Number Of Chymase-positive Cells Research Articles

Pathophysiological Role of Chymase-Activated Matrix Metalloproteinase-9.

Chymase present in mast cells can directly form matrix metalloproteinase (MMP)-9 from proMMP-9. Chymase-activated MMP-9 has been reportedly closely related to the pathogenesis of various diseases, and inflammation-related diseases in particular. Upregulated chymase and MMP-9 have been observed in tissues from patients and animal models of aortic aneurysm, inflammatory gastrointestinal and hepatic diseases, acute pancreatic failure, atopic dermatitis and rheumatoid arthritis. Chymase at these regions is only derived from mast cells, while MMP-9 is derived from macrophages and neutrophils in addition to mast cells. Chymase inhibitors attenuate MMP-9 formation from pro-MMP-9, and ameliorate the development and progression of these disorders, along with reduction in inflammatory cell numbers. MMP-9 activated by chymase might also be involved in angiogenesis in the tumor environment. Development of angiogenesis around several cancers is closely related to the expression of chymase and MMP-9, and postoperative survival curves have revealed that patients with a higher number of chymase positive cells have lower survival rates. In this review, we wanted to clarify the role of chymase-activated MMP-9, which might become an important therapeutic target for various inflammatory disorders.

Activation of Mast-Cell-Derived Chymase in the Lacrimal Glands of Patients with IgG4-Related Ophthalmic Disease.

The purpose of this present study was to investigate the distribution and expression of chymase in the lacrimal glands (LGs) of patients afflicted with IgG4-related ophthalmic disease (IgG4-ROD). LGs from patients with severe canalicular obstruction were considered the control group. Toluidine blue staining confirmed a significant increase in the number of mast cells in the LGs obtained from the IgG4-ROD patients. In addition, immunostaining of serial sections from the LGs showed a significant increase in the number of chymase-positive cells and tryptase-positive cells in the IgG4-ROD LGs compared to the normal control LGs. The mRNA expression of chymase, tryptase, TGF-β1, and collagen-I tended to increase in the IgG4-ROD LGs. Immunostaining of vimentin and α-smooth muscle actin (α-SMA) showed that myofibroblasts were the main cellular components in severely fibrotic regions of LGs in patients with IgG4-ROD. Linear regression analyses on the number of mast cells, chymase-positive cells, and tryptase-positive cells revealed significant positive correlations between those respective cells. Our findings suggest that chymase may play a role in the fibrotic disorder of IgG4-ROD LGs through the regulation of TGF-β1 activation and collagen-I deposition, and that it may be a therapeutic target for patients afflicted with IgG4-ROD.

The intricate role of mast cell proteases and the annexin A1-FPR1 system in abdominal wall endometriosis.

Endometriosis is a continuous and progressive disease with a poorly understood aetiology, pathophysiology and natural history. This study evaluated the histological differences between eutopic and ectopic endometria (abdominal wall endometriosis) and the expression of mast cell proteases (tryptase and chymase), annexin A1 (ANXA1) and formyl peptide receptor 1 (FPR1). Ectopic endometrium from 18 women with abdominal wall endometriosis and eutopic endometrium from 10 women without endometriosis were obtained. The endometrial samples were analysed by histopathology, immunohistochemistry and ultrastructural immunogold labeling to determine mast cell heterogeneity (tryptase and chymase positive cells) and the expression levels of ANXA1 and FPR1. Histopathological analysis of the endometriotic lesions showed a glandular pattern of mixed differentiation and an undifferentiated morphology with a significant influx of inflammatory cells and a change in mast cell heterogeneity, as evidenced by a significant increase in the number of chymase-positive cells and endogenous chymase expression. The undifferentiated glandular pattern of endometriotic lesions was positively associated with a marked increase and co-localization of ANXA1 and FPR1 in the epithelial cells. In conclusion, the co-upregulated expression of mast cell chymase and ANXA1-FPR1 system in ectopic endometrium suggests their involvement in the development of endometriotic lesions.

