基于外泌体的细胞间通讯是目前的研究热点。LPS是脓毒症促进肝衰竭的重要介质，巨噬细胞受LPS刺激后可促进肝细胞损伤。外泌体如何介导上述细胞间通讯鲜见报道。我们的前期研究发现，LPS刺激的巨噬细胞分泌的外泌体中HMGB1含量显著增高，该外泌体可引起肝细胞NLRP3炎症小体活化及焦亡；血管紧张素1-7（Ang（1-7））可抑制LPS诱发的肝损伤，然而具体机制不明。因此，我们设想：LPS诱导巨噬细胞释放外泌体中的HMGB1引起肝细胞NLRP3炎症小体活化及细胞焦亡，进而促进肝衰竭；Ang（1-7）对LPS有抑制作用。本研究拟从体内、外层面探讨LPS诱导巨噬细胞HMGB1以RAGE依赖途径装配至外泌体的机理；HMGB1外泌体经NLRP3-ASC-Caspase1轴诱导肝细胞焦亡，进而调节巨噬细胞表型的分子机制；观察Ang（1-7）对LPS的抑制作用。本研究为拓展外泌体在肝衰竭的调控机制提供新思路。

Exosomes have emerged as important vectors of intercellular cross talk. Lipopolysaccharide (LPS) plays a pivotal role in the pathogenesis of acute liver failure caused by sepsis. Through the expression of Toll-like receptor 4 (TLR4), macrophage can efficiently take up LPS, leading to inflammation and hepatocyte injury. To date, the underlying mechanism of how LPS activated macrophage derived exosomes mediate hepatocyte injury remains unclear. Preliminary studies showed LPS induced secretion of significant higher concentrated HMGB1-bearing exosomes from macrophage, contributing to inflammasome activation and pyroptosis of hepatocyte. Moreover, we found angiotensin (1-7) alleviated this inflammation activity, which needed further investigation. Therefore, we assumed that LPS could induce the release of HMGB1 contained exosomes from macrophages which triggered the pyroptosis of hepatocytes through NLRP3 inflammasome pathway and leading to liver failure. Angiotensin (1-7) alleviated these effect induced by LPS. In this study, we plan to investigate the mechanism of how LPS induces macrophage to assemble HMGB1 into exosomes via RAGE-dependent pathway in vitro and in vivo as well as how these HMGB1-bearing exosomes trigger hepatocyte pyroptosis with macrophage phenotype regulation in return. Furthermore, the effect of angiotensin (1-7) on LPS will be explored. This project provides novel insight into pathogenesis of liver failure during sepsis.