RNS诱导肺泡巨噬细胞焦亡促进体外循环术后急性肺损伤启动因子HMGB1分泌的机制研究

急性肺损伤（ALI）是体外循环（CPB）术后的严重并发症。我们已发现CPB能引起HMGB1分泌进而诱发ALI，但机制未明。巨噬细胞焦亡能引起HMGB1分泌，并相互促进放大炎性反应。CPB术后缺血再灌注损伤（IRI）可引起活性氧（ROS）及一氧化氮（NO）释放，两者极易相互作用形成氧化能力更强的活性氮（RNS）。我们发现RNS可能诱导肺泡巨噬细胞焦亡，由此推测：CPB术后因IRI产生的ROS与NO能生成RNS并诱导巨噬细胞焦亡，致HMGB1释放和ALI。本课题利用大鼠CPB模型以及肺泡巨噬细胞氧糖剥夺模型，深入研究CPB术后HMGB1异常分泌的机制，明确RNS诱导肺泡巨噬细胞焦亡在以上过程中的作用。并通过抑制ROS和NO合成以阻断RNS生成，抑制细胞焦亡，进而减少HMGB1分泌，并改善CPB术后ALI。本课题有望从细胞焦亡的角度进一步探讨CPB术后ALI的发病机制，为该病的有效防治奠定基础。

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are common complications of cardiopulmonary bypass (CPB) operation. Applicant found that high mobility group box-1 protein (HMGB1) generated during ischemia-reperfusion injury(IRI) could induce ALI. However, the mechanism contributed to HMGB1 secretion during CPB remains unknown. Other studies indicated that macrophage pyroptosis might induce HMGB1 secretion and then aggravate inflammation. Increased synthesis of ROS and NO during IRI may react with each other and result in formation of reactive nitrogen species (RNS). Applicant found that RNS may induce macrophage pyroptosis. Thus, we hypothesized that IRI during CPB induced formation of RNS. Then, RNS actived macrophage pyroptosis that might induce HMGB1 secretion and ALI. At present study, we want to establish pulmonary macrophage IRI model induced by oxygen-glucose deprivation (OGD) and animal ALI model after CPB operation to investigate RNS synthesis, activation of macrophage pyroptosis, HMGB1 accumulation and inflammatory reaction in lung tissue during CPB. RNA interference and other strategies will also be used to interfere RNS formation and macrophage pyroptosis to alleviate inflammatory reaction in lung tissue during the process of ALI after CPB operation. The present study focuses on the activation of macrophage pyroptosis by RNS to investigate the mechanism of ALI after CPB operation, which can provide theoretical foundation for formulating perioperative lung protective strategy for CPB operation and can lay foundation for exploring gene therapy approach for ALI after CPB operation.