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Immunopathology
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
A variety of degradative enzymes may generate new mediators from local substrates (complement, kininogen, coagulation factors, etc.). These propagate and/or modify an ongoing inflammatory process. The neutral proteases tryptase and chymase distinguish two major types of mast cells (see above). Tryptase is a serine protease with Mr 31–35 kDa, it is active as a tetramer and has activity similar to trypsin. The physiologic role of tryptase is unclear. It cleaves vasoactive intestinal peptide (VIP) and a few other neuropeptides with bronchodilator activity, hence tryptase may lead indirectly to bronchoconstriction. Tryptase may also be mitogenic for fibroblasts. Chymase is actually a group of enzymes related to cathepsin G, elastase, and cytotoxic T cell granzymes (see Chapter 6). These enzymes have Mr 28–32 kDa and have activity similar to α-chymotrypsin. Chymase converts angiotensin I to angiotensin II, it degrades bradykinin, it cleaves neuropeptides VIP and substance P (and others), and may increase mucus secretion in airways. Mast cell carboxypeptidase has Mr 36 kDa and activity similar to carboxypeptidase A. It has been shown to degrade neurotensin, enkephalins, and other neuropeptides. Like other neutral proteases, its role in allergic inflammation requires clarification.
Asthma and Allergens
Published in Jonathan A. Bernstein, Mark L. Levy, Clinical Asthma, 2014
James L. Friedlander, Sachin Baxi, Wanda Phipatanakul
In allergic asthma, individuals are sensitized to a variety of allergens. On reexposure to an offending inhaled allergen, surfaces of mast cells and triggers a rapid release of inflammatory mediators from the mast cells, including histamine, tryptase, and chymase. Within several hours, a late-phase reaction occurs, which is characterized by the release of leukotrienes, prostaglandins, and cluster of differentiation 4 (CD4+) type 2 helper T cell cytokines, such as interleukin (IL)-3, IL-4, IL-5, and IL-13. IL-4 is the major stimulus for IgE production, whereas IL-5 promotes the recruitment of eosinophils. An inflammatory mediator release causes increased vascular permeability, bronchial smooth muscle contraction, mucous secretion, and connective tissue matrix remodeling. The end result is chronic inflammation of the airways.
Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufficiency
Published in Peter Gloviczki, Michael C. Dalsing, Bo Eklöf, Fedor Lurie, Thomas W. Wakefield, Monika L. Gloviczki, Handbook of Venous and Lymphatic Disorders, 2017
Deoranie N. Abdel-Naby, Walter N. Duran, Brajesh K. Lal, Frank T. Padberg Jr., Peter J. Pappas
The most striking differences in cell type and distribution were observed with mast cells and macrophages (Figure 6.3). In both gaiter and thigh biopsies, mast cell numbers were two- to four-times greater than those of controls in class 4 and 5 patients around arterioles and PCVs (P < 0.05). Class 6 patients demonstrated no difference in mast cell number compared to controls. Mast cell numbers around capillaries did not differ across groups in either gaiter or thigh biopsies. Macrophages demonstrated increased numbers in class 5 and 6 patients around arterioles and PCVs, respectively (P < 0.05). Differences in macrophage numbers around capillaries were observed primarily in class 4 patients in both gaiter and thigh biopsies. Surprisingly, lymphocytes, plasma cells and neutrophils were not present in the immediate perivascular space. Fibroblasts were the most common cells observed in both gaiter and thigh biopsies. It was speculated that mast cells and macrophages may function to regulate tissue remodeling, resulting in dermal fibrosis.39,45 The mast cell enzyme chymase is a potent activator of MMP-1 and -3 (collagenase and stromelysin).46–48 In an in vitro model using the human mast cell line HMC-1, these cells were reported to spontaneously adhere to fibronectin, laminin, and collagen type I and III, all of which are components of the perivascular cuff (see Figure 6.4).48 Chymase also causes the release of latent transforming growth factor-β1 (TGF-β1), which is secreted by activated endothelial cells, fibroblasts, and platelets from extracellular matrices.49 Release and activation of TGF-β1 initiates a cascade of events in which macrophages and fibroblasts are recruited to wound healing sites and are stimulated to produce fibroblast mitogens and connective tissue proteins, respectively.50 Mast cell degranulation leading to TGF-β1 activation and macrophage recruitment may explain why decreased mast cell and increased macrophage numbers were observed in class 6 patients. Macrophage migration, as evidenced by the frequent appearance of cytoplasmic tails in perivascular macrophages, further substantiates the concept of inflammatory cytokine recruitment.
