CIRP通过调节自噬和焦亡参与急性肺损伤的机制研究

Hemorrhagic or septic shock is often complicated by acute lung injury (ALI), while the pathogenesis remains obscure and the medical intervention proves challenging. The cytological behavior of type II alveolar epithelial cells (AECII) is the key turning point for ALI. In recent years, it is found that the Cold-inducible RNA-binding protein (CIRP) is up-regulated in these patients, which acts as a pro-inflammatory DAMP molecule. Our preliminary experiments showed that 1. CIRP is significantly up-regulated in hemorrhage-lipopolysaccharides (LPS) “two hits” mice, 2.AECII stimulated by CIRP experienced pyroptosis and weakened autophagy. Previous studies have found that pyroptosis can promote inflammation while autophagy can alleviate inflammation. Therefore we hypothesized that ALI might be related with CIRP 1. as a DAMP molecule to induce pyroptosis accompanied with activation of IL-1β - IL-1RI (IL-1β receptor I) positive feedback pathway ; 2. as a RNA binding protein (RBP) to regulate the transcription and translation of inflammation associated proteins such as hypoxia inducible factor-1 alpha, telosome enzymes, adhesion to inhibit autophagy. In this project we try to explore the participation of CIRP in ALI via regulation of autophagy and pyroptosis. Our research may elucidate the vital roles of CIRP and AECII in the progress of pulmonary inflammation, and provide new therapeutic targets for the prevention and treatment of ALI secondary to hemorrhagic or septic shock.

失血性/感染性休克患者易发生急性肺损伤（ALI），发病机制复杂，临床防治效果不佳。II型肺泡上皮细胞(AECII)的细胞学行为是ALI的关键转折点。冷诱导RNA结合蛋白(CIRP)是近年发现的危险信号分子，其表达在急性炎症反应后迅速上调。课题组前期研究发现：1.“二次”打击（失血性休克+感染）小鼠AECII内CIRP显著上调；2.CIRP体外刺激AECII，自噬活性下降、caspase-1激活伴部分细胞焦亡，促炎因子分泌增加。据此我们推测CIRP可能通过抑制自噬、促进焦亡放大炎症反应导致ALI。本课题拟通过体内、外实验及临床样本分析，探讨CIRP作为胞内RNA结合蛋白及胞外DAMP（damage-associated molecular pattern）分子调节AECII自噬和焦亡，参与失血性/感染性休克继发ALI的可能机制，为ALI防治提供新的作用靶点和理论依据。

失血性/感染性休克患者易发生急性肺损伤（ALI），发病机制复杂，临床防治效果不佳。II型肺泡上皮细胞(AECII)的细胞学行为是ALI的关键转折点。冷诱导RNA结合蛋白(CIRP)是近年发现的危险信号分子，其表达在急性炎症反应后迅速上调。课题组前期研究发现：1.“二次打击“（失血性休克+感染）小鼠AECII内CIRP显著上调；2.CIRP体外刺激AECII，部分细胞焦亡，促炎因子表达增加。据此我们推测CIRP可能通过诱导焦亡促进炎症反应导致ALI。在预实验基础上，课题组通过小鼠体内、体外实验及临床样本分析，深入研究了CIRP作为胞内RNA结合蛋白及胞外DAMP（damage-associated molecular pattern）分子调节AECII炎症反应、参与失血性/感染性休克继发ALI的可能机制。课题组研究发现CIRP通过线粒体的组蛋白去乙酰化酶SIRT3，清除线粒体ROS、调控糖代谢，抑制NLRP3炎性小体组装和焦亡，维持AECII的数量和功能稳态，减轻肺部过度炎症反应。课题组研究结果确认失血性/感染性休克后CIRP引发AECII过度焦亡放大炎症反应导致ALI，其中细胞糖代谢重编程可能是重要参与机制；通过干预CIRP，可以调控“二次打击”后失控的肺部炎症反应。.AECII是肺泡上皮细胞的干细胞，CIRP是近年关注度较高而未能充分阐明作用机制的促炎蛋白，焦亡与多种炎症性疾病的发生、发展及预后关系密切。本课题的研究成果提供了失血性/感染性休克后发生ALI的新机制，也为进一步开展转化医学研究休克继发ALI的患者防治提供实验基础和潜在作用靶点——CIRP。课题组截止目前已在SCI收录期刊发表论文1篇，核心期刊发表综述2篇，在投SCI期刊论文3篇。