of the renin-angiotensin system. The authors specifically review the role of angiotensin-converting enzyme 2 (ACE2) in limiting angiotensin II levels and lung disease caused by inflammatory stimuli. ACE2 is also a mediator of coronavirus attack on the lung.

Collectively, studies involving sphingosine-1-phosphate, adenosine, PPAR agonists and ACE2 demonstrate innovation and progress toward new treatment strategies for lung disease. Importantly, exploitation of these pathways has also revealed new auxiliary pathways that can be targeted therapeutically. In all cases, the authors contend that initiation or continuation of clinical investigation is required before the full potential of these strategies can be appreciated in humans.

In addition to dietary factors and modulation of endogenous reactive intermediates, normal host function of the airway requires the formation of a protective shield. As such, Kingma and Whitsett provide a state-of-the-art update on two collectin family members: surfactant proteins A and D (SP-A and SP-D). Once thought to act primarily as molecules that lubricate the alveolar region and help maintain anatomical structure, it is now clear that collectins play a much greater role and are able to facilitate pathogen removal through phagocytosis, enhance oxidant production and modulate the inflammatory response. Although not yet fully characterized, the mechanisms by which SP-A and SP-D trigger the innate immune response are becoming clearer, and involve multiple pathways that include, but are not limited to, the Toll receptors. From these observations, a picture emerges that places collectins at the critical interface between pathogen and innate cellular defence. Collective observations suggest that both proteins can either accentuate or dampen the host inflammatory response depending upon the pathogen and the context by which they engage the lung. Although knockout animals suggest that surfactants are a vital component of the host innate response, evidence of functionally abnormal phenotypes remain to be identified in humans. Despite the attractive therapeutic potential of collectin replacement therapy to prevent pulmonary infection and suppress inflammation, the authors once again acknowledge that a more complete understanding of the mechanisms of action of SP-A and SP-D in the lung are needed to exploit their full potential in the treatment of acute and chronic pulmonary disease.

Finally, Bhatt et al. provide a comprehensive review of the current status of conventional therapy and investigational new agents for the treatment of pulmonary fibrosis, a disease that develops from alterations of both the acute and the chronic inflammatory response, culminating in irreversible tissue remodelling. Closing with this article is fitting in that pulmonary fibrosis continues to be one of the most difficult lung diseases to treat, and therefore is deserving of intense investigation to derive new therapy. As the authors indicate, success from conventional therapy is limited, which has undoubtedly fostered intense investigation in several areas ranging from re-evaluation of approved medications and derivation of novel synthetic compounds to development of biological strategies to modulate endogenous pathways that influence tissue injury (early phase) or remodelling (late phase). Complimentary to this report, evidence highlighted by Cuzzocrea (PPAR activation), Ryter and Choi (CO), and Kuba, Imai and Penninger (angiotensin II) indicate that these new agents are also being investigated across the spectrum of this complicated disease.

In closing, we extend our gratitude to the authors for their substantial contributions, both in terms of time and willingness to share their valuable insight, to this issue of Current Opinion in Pharmacology. It is our goal that this series of articles can serve as an effective bridge between promising basic scientific progress and the discovery of novel therapeutic agents that will one day improve the treatment of lung disease.

Biographies

Dale G. Hoyt is Associate Professor of Pharmacology. His research interests are in pulmonary and macrovascular endothelial injury and inflammatory activation.

Daren Knoell is Associate Professor of Pharmacy and Internal Medicine. His research interests are in acute lung injury and experimental therapeutics that prevent or correct common lung disorders.