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. 2012 Oct;167(4):732–740. doi: 10.1111/j.1476-5381.2012.02055.x

Chymase inhibition as a pharmacological target: a role in inflammatory and functional gastrointestinal disorders?

S Heuston 1,2, NP Hyland 1,2
PMCID: PMC3575774  PMID: 22646261

Abstract

Chymase has been extensively studied with respect to its role in the pathophysiology of cardiovascular disease, and is notable for its role in the generation of angiotensin II, a mediator crucial in vascular remodelling. However, in more recent years, an association between chymase and several inflammatory diseases, including gastrointestinal (GI) disorders such as inflammatory bowel diseases (IBD) have been described. Such studies, to date, with respect to IBD at least, are descriptive in the clinical context; nonetheless, preclinical studies implicate chymase in the pathogenesis of gut inflammation. However, studies to elucidate the role of chymase in functional bowel disease are in their infancy, but suggest a plausible role for chymase in contributing to some of the phenotypic changes observed in such disorders, namely increased epithelial permeability. In this short review, we have summarized the current knowledge on the pathophysiological role of chymase and its inhibition with reference to inflammation and tissue injury outside of the GI tract and discussed its potential role in GI disorders. We speculate that chymase may be a novel therapeutic target in the GI tract, and as such, inhibitors of chymase warrant preclinical investigation in GI diseases.

Keywords: chymase, gastrointestinal, permeability, inflammation, mast cell

Introduction

Derived from bone marrow, mast cells (MC) are classically recognized as key cells involved in a number of non-allergic diseases and hypersensitivity (He, 2004). They contain secretory granules, which, upon stimulation, release various cytokines, biogenic amines, proteoglycans and proteases such as, tryptase, carboxypeptidase A and notably, in the context of this review, chymase (Pejler et al., 2010; Scandiuzzi et al., 2010).

In humans MC classification is less complex than that in rodents and is based on their protease content, the latter being predominantly tryptase or chymase, thereby leading to their classification as MCT, those expressing MC tryptase only, and MCTC, a subgroup expressing both tryptase and chymase (Scandiuzzi et al., 2010).

With respect to MC chymase (EC 3.4.21.39), it is a serine protease that possesses chymotrypsin-like cleavage specificity. Pereira et al. (1999) determined the crystal structure of human chymase complexed with the peptide inhibitor, succinyl-Ala-Ala-Pro-Phe-chloromethylketone. Human chymase is synthesized as an inactive prepro-enzyme, which is then converted to the pro-enzyme. The thiol proteinase, dipeptidyl peptidase I is necessary for activation of chymase within the secretory granules (Murakami et al., 1995). When stored in secretory granules of MC, chymase remains enzymatically inactive at pH 5.5; its optimum enzymatic activity being achieved at a pH of 7 to 9 following release into the interstitial tissues (where a pH 7.4 is observed) (Takai et al., 2010) (Figure 1). MC containing chymases reside primarily in the connective tissue and the submucosa (Irani et al., 1986). This chymotrypsin-like serine protease is common to several other species, namely primates, dogs, sheep and hamsters. Humans possess a single α-chymase gene, whereas rats and mice possess not only a single α-chymase gene, mouse mast cell protease-5 (mMCP-5) and rat mast cell protease-5 (rMCP-5), but also up to 14 β-chymase genes (Gallwitz and Hellman, 2006). Moreover, significant species variability has contributed to the controversy over the possible physiological roles for chymase (Miyazaki et al., 2006). Despite such complexity, however, rodent models have been generated with targeted deletions in the phylogenetic homologues to the human α-chymase allowing for extrapolation of preclinical data to human conditions. Identifying the functional homologue to human chymase has been the focus of several studies (Kunori et al., 2002; Hochegger et al., 2005), not all yielding the expected outcome. For example, Kunori et al. (2002), using a molecular phylogenetics approach, demonstrated rMCP-5 and mMCP-5, although homologous to human chymase, exhibited marked differences in substrate specificity conferring elastase-like, rather than chymase activity, and the closest homologues to human chymase in terms of functional properties and tissue localization appear to be murine β-chymase, mMCP-4 and rMCP-1 (Tchougounova et al., 2003; Andersson et al., 2008).

Figure 1.

