THE INFLAMMATORY ACTIVITIES OF MAST CELL PROTEINASES TRYPTASE AND CHYMASE.

为了研究过敏反应的病理生理机制，我们检测了肥大细胞蛋白酶、胰蛋白酶和乳糜酶的炎症活性。肥大细胞胰蛋白酶从人血浆和激肽原中产生血管通透性增强（VPE）活性。胰蛋白酶通过钾likin前激活直接从激肽原释放缓激肽。与胰酶共同释放的肥大细胞乳糜酶可使胰酶VPE活性增加2 ~ 3倍。中性粒细胞弹性酶也增强了胰蛋白酶VPE活性的产生。值得注意的是，中性粒细胞弹性酶本身从激肽原产生VPE活性，表明弹性酶释放了新的激肽。为了确定激肽的产生是否参与过敏反应诱导的VPE，我们采用豚鼠过敏模型研究了缓激肽b_2受体拮抗剂FR173657的作用。I型和III型过敏反应诱导的VTE分别被拮抗剂抑制34%和30%，提示缓激肽对过敏反应诱导的VPE有显著贡献。这些结果表明肥大细胞胰蛋白酶是变应性炎症的有效化学介质，肥大细胞乳糜酶和中性粒细胞弹性酶可增强其炎症活性。因此，这些蛋白酶特异性抑制剂的开发将与过敏性疾病的治疗贡献联系在一起。

In order to study the pathophysiology of allergic reactions, mast cell proteases tryptase and chymase were investigated the inflammatory activities. Mast cell tryptase produced vascular permeability enhancement (VPE) activity from human plasma and kininogens. Tryptase releases bradykinin through prekallikrein activation and directly from kininogens. The tryptase VPE activity generation was augmented to 2-3 fold by mast cell chymase released together with tryptase. Neutrophil elastase also augmented the tryptase VPE activity production. Notably, neutrophil elastase by itself generated VPE activity from kininogens, indicating a new kinin liberation by elastase. To determine whether kinin generation is involved in VPE induced by allergic reactions, the effect of bradykinin B_2-receptor antagonist FR173657 was investigated using guinea pig allergy models. VTE induced by type I or type III allergic reactions was inhibited by the antagonist by 34% and 30%, respectively, suggesting a significant contribution of bradykinin to allergic reaction-induced VPE.These results indicate that mast cell tryptase is a potent chemical mediator of allergic inflammation and its inflammatory activity is augmented by mast cell chymase and neutrophil elastase. The development of these proteinase-specific inhibitors, therefore, would be linked to therapeutic contribute to allergic diseases.