Roles of chymase in stenosis occurring after polytetrafluoroethylene graft implantations.

Chymase is an important enzyme for the generation of angiotensin (Ang) II and in the activation of transforming growth factor (TGF)-beta1. Therefore, chymase may be involved in the hemodialysis access dysfunction, which is caused by intimal hyperplasia that occurs after polytetrafluoroethylene (PTFE) graft implantations. Bilateral U-shaped PTFE grafts were placed between the femoral vein and artery in dogs. Chymase inhibitor (NK3201, 1 mg/kg per day, p.o.) treatments were initiated 3 days before the operation. After the implantation, the stenosis by neointima proliferation was most frequently observed in the venous side of the PTFE grafts. In the hyperplastic neointima, myofibroblasts were the main cellular components. On the other hand, fibroblasts only occupied cellular components in a much smaller proportion in the neointima. However, these cells seem to be rich in the properties of proliferation and migration. After PTFE graft implantations, extensive accumulations of chymase-positive mast cells were found mainly in the tissue surrounding the grafts. The Ang II- and TGF-beta-positive cells were found in an adjacent section that was in close proximity to the chymase-positive cells. In contrast, the AT(1) receptors, as well as TGF-beta type II receptors, were expressed either in the neointima or in the outside adventitia of the PTFE grafts. Chymase inhibitor treatment resulted in a reduction of chymase, Ang II and TGF-beta1 expression, leading to a significant inhibition of neointimal formation. These findings indicating that an increase of chymase via promoting Ang II and TGF-beta1 generation plays a pivotal role in the neointimal formation after the implantation of PTFE grafts and also suggesting that chymase inhibition may be a new strategy that can be used to prevent PTFE graft dysfunctions in clinical settings.

The significance of chymase in the progression of abdominal aortic aneurysms in dogs.

In this study, we investigated the effect of a specific chymase inhibitor, NK3201, in the progression of abdominal aortic aneurysm in a dog experimental model. Abdominal aortic aneurysms were induced in dogs by injecting elastase into the abdominal aorta. NK3201 (1 mg/kg per day, p.o.) or a placebo was started 3 days before elastase injection and continued for 8 weeks after the injection. On abdominal ultrasound, the aortic diameter was seen to gradually expand in the placebo-treated group, but not in the NK3201-treated group. Eight weeks after elastase injection, the ratio of the medial area to the total area in the placebo-treated group was significantly smaller than that in the normal group, but it was significantly larger than that in the NK3201-treated group. In addition to chymase activity, angiotensin II-forming and matrix metalloproteinase-9 activities were significantly higher in the placebo-treated group than in the normal group; in the NK3201-treated group, all of these activities were significantly decreased. On immunohistochemical analyses, there was a significantly greater number of chymase-positive cells in the placebo-treated group than in the normal group, but the number was significantly smaller in the NK3201-treated group than in the placebo-treated group. Thus, chymase inhibition may become a useful strategy for preventing abdominal aortic aneurysms.

The relationship of tryptase- and chymase-positive mast cells to angiogenesis in stage I non-small cell lung cancer.

OBJECTIVE: There are two types of human mast cells, tryptase-positive mast cells (MC(T)) and tryptase- and chymase-positive mast cells (MC(TC)). Although MC(T) have been reported to be related to the generation of angiogenesis, little is known about the involvement of MC(TC) in tumor angiogenesis. In this study, to clarify the relationship between MC(TC) and lung cancer angiogenesis, we evaluated MC(TC), MC(T), and microvessel counts in normal, border, and central lung cancer regions. METHODS: Tumor sections from 32 cases of adenocarcinoma and 13 cases of squamous cell carcinoma were immunostained for chymase to evaluate MC(TC), tryptase to evaluate MC(T,) and CD34 to evaluate microvessel counts. RESULTS: Both MC(TC) and MC(T) counts in the border lung cancer region were significantly higher than in the central region, and the MC(TC) and MC(T) counts in the central region were significantly higher than those in the normal regions. The microvessel counts in the border region were higher than those in the central region. The ratio of MC(TC) to MC(T) in the border region, but not in the central region, was significantly higher than that in the normal region. In the border region, significant correlations not only between MC(T) and microvessel count, but also between MC(TC) and microvessel count were observed. In the central region, a significant correlation between MC(TC) and the microvessel count was observed, but there was no significant correlation between MC(T) and the microvessel count. CONCLUSIONS: These findings suggest that MC(TC) may be involved in the pathogenesis of angiogenesis in lung cancer.