Figure 1

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Role of chymase in disease pathogenesis. Angiotensin converting enzyme inhibitor-independent angiotensin II synthesis by chymase has been implicated in the structural remodelling associated with cardiovascular disease and can induce activation of TGF-β, a major regulator of tissue fibrosis, and MMP-9 activity (top right panel), thereby collectively contributing to the pathological role of chymase in cardiovascular, fibrotic and inflammatory diseases, including IBD (bottom right panel). Both mast cell tryptase (MCT) and mast cell chymase (MCC) have been implicated in regulating epithelial barrier function in the gastrointestinal tract. Thus, in addition to inhibiting downstream TGF-β and MMP-9 activity, chymase inhibition may enhance epithelial barrier function, which is known to be compromised in inflammatory and functional bowel diseases. (left-hand pictogram).

Chymase inhibition: a validated target in cardiovascular and inflammatory diseases

Chymase-dependent angiotensin (Ang) II formation in cardiovascular disease

Chymase has largely been documented for its involvement in the synthesis of Ang II from Ang I in addition to endothelin-1. Studies to decipher the pathophysiological role of chymase in cardiac disease have gained momentum in recent times, and ACE-independent Ang II synthesis by chymase has been implicated in the structural remodelling associated with cardiovascular disease (Doggrell and Wanstall, 2004; 2005). Evidence suggests Ang II formation may depend to a greater extent on chymase rather than ACE, with one recent study suggesting that up to 75% of Ang II formation is dependent on chymase in human cardiac tissue (Takai et al., 2011). Studies with coronary artery homogenates from human hearts demonstrated that chymostatin had the capacity to reduce Ang II formation in contrast to the ACE inhibitor, captopril (Doggrell and Wanstall, 2004). Therefore, studies have focussed on reducing the availability of the enzyme through the use of the MC stabilizer, tranilast, rather than chymase inhibition per se, in animal models of cardiovascular disease. However, although tranilast proved effective pre-clinically, unfortunately, clinical trials proved unsuccessful (Doggrell and Wanstall, 2004).

Chymase-induced activation of TGF-β and MMP-9: implications in cardiac disease

In addition to its direct enzymatic effects, chymase can also induce activation of TGF-β, a major regulator of tissue fibrosis, as well as MMP-9 (Takai et al., 2010), the latter being involved in extracellular matrix (ECM) turnover with potential to induce organ damage (Takai et al., 2010). Thus, chymase has a crucial role to play in tissue fibrosis and remodelling thereby implicating a role for this protease in regulating homeostatic function (Pejler et al., 2010) and it is in this context that chymase may contribute to abdominal aortic aneurysm (AAA) lesions (Takai et al., 2010). This was substantiated in vitro in vascular tissue from human AAA lesions, in which a significant increase in MMP-9 activity was observed when the lesions were incubated with purified human chymase (Takai et al., 2010). Not surprisingly therefore, mice lacking mMCP-4 had markedly reduced AAA formation in an experimental model of AAAs. The underlying mechanisms by which mMCP-4 contribute to AAA lesions include vascular cell apoptosis, elastase degradation and angiogenesis (Sun et al., 2007).

Atherosclerosis is associated with aortic aneurysm development, and a recent study by Bot et al. (2011) examined the contribution of chymase to atherosclerotic plaque stability in the apolipoprotein mouse model (apoE−/− mice) of human atherosclerosis. Bot et al. had previously demonstrated that perivascular MC play a crucial role in plaque destabilization and progression, and their subsequent findings were the first to demonstrate that chymase inhibition, using the selective chymase inhibitor, RO5066852 (Tables 1 and 2) reduced plaque progression and enhanced plaque stability (Bot et al., 2011). Specifically, oral administration of RO5066852 to apoE−/− mice reduced spontaneous atherosclerosis and plaque progression, changes which corresponded to enhanced plaque stability and diminished frequency and area of intraplaque haemorrhages (Bot et al., 2011). Of note is the reported presence of mMCP-4-containing MC in aortic atherosclerotic plaques, thereby further implicating chymase in plaque formation (Sun et al., 2007). In a related study, using hamsters with elevated cholesterol, chymase secretion contributed to plaque vulnerability and treatment with the MC stabilizer, tranilast enhanced plaque stability presumably through inhibition of chymase release (Guo et al., 2009).

Table 1.