Chymase inhibition attenuates tetrachloride‐induced liver fibrosis in hamsters

Chymase converts angiotensin I to angiotensin II, which may promote the development of liver fibrosis. In this study, whether a chymase inhibitor TY-51469 attenuated tetrachloride (CCl(4))-induced liver fibrosis was examined. Liver fibrosis was induced by the s.c. injection of 1 mL/kg of CCl(4) twice weekly for 8 weeks, and each hamster was given TY-51469 (1 mg/kg per day) or placebo. Untreated hamsters were used as a control group. Significant increases of serum alanine aminotransferase, total bilirubin and hyaluronic acid levels were observed in the placebo-treated group compared with the control group, but these levels were significantly attenuated in the TY-51469-treated group. Liver chymase activity was significantly higher in the placebo-treated group than in the control group, whereas the activity in the TY51469-treated group was not. Total angiotensin II-forming activity in the liver was also significantly higher in the placebo-treatedgroup than in the control group or the TY-51469-treated group. The ratio of the fibrotic area to the total area in the liver was significantly higher in the placebo-treated group than in the control group, but the ratio was significantly lower in the TY-51469-treated group than in the placebo-treated group. A significant decrease in the number of alpha-smooth muscle actin (SMA)-positive cells was seen in the TY-51469-treated group compared to the placebo-treated group. Significant correlations between the number of chymase-positive cells and the degree of fibrosis and between the numbers of chymase-positive cells and alpha-SMA-positive cells were observed. Thus, chymase inhibition may be a useful strategy for preventing liver fibrosis.

Increased chymase-positive mast cells in children with crescentic glomerulonephritis

Mast cell-derived chymase is an angiotensin II-forming enzyme that appears to be involved in tubulointerstitial fibrosis in the kidneys. Previous studies have shown that the level of chymase increases in grafted kidneys after rejection and in adult patients with diabetic nephropathy. However, the significance of chymase in children with renal diseases has not been investigated. Using immunohistochemistry, we have investigated chymase expression in biopsy samples of renal tissue from 104 children with kidney diseases, including rapidly progressive crescentic glomerulonephritis (n = 3), diabetic nephropathy (n = 2), allografted kidney (n = 3), membranoproliferative glomerulonephritis (n = 6), immunoglobulin A nephropathy (n = 33) and Henoch-Schönlein purpura nephritis (n = 23). Increased numbers of chymase-positive mast cells were observed in the renal cortex of all three patients with crescentic glomerulonephritis (mean 26.0/mm(2); range 19.3-36.8/mm(2)). Chymase-positive cells were also observed in the renal biopsy of an allografted kidney and in those from children with diabetic nephropathy. The mean number of chymase-positive cells in renal tissue samples characterized by each renal disease was significantly correlated with the mean intensity of the interstitial fibrosis in that same tissue sample (Spearman's rank correlation test p = 0.0013; rank correlation coefficient 0.84). These findings suggest that mast cell-derived chymase plays an important role in juvenile crescentic glomerulonephritis.

Significance of chymase‐dependent angiotensin II formation in the progression of human liver fibrosis

Angiotensin II may contribute to liver fibrogenesis. In addition to angiotensin-converting enzyme (ACE), chymase, which is expressed by mast cells, is also known to be an angiotensin II-forming enzyme. However, it is unclear which of these two angiotensin II-forming enzymes plays a more important role in liver cirrhosis progression. In the present study, the role of angiotensin II-forming enzymes in the progression of liver cirrhosis was clarified. A total of 77 patients (16 in F0 stage, 10 in F1 stage, 22 in F2 stage, 12 in F3 stage, and 17 in F4 stage) were classified according to the new Inuyama classification into a non-cirrhosis (F0) group, an early cirrhosis (F1 + F2) group, and a chronic cirrhosis (F3 + F4) group. Both chymase and total angiotensin II-forming activities were significantly higher in chronic cirrhosis patients than in the other two groups. However, there was nodifference among the three groups in ACE activity. On immunohistology, the number of chymase- and angiotensin II-positive cells was significantly higher in the chronic cirrhosis group than in the non-cirrhosis and early cirrhosis groups. There were significant correlations between the number of chymase-positive cells and the number of angiotensin II-positive cells, between the number of chymase-positive cells and the degree of fibrosis, and between the number of angiotensin II-positive cells and the degree of fibrosis. These results suggest that chymase-dependent angiotensin II formation may play an important role in hepatic fibrosis of patients with cirrhosis.

