肝星状细胞NLRP3/caspase-1信号通路持续活化在慢性和传播阻断后血吸虫病致病中的作用机制

项目名称： 肝星状细胞NLRP3/caspase-1信号通路持续活化在慢性和传播阻断后血吸虫病致病中的作用机制

项目编号： No.81471573

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王勇

作者单位： 南京医科大学

项目金额： 71万元

中文摘要： 慢性血吸虫病及传播阻断后血吸虫病以肝纤维化为主要致病基础，肝星状细胞活化起关键作用，但肝星状细胞持续活化的诱导因子、细胞信号通路等详细机制，尚未明了，临床缺乏抗血吸虫病肝纤维化的有效手段，使之成为制约防治工作质量的因素。本申请综合对肝星状细胞能形成炎症小体和炎症小体活化与纤维化紧密相关等认识，提出研究假设：血吸虫虫源性分子和活性氧等内源性DAMPs通过NLRP3/caspase-1信号通路活化肝星状细胞，释放IL-1β等促炎因子构成肝脏炎症微环境，并启动肝纤维化过程；而肝星状细胞NLRP3持续活化，构成传播阻断后血吸虫病肝纤维化病理发展的基础。拟试验证明血吸虫病肝纤维化致病中肝星状细胞存在NLRP3/caspase-1炎症小体信号通路活化，明确血吸虫感染相关PAMPs和DAMPs因子与肝星状细胞NLRP3/caspase-1通路活化的关系，以期揭示血吸虫病肝纤维化致病中炎症小体介导的机制。

中文关键词： 血吸虫病；炎症小体；信号通路；损伤相关分子模式；肝星状细胞

英文摘要： The main clinical manifestation of chronic schistosomiasis japonica and/or post-transmission schistosomiasis is progressive hepatic fibrosis. Although hepatic stellate cells have been proved to play a key role in the pathogenisis of hepatic fibrosis,the detail mechanism relate to resulting factors and cellular signal pathways to keep sustained activation of them,is not well known. As a result,there are few available treatments for the patients with schistosomiasis hepatic fibrosis. Based on integrating current understandings that inflammasome can be assembled in hepatic stellate cells and that activated inflammasomes mediate or orchestra fibrogenic processes, we hypothesize that some schistosoma-origined molecules and the infection-induced reactive oxygen species may activate hepatic stellate cells through NLRP3/caspase-1 pathway, and then releasing matured IL-1β,the pro-inflammatory cytokine, to start liver fibrogenesis. Consequently, the sustained activation of NLRP3 inflammasome in hepatic stellate cells causes progressive liver fibrosis. So,in this study,we design to confirm that there exists activation of NLRP3/caspase-1 pathway in the hepatic stellate cells of mice in infection with Schistosoma japonicum, to reveal the relationship between NLRP3/caspase-1 pathway and the inflammation-causing elements involved and finally to demonstrate the inflammasome-mediated mechanism in hepatic fibrosis of schistosomiasis.

英文关键词： schistosomiasis;inflammasome;signal pathway;DAMPs;hepatic stellate cells