Therapeutic application of chymase inhibitors

Chymase inhibitors Therapeutic potential Reference
SUN-C8257 Atherosclerosis, pulmonary fibrosis, skin disease Doggrell (2008)
SUN13834a Atopic dermatitis Ogata et al. (2011)
BCEAB Cardiac disease Doggrell (2008)
Compound 17 Cardiac or circulatory disease, asthma Doggrell (2008)
NK3201 Cardiac disease Doggrell (2008)
TEI-E548 Cardiac disease Hoshino et al. (2003)
RO5066852 Atherosclerosis Bot et al. (2011)
JNJ-10311795 Anti-inflammatory De Garavilla et al. (2005)
Suc-Val-Pro-PheP (OPh)2 Cardiac adhesions Soga et al. (2004)
Y-40613 Atopic dermatitis Akahoshi et al. (2001)
Imada et al. (2002)
Y-40079b Akahoshi et al. (2001)
TY-51469 Cardiac disease, liver fibrosis, gastrointestinal disease, diabetes Oyamada et al. (2011)
Komeda et al. (2010)
Kakimoto et al. (2010)
Takai et al. (2009)
Chymostatin Glaucoma, chorioretinal, gastrointestinal diseases Doggrell (2008)
Groschwitz et al. (2009)
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a

Currently in phase II clinical trial.

b

Yet to be tested in experimental disease models.

Table 2.

Species in which chymase inhibitors have been validated in preclinical disease models

Chymase inhibitor Substrate specificity Species Reference
SUN-C8257 Chymase, cathepsin G Human, hamster, dog Matsumoto et al. (2003)
Doggrell (2008)
SUN13834a Chymase, cathepsin G Mouse, human Ogata et al. (2011)
BCEAB Chymase Hamster Doggrell (2008)
Compound 17 Chymase Sheep Doggrell (2008)
NK3201 Chymase Hamster Doggrell (2008)
TEI-E548 Chymase Hamster Hoshino et al. (2003)
RO5066852 Chymase Mice Bot et al. (2011)
Suc-Val-Pro-PheP (OPh)2 Chymase Hamster Soga et al. (2004)
JNJ-10311795: RWJ-355871 Cathepsin G, chymase Rats, mice, sheep De Garavilla et al. (2005)
Maryanoff et al. (2010)
Y-40613 Chymase Mice Akahoshi et al. (2001)
Imada et al. (2002)
TY-51469 Chymase Rats, hamster, pigs Komeda et al. (2010)
Kakimoto et al. (2010)
Takai et al. (2009)
Oyamada et al. (2011)
Chymostatin Chymase Rabbit Doggrell (2008)
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In a more acute cardiac process, Oyamada et al. (2011) recently assessed the effects of the chymase inhibitor, TY-51469 on myocardial protection and fibrosis after acute myocardial ischaemia/reperfusion in which chymase inhibition played a crucial role in myocardial protection and was associated with decreased MMP-9 activity. Additionally, myocardial infarct size and neutrophil infiltration were decreased, as was inflammatory gene expression (Oyamada et al., 2011). However, MMP-9 is not the only significant downstream effector molecule activated by chymase, and as already alluded to, chymase can activate TGF-β, which in turn promotes tissue fibrosis. With this in mind, Soga et al. (2004) investigated the role of chymase in cardiac adhesion formation using the chymase specific inhibitor, Suc-Val-Pro-PheP(OPh)2 and assessed cardiac adhesions in a post operative hamster model. Suc-Val-Pro-PheP(OPh)2 was administered into the thoracic cavity surrounding the surgical lesions and was effective in reducing cardiac chymase activity, the density of MC, in addition to suppressing the levels of TGF-β1, resulting in a reduction in postoperative cardiac adhesions (Soga et al., 2004).

Chymase inhibitors: anti-inflammatory properties as a pharmacological mechanism of action

Chymase promotes inflammation, tissue remodelling and matrix destruction by several mechanisms, including the enzymatic activation of TGF-β and MMP-9 (Figure 1). Therefore, chymase inhibition is likely to attenuate both TGF-β and MMP-9 activation, thereby directly influencing tissue inflammation and fibrosis beyond cardiac diseases. Indeed, chymase has been associated with the pathogenesis of inflammatory disorders such as atopic dermatitis (AD) (Ong, 2009), one of the most common chronic inflammatory or allergic skin diseases, and autoimmune arthritis (Magnusson et al., 2009). Moreover, the association of chymase with AD has been strengthened by several genetic studies in which a correlation between an allelic polymorphism in the chymase gene and the incidence of AD has been reported (Mao et al., 1996; Tanaka et al., 1999; Watanabe et al., 2007). Moreover, the results obtained after targeting chymase in pre-clinical animal models of AD have been promising, and the chymase inhibitor, SUN13834 is currently in phase II clinical trials for the treatment of AD (Asubio Pharmaceuticals Inc, 2011; Ogata et al., 2011).

