小鼠酒精性肝病的补体依赖性机制及干预

Alcohol-induced liver disease (ALD) is a disease which progresses from early steatosis, inflammation and necrosis to fibrosis and cirrhosis in some people, and ALD is one of the major causes of mortality and morbidity in the world. Ethanol metabolism causes the liver injury, at least in part, by producing significant levels of complement activities. It also appears that the overproduction of oxidative stress, cytotoxic, pro-inflammatory, and pro-fibrogenic cytokines may be critical in the pathogenesis of ALD. Liver injury of ALD is significantly reduced in complement C3 or C5-deficient but increased in C6-deficient animals.Specifically, Complement system was activated in ALD through the typical pathway. Complement C3-deficient mice have been shown to decrease steatosis and to decrease pro-inflammatory cytokine secretion. C5 is involved in alcohol-induced liver cell injury but not steatosis. C6-deficient rat were more susceptible to ethanol-induced liver damage. Ethanol-fed CD55/DAF knockout mice showed both increased steatosis and increased ALT levels compared with wild-type mice fed ethanol. Our preliminary studies highlight the important roles of complement in ALD. Using a mouse model of Ethanol-fed induced ALD we have shown that absence of fB or C3 results in protection from ethanol-induced hepatic injury. CD59-deficient, which potentially results in excessive terminal pathway activation, contributes to severe steatosis and liver damage. Furthermore, our targeted complement inhibitors significantly reduced these injuries. Finally, steatosis livers of ethanol-fed wild-type mice developed suppression of liver regeneration as compared with lean livers, More interestingly，we firstly demostrated that targeted complement inhibitor significantly improves liver regeneration. Our preliminary data indicate that excessive complement productions are implicated in the pathogenesis of ALD, moreover, the intervention in the complement system using recombinant complement regulatory proteins may represent a promising strategy to manage patients with ALD. Based on these novel findings, the general goal of this proposal is to understand the role of complement in the pathogenesis of ALD and determine the therapeutic efficacy of complement inhibition.Hence, we hypothesize that ethanol metabolism in the liver causes a series of downstream effects leading to liver injury, with increased complement activity playing critical role, and that this injury can be significantly decreased by targeted complement inhibition. Our objectives in this proposal are to better characterize the process of ethanol-induced liver cell injury with a special emphasis on the role of complement system, and to design effective targeted complement inhibitors approach to direct complement inhibition therapeutics to the injurious location with an emphasis on further delineating the mechanisms by which ethanol causes ALD.

研究证实活化的补体成分参与酒精性肝病（Alcohol-induced liver disease ，ALD）发病进程，预示通过补体干预改善ALD的新思路。酒精性脂肪肝和炎症处于ALD发病早期，病程可逆，是实施干预的有效时机，通过补体调控减轻酒精性肝损伤的研究鲜见报道。我们提出的工作假设是：乙醇诱发肝脏的补体过度激活，过度活化的补体成分参与ALD的关键性致损机制；补体系统在酒精性肝脏损伤与修复中扮演双刃剑角色，不同的损伤补体成分有不同效应机制；合理的补体调控可能有效减轻肝损伤，延缓甚至逆转ALD疾病进程。本研究拟借助小鼠急慢性肝脏损伤模型，利用C57BL/6背景的野生型或不同补体基因缺失小鼠以及不同补体抑制剂处理探讨ALD的补体依赖性损伤作用及其相关机制，验证选择性靶向性补体抑制剂的治疗效应。从补体调控角度探究补体过度激活参与ALD的致病机制，并探索潜在的干预方式，为ALD的防治提供新策略。

研究证实活化的补体成分参与酒精性肝病（Alcohol-induced liver disease ，ALD）发病进程，预示通过补体干预改善ALD的新思路。酒精性脂肪肝和炎症处于ALD发病早期，病程可逆，是实施干预的有效时机，通过补体调控减轻酒精性肝损伤的研究鲜见报道。我们提出的工作假设是：乙醇诱发肝脏的补体过度激活，过度活化的补体成分参与ALD的关键性致损机制；补体系统在酒精性肝脏损伤与修复中扮演双刃剑角色，不同的损伤补体成分有不同效应机制；合理的补体调控可能有效减轻肝损伤，延缓甚至逆转ALD疾病进程。本研究拟借助小鼠急慢性肝脏损伤模型，利用C57BL/6背景的野生型或不同补体基因缺失小鼠以及不同补体抑制剂处理探讨ALD的补体依赖性损伤作用及其相关机制，验证选择性靶向性补体抑制剂的治疗效应。从补体调控角度探究补体过度激活参与ALD的致病机制，并探索潜在的干预方式，为ALD的防治提供新策略。