补体C5a/C5aR途径促Fgl2表达和C5b-9形成的机制及其在暴发性肝衰竭中的作用

研究暴发性肝衰的发病机制，无疑对其预防和治疗有重要意义。补体在病毒诱导的暴发性肝衰中的作用未见报道。MHV-3诱导的暴发性肝衰模型，是最常用的动物模型。利用该模型我们发现，C5aR基因敲除小鼠死亡率显著下降，C5b-9的沉积显著减少。进一步实验发现，C5a/C5aR可调控Fgl2的表达。我们提出，C5a/C5aR可能通过影响Fgl2表达来调节凝血系统的活化并正反馈调节补体C5的活化，促进暴发性肝衰的发生。本课题拟通过体内和体外实验探讨C5a/C5aR促进Fgl2表达的分子机制；通过对Fgl2和凝血酶等的干预实验证实C5a/C5aR通路调节C5活化的正反馈途径；通过对C6的干预来探讨C5b-9在暴发性肝衰中的作用。本课题的结果无疑可使我们深入了解补体和凝血这两个复杂系统的相互作用以及补体自身调节机制；同时可加深对暴发性肝衰发病机理的认识，为通过干预补体活化来减少暴发性肝衰的风险提供理论依据。

The study to provide significant insights into the mechanisms underlying the pathogenesis of the fulminant liver failure will ultimately be very useful in the prophylaxis and therapy of viral hepatitis.The role of complement in fulminant viral hepatitis is unclear. The clinical syndrome of acute liver failure produced by fulminant viral hepatitis can be reproduced in mice by infection with murine hepatitis virus strain 3 (MHV-3), so it becomes an ideal animal model in the study. We found that mice mortality rate and C5b-9 deposition in liver tissue in C5aR KO mice was significant lower than that of WT mice in this murine model of fulminant viral hepatitis. In further studies, we found that C5a/C5aR pathway played an important role in the modulation fgl2 expression. We therefore hypothesized that C5a/C5aR pathway mediates hepatocellular injury in viral hepatitis via the potentiation of Fgl2 induced coagulation and feedback regulation on C5 activation. In the present studies, we will define cellular mechanisms involved in C5a/C5aR regulation in fgl2 expression by series of in vivo and in vitro experiments, confirm the feedback loop of C5a/C5aR pathway on C5 activation, and explore the effect of C5b-9 on the induction of fulminant hepatic failure. Anticipative results will help us further unravel the precise intercommunication between the complement and coagulation systems and the pathogenesis of fulminant liver failure, which may ultimately suggest novel treatment strategies for clinical disease.