It is widely established that MC are present in increased numbers and have been implicated in airway remodelling associated with asthma (Lazaar et al., 2002). Despite the evidence discussed thus far on the benefits of chymase inhibition, it is noteworthy that a possible protective effect of chymase has been suggested from studies in humans with severe asthma (Balzar et al., 2005), and have been corroborated by studies in mMCP-4-deficient mice, which suggest the absence of chymase may lead to increased tissue inflammation and smooth muscle layer thickening (Waern et al., 2009). In contrast to in vivo studies, in vitro studies on human airway smooth muscle suggest a detrimental effect of chymase and its contribution to airway remodelling (Lazaar et al., 2002), perhaps suggesting that the microenvironment in vivo determines the final outcome in terms of smooth muscle remodelling. Moreover, a single nucleotide polymorphism in CMA1, the MC chymase gene, was found to be associated with childhood asthma (Hossny et al., 2008). The evidence from renal studies similarly suggests a potential dual role for chymase, or MC at least, in glomerulonephritis (Hochegger et al., 2005; Scandiuzzi et al., 2010). Hochegger et al. reported a dramatic increase in glomerular damage in mice deficient in MC, providing evidence of the protective properties of MC (Hochegger et al., 2005). In contrast, Scandiuzzi et al. (2010) investigated the role of MC chymase in experimental antiglomerular basement membrane-induced glomerulonephritis. Here they demonstrated that mMCP-4-deficient mice developed less severe renal damage. Contrary to the previous study these results highlight the possible detrimental role of chymase in kidney disease.

Chymase inhibition: a novel therapeutic target in gastrointestinal (GI) disorders?

The role of chymase in inflammatory bowel disease (IBD)

With regard to inflammation in the GI tract, an association between IBD and increased MC number has long been reported (Dvorak et al., 1980; Nolte et al., 1990; Gelbmann et al., 1999). However, until relatively recently, little was known about the role of chymase in IBD patients. Andoh et al. (2006) were one of the first to report a marked change in the distribution and number of chymase immunopositive MC in IBD biopsies. IBD is characterized by chronic inflammation and encompasses both ulcerative colitis (UC) and Crohn's disease (CD); in UC, however, the inflammation is limited to the mucosa of the colon, while in CD any region of the intestine may be affected and this inflammation is often transmural (Abraham and Cho, 2009). Given the ability of chymase to convert TGF-β and MMP-9 into their active forms (Takai et al., 2010), and the association of both these chymase-induced mediators in the pathophysiology of IBD, one may speculate that targeting chymase in IBD may be of therapeutic relevance. TGF-β, for example, is known to play a central role in severe fibrotic diseases, such as CD, through an increased production of ECM components (Pohlers et al., 2009). Of note, however, with respect to chymase in IBD are the divergent changes which occur in chymase-containing MC number between UC and CD, as well as between active and inactive phases of inflammation (Andoh et al., 2006). In particular, Andoh et al. (2006) noted a marked increase in chymase immunopositive MC in the colonic mucosa of active CD patients, not only in the laminia propria but also in the submucosa, propria muscularis and in the surrounding fatty tissue. Given that CD is characterized by tissue fibrosis, and MC have been implicated in this process (Gelbmann et al., 1999), this finding is perhaps expected. Indeed, such an observation would be in-keeping with the pro-fibrotic characteristics of chymase observed in patients with chronic hepatitis and liver fibrosis (Satomura et al., 2003), which in preclinical models display sensitivity to chymase inhibition with TY-51469 (Komeda et al., 2010). Conversely, decreased chymase has been associated with active UC in patient biopsies (Andoh et al., 2006). Nonetheless, mechanistic insight into the contribution of chymase in UC emerges from studies that have focussed on determining the role of chymase-dependent MMP-9 activation. MMP-9 is known to play an important role in the degradation of ECM proteins and has been shown to be consistently up-regulated during active inflammation, both in patients and in animal models of colitis (Takai et al., 2010). Tchougounova et al. (2005) further confirmed, by examining a functionally relevant murine protease to human chymase, that mMCP-4 is responsible for the conversion of proMMP-9 to its active form, MMP-9 in vivo. Significantly, this chymase-MMP-9 pathway may well be of significance in IBD, as Ishida et al. (2008) found that both chymase and MMP-9 were significantly increased in the dextran sodium sulphate animal model of colitis. Furthermore, they demonstrated that this increased activity could be suppressed by the chymase inhibitor, NK3201 suggesting an important role for chymase in the development of colitis via MMP-9 activation, and indicative of an indirect role for chymase in the degradation of the ECM. Indeed, this chymase-dependent MMP-9 activation has also been shown to play a significant role in other animal models of GI inflammation, for example, in rats with indomethacin-induced small intestinal damage. Here again, inhibition of chymase by use of TY-51469 significantly attenuated MMP-9 activation and ameliorated small intestinal damage (Kakimoto et al., 2010). Therefore, the preclinical evidence suggests that inhibition of chymase in IBD may be of benefit, but via indirect down-regulation of TGF-β and MMP-9 activation; whether this is of clinical relevance in IBD patients awaits investigation. Of note, however, is the increased presence of chymase-positive MC, not only in active CD, but also in inactive CD, relative to healthy patients (Andoh et al., 2006); again, the clinical significance of this finding is unknown. However, we speculate, as in irritable bowel syndrome (IBS), and given the ability of chymase to increase colonic epithelial permeability (Groschwitz et al., 2009), that these persisting chymase-positive MC may contribute to the increased permeability characteristically observed in quiescent CD biopsies, and therefore may contribute to the rate of relapse in these patients (Wyatt et al., 1993; Hilsden et al., 1999).

