EETs调控NLRP3炎症小体活化对内毒素急性肺损伤的保护作用

急性肺损伤（ALI）是严重危害人类健康的急危重症，其中失控性炎症反应是导致ALI肺组织损伤的关键因素。环氧二十碳三烯酸（EETs）是花生四烯酸经细胞色素P450环氧化酶催化而生成的重要脂质活性分子，具有降压和抗炎等生物活性。本课题组前期实验观察到采用特异性可溶性环氧化物水解酶抑制剂（TPPU）抑制EETs的降解，能减轻LPS诱导的小鼠ALI，显著提高小鼠存活率，但其机制尚不明确。NLRP3炎症小体是胞内重要的模式识别受体，为启动并放大炎症反应的感受装置，EETs是否通过抑制NLRP3炎症小体的活化而减轻ALI值得探讨。申请人假设EETs通过抑制巨噬细胞NLRP3炎症小体启动，以及EETs通过减轻钙超载缓解线粒体损伤，进而抑制NLRP3炎症小体活化。本课题拟从整体和细胞分子水平研究EETs对LPS诱导的ALI小鼠肺内NLRP3炎症小体活化的影响及其机制，为开发ALI新型治疗策略提供理论依据。

Acute lung injury (ALI) has high morbidity and mortality rates. And inflammation plays a vital role in the tissue injury. Epoxyeicosatrienoic acids (EETs) are bioactive eicosanoids produced from arachidonic acid by cytochrome P450 epoxygenases. EETs have varied functions inducing vasodilatation, and anti-inflammation. Our preliminary work found that inhibition the degradation of EETs with TPPU attenuated LPS-induced ALI in mouse. But the underlying mechanism remains unclearly. NLRP3 inflammasome recognizes of endogenous danger, primers and amplifies the inflammation. It is unknown whether EETs could inhibit the activation of NLRP3 inflammasome to protect ALI. We hypothesize that EETs could inhibit the priming of NLRP3 inflammasome; EETs attenuate the mitochondrial injury via suppressing calcium overload, finally inhibit the activation of NLRP3 inflammasome. We will investigate the effect of EETs on LPS-induced ALI and its mechanism from animal and cell levels, providing data for new therapy strategy of ALI.