Chymase-dependent angiotensin II formation in the saphenous vein versus the internal thoracic artery

Objectives: The great saphenous vein graft is known to be less patent than the internal thoracic artery graft. Recently, we reported that chymase-dependent angiotensin II formation plays an important role in the development of intimal hyperplasia in dog grafted veins. In this study we investigated the levels of angiotensin II–forming enzymes, angiotensin-converting enzyme, and chymase in human saphenous veins and internal thoracic arteries. Methods: The saphenous vein and internal thoracic artery specimens were obtained from coronary artery bypass grafts of patients during surgical procedures (saphenous vein, n = 16; internal thoracic artery, n = 16). Activities of angiotensin-converting enzyme and chymase were determined by using the extract from the saphenous vein or internal thoracic artery. Sections of the saphenous vein or internal thoracic artery were stained with van Gieson's elastin stain and were immunostained with anti-human chymase antibody. Results: The activities of angiotensin-converting enzyme in the saphenous vein and internal thoracic artery were 0.34 ± 0.12 and 0.32 ± 0.17 mU/mg protein, respectively, and the difference was not significant. The chymase activity in the saphenous vein was significantly higher than that in the internal thoracic artery (saphenous vein, 10.1 ± 0.81 mU/mg protein; internal thoracic artery, 6.21 ± 1.86 mU/mg protein). Chymase-positive cells in the saphenous vein were located in both the media and adventitia, and those in the internal thoracic artery were located only in the adventitia. The number of chymase-positive cells in the saphenous vein was about 2.6 times that in the internal thoracic artery. Conclusion: The chymase activity, but not the angiotensin-converting enzyme activity, was significantly higher in the saphenous vein, suggesting that the high levels of chymase activity may be related to the poorer performance of the saphenous vein for use as a bypass conduit. (J Thorac Cardiovasc Surg 2001;121:729-34)

Relative localization of angiotensin-converting enzyme, chymase and angiotensin II in human coronary atherosclerotic lesions.

Studies using cell cultures and animal models have indicated an important role for angiotensin II in atherosclerosis. In humans, at least two major enzymes are involved in the conversion of angiotensin I to angiotensin II: so-called angiotensin-converting enzyme (ACE) and chymase. Enhanced activation of chymase in atherosclerotic tissue homogenates has been reported in animal models, but its contribution to the generation of angiotensin II has not been studied. To clarify the localization of chymase and its pathophysiologic role in the formation of angiotensin II, using human coronary arteries. Twenty-four coronary artery segments obtained from 14 autopsied patients were characterized histologically into the following categories: normal coronary arteries with diffuse intimal thickening, hypercellular lesions, atheromatous plaques and fibrosclerotic plaques. We compared the cellular localization of chymase, ACE and angiotensin II expression using immunocytochemical techniques. Chymase was expressed only in the cytosole of mast cells in all segments. On the basis of the histologic study, the number of chymase-positive cells in the intima of atheromatous plaques was significantly higher than that in normal coronary arteries with diffuse intimal thickening. The expression of angiotensin II in the intima was enhanced in hypercellular lesions and atheromatous plaques. Localization of angiotensin II in the intima was associated with that of ACE. Immunodouble staining did not show colocalization of angiotensin II and chymase. These results suggest an important role for the production of angiotensin II by ACE in the progression of atherosclerosis in human coronary arteries. Enhanced expression of chymase appears not to be involved in angiotensin II production in the intima.