The potential role of chymase in the pathophysiology of IBS

Unlike IBD, IBS is a common sensory and motility disorder of the GI tract, characterized by chronic, episodic abdominal pain and discomfort as well as altered bowel habits, the pathophysiology of which is not fully understood (Quigley et al., 2006). Evidence for MC involvement in the pathogenesis of IBS has been mounting with studies in human (Park et al., 2003; Barbara et al., 2004) and in preclinical rodent models (Gue et al., 1997; Barreau et al., 2008; Hyland et al., 2009) in agreement. MC hyperplasia in biopsy tissue obtained from IBS patients occurs in the colon (Barbara et al., 2004), ceacum and rectum (Park et al., 2003), as well as in the small intestine (Guilarte et al., 2007) and, more specifically, their products have been associated with symptom severity in IBS (Park et al., 2003; Barbara et al., 2004). Whether MC, or indeed their products, transpire to be robust and reliable biomarkers of IBS remains unclear. However, a sensitive and specific assay for chymase activity in serum has been developed. Raymond et al. (2009) exploited the α2-macroglobulin binding properties of chymase to assess for chymase activity in the serum of subjects with mastocytosis. Indeed, recent evidence has proposed the use of secretory leucocyte protease inhibitor (SLPI) cleavage products, as a novel biomarker of chymase activity (Belkoski et al., 2008). These authors showed that chymase has the ability to cleave SLPI in a site-specific and unique nature from other proteases. This cleavage was easily detectable in human saliva and correlated with the severity of allergic symptoms observed (Belkoski et al., 2008).

Emerging evidence suggests that patients with IBS have increased intestinal permeability (Dunlop et al., 2006). However, to date, studies have focussed on the involvement of tryptase (Guilarte et al., 2007; Piche et al., 2009; Lee et al., 2010). Guilarte et al. (2007) reported jejunal MC hyperplasia and tryptase release, particularly in diarrhoea-predominant IBS (D-IBS) patients. However, despite these findings, studies examining the integrity of the gut mucosa in colonic biopsies of IBS patients have demonstrated an increase in intestinal epithelial barrier permeability irrespective of IBS subtype and that soluble mediators released from the biopsies of IBS patients significantly increased paracellular permeability of colonic epithelial cells in vitro (Piche et al., 2009). While histamine has been precluded from mediating this effect (Piche et al., 2009), other investigators, using the tryptase inhibitor nafamostat, demonstrated that increased permeability was tryptase-dependant, in D-IBS patients at least (Lee et al., 2010). However, to date, little attention has been given to chymase, or chymase-containing MC, in contributing to the deficits in intestinal permeability in IBS, despite evidence that functionally, and relevant to man, the mouse homologue of human chymase, mMCP-4, regulates intestinal barrier function (Groschwitz et al., 2009). In preclinical studies, largely conducted in rat, the β-chymase, rMCP-2 has been most studied. However, little information exists on rMCP-1, which is functionally more akin to human chymase (Andersson et al., 2008). Increased numbers of mucosal MC expressing rMCP-2 have been identified in both mucosal and connective tissue in an early life stress-induced model of IBS (Barreau et al., 2008; Hyland et al., 2009). While most studies measure circulating or mucosal rMCP-2 release do so as a marker of increased protease activity (Moriez et al., 2007), few have appreciated its effects on epithelial permeability and the implications this may have for IBS. However, of those who have considered the direct effects of rMCP-2 on epithelial barrier function, the data support a direct and detrimental effect on the epithelium. Vergnolle et al. (1998), by exogenously adding rMCP-2, demonstrated increased epithelial paracellular permeability in vitro, while Scudamore et al. (1995) demonstrated the relationship between intestinal mucosal permeability and the release of rMCP-2 in an anaphylaxis response. Likewise, studies in endotoxaemic rats, administered lippopolysaccharide, showed a rMCP-2-dependent increase in colonic permeability, the functional significance of which is yet to be determined (Moriez et al., 2007) but may be very relevant to the pathogenesis of IBS. Moreover, similar chymase-induced effects have been observed outside of the GI tract; human chymase was shown to decrease barrier function and migration of corneal epithelial cells and this activity was inhibited by chymostatin (Ebihara et al., 2005).

