Chymases, serine proteases exclusively expressed by mast cells, have been implicated in various pathological conditions. However, the basis for these activities is not known, i.e. the in vivo substrate(s) for mast cell chymase has not been identified. In this study we show that mice lacking the chymase mouse mast cell protease 4 (mMCP-4) fail to process pro-matrix metalloprotease 9 (pro-MMP-9) to its active form in vivo, whereas both the pro and active form of MMP-9 was found in tissues of wild type mice. Moreover, the processing of pro-MMP-2 into active enzyme was markedly defective in mMCP-4 null animals. Histological analysis revealed an increase in collagen in the ear tissue of mMCP-4-deficient animals accompanied by increased ear thickness and a higher content of hydroxyproline. Furthermore, both lung and ear tissue from the knock-out animals showed a markedly increased staining for fibronectin. MMP-9 and MMP-2 are known to have a range of important activities, but the mechanisms for their activation in vivo have not been clarified previously. The present study thus indicates a key role for mast cell chymase in the regulation of pro-MMP-2 and -9 activities. Moreover, the results suggest an important role for mast cell chymase in regulating connective tissue homeostasis. When mast cells (MCs)1 are activated, they degranulate and thereby release a panel of powerful preformed inflammatory mediators, including histamine, cytokines such as tumor necrosis factor-␣, proteoglycans, and various MC-specific proteases (1, 2). The MC proteases are divided into three main subclasses, tryptases, chymases, and carboxypeptidase A (3-5), all of which are stored in the MC granule in complex with heparin proteoglycan (6, 7). Chymases, serine proteases with chymotrypsin-like substrate specificities, have potent pro-inflammatory properties (8) and have been implicated in a variety of pathophysiological conditions, e.g. angiogenesis (9), heart failure (10), and fibrosis (11). However, it has not been possible to determine the mechanism by which chymases influences these processes, i.e. the physiological substrate(s) for chymase has not been identified.Matrix metalloproteases (MMPs) are known to be involved in a variety of physiological and pathological processes and are currently attracting a large clinical interest as potential drug targets in therapeutic intervention with various diseases (12-16). The MMPs, similar to most proteolytic enzymes, are synthesized with an N-terminal propeptide that needs to be removed to achieve proteolytic activity. Thus, the physiological processes that lead to propeptide cleavage are imperative in terms of regulating the activity of most proteases (17). The MMP family currently comprises Ͼ20 members (18). The members all share common structural features but differ in regard to substrate specificities, although overlapping substrate specificities between certain members of the MMP family occur. Thus, MMP-2 and -9 share the ability to degrade denatured collagen (gelatin) and are therefore also den...
Mast cells store an impressive array of preformed compounds (mediators) in their secretory granules. When mast cells degranulate, these are released and have a profound impact on any condition in which mast cell degranulation occurs. The preformed mast cell mediators include well-known substances such as histamine, proteoglycans, proteases, and preformed cytokines, as well as several recently identified compounds. Mast cells have recently been implicated in a large number of novel pathological settings in addition to their well-established contribution to allergic reactions, and there is consequently a large current interest in the molecular mechanisms by which mast cells act in the context of a given condition. In many cases, preformed mast cell mediators have been shown to account for functions ascribed to mast cells, and these compounds are hence emerging as major players in numerous pathologies. In this review we summarize the current knowledge of preformed mast cell mediators.
Nonselective inhibition of PG synthesis augments inflammation in mouse models of airway disease, but the roles of individual PGs are not completely clarified. To investigate the role of PGE2 in a mouse model of airway inflammation induced by a natural allergen, we used mice lacking the critical terminal synthetic enzyme, microsomal PGE2 synthase (mPGES)-1. Mice lacking mPGES-1 (ptges−/− mice) and wild-type C57BL/6 controls were challenged intranasally with low doses of an extract derived from the house dust mite Dermatophagoides farinae (Der f). The levels of PGE2 in the bronchoalveolar lavage fluids of Der f-treated ptges−/− mice were ~80% lower than the levels in wild-type controls. Der f-induced bronchovascular eosinophilia was modestly enhanced in the ptges−/− mice. Both Der f-treated strains showed similar increases in serum IgE and IgG1, as well as comparable levels of Th1, Th2, and Th17 cytokine production by Der f-stimulated spleen cells. These findings indicated that mPGES-1-derived PGE2 was not required for allergen sensitization or development of effector T cell responses. Unexpectedly, the numbers of vascular smooth muscle cells and the thickness of intrapulmonary vessels were both markedly increased in the Der f-treated ptges−/− mice. These vascular changes were suppressed by the administration of the stable PGE2 analog 16, 16-dimethyl PGE2, or of selective agonists of the E-prostanoid (EP) 1, EP2, and EP3 receptors, respectively, for PGE2. Thus, mPGES-1 and its product, PGE2, protect the pulmonary vasculature from remodeling during allergen-induced pulmonary inflammation, and these effects may be mediated by more than one EP receptor.
The octapeptide angiotensin II (Ang II) exerts a wide range of effects on the cardiovascular system but has also been implicated in the regulation of cell proliferation, fibrosis, and apoptosis. Ang II is formed by cleavage of Ang I by angiotensin-converting enzyme, but there is also evidence for non-angiotensin-converting enzyme-dependent conversion of Ang I to Ang II. Here we address the role of mast cell proteases in Ang II production by using two different mouse strains lacking mast cell heparin or mouse mast cell protease 4 (mMCP-4), the chymase that may be the functional homologue to human chymase. Ang I was added to ex vivo cultures of peritoneal cells, and the generation of Ang II and other metabolites was analyzed. Activation of mast cells resulted in marked increases in both the formation and subsequent degradation of Ang II, and both of these processes were strongly reduced in heparin-deficient peritoneal cells. In the mMCP-4 ؊/؊ cell cultures no reduction in the rate of Ang II generation was seen, but the formation of Ang-(5-10) was completely abrogated. Addition of a carboxypeptidase A (CPA) inhibitor to wild type cells caused complete inhibition of the formation of Ang-(1-9) and Ang-(1-7) but did not inhibit Ang II formation. However, when the CPA inhibitor was added to the mMCP-4 ؊/؊ cultures, essentially complete inhibition of Ang II formation was obtained. Taken together, the results of this study indicate that mast cell chymase and CPA have key roles in both the generation and degradation of Ang II.
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