Chymase inhibitors for the treatment of cardiac diseases: a patent review (2010–2018)
Published in Expert Opinion on Therapeutic Patents, 2018
Sarfaraz Ahmad, Carlos M. Ferrario
Chymase has been shown to be closely associated with tissue damage although it does not appear to directly alter the elevated blood pressure in hypertensive rat models [66–68]. Metabolism of Ang peptides in the circulation seems to be predominantly ACE-mediated because ACE is present in the plasma and it is located in endothelial cell membranes with its catalytic site exposed to the luminal surface. In contrast, chymase is located intracellularly or in the interstitial spaces of the heart. Studies reported either no chymase in the plasma [69] or its catalytic activity inhibited by various protease inhibitors present in the serum (such as α2-macroglobulin and α1-antichymotrypsin) [70]. An early and sustained increase in chymase activity has been reported in the hamster’s infarcted left ventricle to be present ahead of any changes in ACE activity [71]. MC numbers are increased in patients with gastrointestinal tract disorders (such as inflammatory bowel disease, IBD) [72]. Preclinical studies suggest that inhibition of chymase in IBD could be beneficial by downregulating profibrotic mediators TGF-β1 and matrix metalloprotease-9 (MMP-9) [73].
Risk factors and treatment of refractory anaphylaxis - a review of case reports
Published in Expert Review of Clinical Immunology, 2018
Wojciech Francuzik, Sabine Dölle, Margitta Worm
Severe anaphylaxis is a critical medical condition requiring an immediate intervention. According to the international guidelines, adrenaline given i.m. is a rapid and relatively safe treatment stabilizing the symptoms quickly in a given patient. However, in a few patients, this intervention might not be sufficient and, concomitantly to repeating its doses, other therapeutical measures may be required. Such cases are defined as refractory anaphylaxis and are frequently seen when the elicitor of a reaction is reaching the organism intravenously. This route is associated with a high systemic load of a given allergen or other mast cell activating molecule inducing a rapid onset of mediator release like histamine, but also tryptase and chymase, which are proteases and which may in addition to histamine promote severely anaphylaxis via activation of the plasma kallikrein and to enhancement of vascular permeability [64].
Positive correlation between blood pressure or heart rate and chymase-dependent angiotensin II-forming activity in circulating mononuclear leukocytes measured by new ELISA
Published in Clinical and Experimental Hypertension, 2018
Keisuke Okamura, Tetsu Okuda, Kazuyuki Shirai, Hidenori Urata
Human chymase is a serine proteinase that forms angiotensin II, and it has been isolated from the hearts obtained by the heart transplantation program of The Cleveland Clinic Foundation (1,2). Human cardiovascular organs have a much higher content of chymase compared with angiotensin-converting enzyme (3), suggesting that it makes an important contribution to local formation of angiotensin II, but not to circulating angiotensin II. On the other hand, ACE is more important for generation of circulating angiotensin II because chymase is inactivated by potent serine proteinase inhibitors in the blood. However, the physiological and/or pathological roles of chymase in humans remain unclear due to the lack of a clinically available chymase inhibitor. Animal studies have indicated that local angiotensin II formation makes a significant contribution to atherosclerosis in hamsters on a high-fat diet (4) since treatment with a chymase inhibitor (SUN-C8257) significantly reduced aortic atherosclerotic plaque (4). Also, another chymase inhibitor (TEI-E548) significantly decreased mortality in hamsters with myocardial infarction (5).