Even if we do recognize that chymase may have a role to play in the barrier breakdown associated with IBS, is it doing so independently of tryptase? Evidence suggests that tryptase release is under the regulatory control of chymase (He and Xie, 2004), therefore, it is possible that both chymase and tryptase, in concert, contribute to the symptoms associated with IBS. Despite the identification of a chymostatin-sensitive tryptase-release pathway in MC isolated from the GI tract (He and Xie, 2004), to date, this pathway has not been investigated in IBS.

Conclusions and perspective

Mice and rats have been the experimental models of choice in characterizing the role of chymase in the pathogenesis of several diseases primarily due to availability (Table 2). However, extrapolating data from such animal models to humans is complicated by multiple β-chymases in contrast to the fewer α-chymase(s) present in humans, primates, dogs, hamsters and sheep. Nonetheless, human chymase and rodent, rMCP-1 and mMCP-4 have well-characterized chymotrytic substrate recognition profiles (Andersson et al., 2008; 2009) and have been shown to display similar substrate specificities (Andersson et al., 2008). While mMCP-4 knockout mice have been used to examine the contribution of this human chymase homologue in several disease models, the total impact of all the murine chymases cannot be excluded (Pejler et al., 2010). The rationale behind the extensive duplication of the chymase gene in rodents remains unclear. However, these gene duplications may be important in the process of speciation where, a particular function, such as immunity, a sense of taste and smell, may provide selective advantages in a novel environment (Gallwitz and Hellman, 2006). Indeed, such diversity must be taken into account when characterizing chymase inhibitors, as demonstrated by Kervinen et al. (2010) who noted a strikingly wide variation of inhibitory potency across species. Despite such limitations, numerous orally-active chymase inhibitors have been developed and patented, for example, BCEAB, Compound 17, NK3201 and SUN-C8257 (Doggrell, 2008), although few have been tested in preclinical models of GI disease. Such studies may well be compounded by species variability, but have, in the setting of non-GI disorders, been useful tools in characterizing the role of chymase in the pathogenesis of cardiovascular and inflammatory diseases among others. Unfortunately, there remains a paucity of studies investigating the pathophysiological role of chymase in GI disorders, and particularly so with respect to IBS, with the mechanisms involved still to be fully elucidated. However, the current preclinical data are tantalizing with respect to a role for chymase in both inflammatory and functional bowel diseases.

Acknowledgments

The authors acknowledge financial support from the Health Research Board (Ireland) and a centre grant to the Alimentary Pharmabiotic Centre from Science Foundation Ireland. We also acknowledge Dr. Marcela Julio-Pieper for producing Figure 1.

Glossary

AAA

abdominal aortic aneurysm

AD

atopic dermatitis

Ang

angiotensin

CD

Crohn's disease

CMA1

mast cell chymase gene

D-IBS

diarrhoea-predominant irritable bowel syndrome

ECM

extracellular matrix

GI

gastrointestinal

IBD

inflammatory bowel disease

IBS

irritable bowel syndrome

MC

mast cells

mMCP

mouse mast cell protease

rMCP

rat mast cell protease

SLPI

secretory leucocyte protease inhibitor

UC

ulcerative colitis

Conflicts of interest

None.

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