Tryptase mediates hyperresponsiveness in isolated guinea pig bronchi
Tryptase mediates hyperresponsiveness in isolated guinea pig bronchi
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DOI：
10.1016/s0024-3205(98)00518-9
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发表时间：
1998-11-20
期刊：
影响因子：
6.1
通讯作者：
Wright, CD
中科院分区：
文献类型：
--
作者：
Barrios, VE;Middleton, SC;Wright, CD
气道平滑肌对变应原和环境因素的高反应性长期以来与哮喘的病理生理学相关。类胰蛋白酶，肺肥大细胞的丝氨酸蛋白酶，已被牵连作为参与诱导高反应性的介质之一。因此，类胰蛋白酶抑制剂已成为研究的主题，作为潜在的新的治疗哮喘的药物。分泌性白细胞蛋白酶抑制剂（SLPI）是一种天然存在于人气道的蛋白质，具有抗类胰蛋白酶活性。为了评估SLPI在哮喘中的潜在治疗效用，使用气道高反应性的体外和离体模型评估其作用，并与小分子类胰蛋白酶抑制剂APC-366的作用进行比较。我们的研究结果表明，SLPI抑制类胰蛋白酶介导的高反应性在体外，并减弱在抗原致敏的动物进行抗原暴露的气道平滑肌中观察到的高反应性。小分子类胰蛋白酶抑制剂APC-366具有类似的抑制作用。因此，类胰蛋白酶似乎是这些模型中高反应性发展的重要贡献者。类胰蛋白酶促进哮喘的发生和发展，SLPI可能会增加这种疾病的治疗潜力。
Hyperresponsiveness of airway smooth muscle to allergens and environmental factors has long been associated with the pathophysiology of asthma. Tryptase, a serine protease of lung mast cells, has been implicated as one of the mediators involved in the induction of hyperresponsiveness. As a consequence, tryptase inhibitors have become the subject of study as potential novel therapeutic agents for asthma. Secretory leukocyte protease inhibitor (SLPI) is a naturally occurring protein of human airways which exhibits anti-tryptase activity. To assess the potential therapeutic utility of SLPI in asthma, its effects were evaluated using in vitro and ex vivo models of airway hyperresponsiveness and compared with the effects of the small molecule tryptase inhibitor APC-366. Our results demonstrate that SLPI inhibits tryptase-mediated hyperresponsiveness in vitro and attenuates the hyperresponsiveness observed in airway smooth muscle from antigen-sensitized animals subjected to antigen exposure. The small molecule tryptase inhibitor APC-366 has a similar inhibitory effect. Thus, tryptase appears to be a significant contributor to the development of hyperresponsiveness in these models. To the extent that tryptase contributes to the development and progression of asthma, SLPI may posses therapeutic potential in this disease setting.