血管紧张素Ⅱ及血管紧张素（1-7）对肺成纤维细胞NLRP3炎症小体及自噬调控作用：肺纤维化的新机制

NLRP3炎症小体及自噬是肺纤维化的研究热点。氧化/抗氧化反应失衡激活的NLRP3炎症小体对肺成纤维细胞激活和胶原持续分泌有重要意义，自噬可抑制该效应。血管紧张素Ⅱ（AngⅡ)和血管紧张素（1-7）（Ang1-7)是肺纤维化治疗新靶点，然而对炎症小体和自噬的调控机理不明。本前期研究发现，AngⅡ可诱发氧化应激，激活肺成纤维细胞NLRP3炎症小体，Ang(1-7)可抑制该作用。我们设想：AngⅡ通过氧化应激激活肺成纤维细胞NLRP3炎症小体，促进肺纤维化；Ang(1-7)可抑制该效应；p62/SQSTM1介导的线粒体自噬对此有调控作用。拟从体内外观察AngⅡ及Ang(1-7)对肺成纤维细胞NOX4介导氧化/Nrf-2介导抗氧化反应、线粒体功能、NLRP3炎症小体活化及胶原生成的影响；观察p62/SQSTM1介导的选择性自噬对NLRP3炎症小体通路的负调控作用。本研究为肺纤维化防治提供新策略。

The NLRP3 inflammasome and autophagy have been considered as hot area of research in pulmonary fibrosis at present. The NLRP3 inflammasome, activated by redox imbalance, plays a key role in maintaining the activative phenotype of lung fibroblasts and accumulation of collagen, which can be inhibited by mitochondrial autophagy. Angiotensin Ⅱ(Ang Ⅱ) and angiotensin(1-7) (Ang(1-7)) are the new targets of pulmonary fibrosis therapy, however, the exact molecular mechanism of them in regulating the NLRP3 inflammasome and autophagy is still unclear. Our preliminary findings suggested that Ang Ⅱ, suppressed by Ang(1-7), could induce oxidative stress and activate the NLRP3 inflammasome. Therefore, we suppose that Ang Ⅱaccelerates pulmonary fibrosis via oxidative stress activated NLRP3 inflammasome, which could be reversed by Ang(1-7), these effects might be regulated by mitochondrial autophagy. Our research aims to observe the effects of AngⅡ and Ang(1-7) on NOX4-induced oxidative reaction/Nrf2-induced anti-oxidative reaction, mitochondrial dysfunction, NLRP3 inflammasome activity, and collagen synthesis. Additionally, we also observe the negative regulatory role of p62/SQSTM1 induced selective mitochondrial autophagy in NLRP3 inflammasome signal pathways. This research would provide novel strategy for prophylaxis and treatment of pulmonary fibrosis.