肝脏衰老及再生障碍的补体依赖性机制与调控

Liver failure is prone to occur after hepatectomy in elderly patients. Aging-induced senescence is considered to be one of the key factors leading to its occurrence. However, the precise senescence related mechanisms involved in liver failure are not well defined, which poses a significant clinical challenge. Traditionally, complement components are necessary for liver regeneration, and complement C3a and C5a are considered to promote liver regeneration. We spearheaded the development of a program to study the role of complement in liver injury and regeneration, which covered aspects of the role of complement in liver senescence and regeneration. Our preliminary studies highlight the important divergent roles of complement in liver senescence (promoting senescence) and liver regeneration (sparing liver regeneration). However, excessive activation of the complement system is implicated in the impairment of liver regeneration. More interestingly, we confirmed that aggravated activation of complement system participates in fatal liver failure after extended hepatectomy in mice through stress-inducing premature senescence and our targeted complement inhibitor rescue the liver failure by preventing or reversing some aspects of premature senescence. Based on these novel findings, the general goal of this proposal is to explore the role of complement in liver senescence and liver failure and determine the therapeutic efficacy of site-targeted complement inhibition. Our working hypothesis is that complement plays dual roles in liver injury and repair, not only playing a key role in accelerating hepatocyte senescence, but also having important functions in sparing liver regeneration. However, excessive and aggravated activation of the complement system is implicated in both senescence and the impairment of liver regeneration and our targeted complement inhibitory strategies may prove an effective treatment option, not only for amelioration of liver senescence but also in promoting liver regeneration. The aim of this study is to better define the complement dependent mechanisms involved in senescence and liver repair, and depending on the role of complement in senescence vs regeneration, we hypothesize that a balanced approach of complement inhibition, or site-targeted inhibition at certain points in the complement pathway, will provide effective therapeutic benefit in elderly patients for hepatectomy.

老年病人肝切除术后易出现肝功能衰竭，衰老致肝脏再生障碍被认为是导致其发生的关键因素。补体与衰老相关；传统观念认为，补体成分为肝脏再生必须，需要补充补体促进肝脏再生。我们研究发现过度激活的补体产物是引起肝脏损伤、妨碍肝脏再生的重要因素。进一步证实激活的补体可能与小鼠肝脏衰老相关，靶向补体抑制可减轻应激诱导过早衰老，促进肝脏再生，改善小鼠扩大性肝切除预后。据此提出假说：补体参与肝脏衰老进程；补体系统的过度激活参与肝脏应激性早衰机制阻碍肝脏再生导致小鼠肝切除致命性肝功能衰竭，靶向补体抗体的平衡抑制对挽救此类肝功能衰竭有益。本课题拟建立老年性动物肝切除模型，探讨不同补体成分与肝脏衰老以及肝脏再生障碍之间的关系，揭示补体系统的过度激活引起肝脏应激性早衰与肝切除术后致命性肝衰的作用及机制，验证靶向性补体调控有效防止老年性肝切除肝脏细胞的应激性衰老触发的致命性肝衰，从而为临床应用提供理论与实验依据。

老年病人肝切除术后易出现肝功能衰竭，衰老致肝脏再生障碍被认为是导致其发生的关键因素。传统观念认为，补体成分为肝脏再生必须，需要补充补体促进肝脏再生。我们研究发现过度激活的补体产物是引起肝脏损伤、妨碍肝脏再生的重要因素。我们的研究证实激活的补体可能与小鼠肝脏衰老相关，靶向补体抑制可减轻应激诱导过早衰老，促进肝脏再生，改善小鼠扩大性肝切除预后。据此提出假说：补体参与肝脏衰老进程；补体系统的过度激活参与肝脏应激性早衰机制阻碍肝脏再生导致小鼠肝切除致命性肝功能衰竭，靶向补体抗体的平衡抑制对挽救此类肝功能衰竭有益。本项目通过建立D-gal诱导小鼠肝脏衰老模型和自然衰老模型，以及利用补体基因缺陷小鼠和靶向性补体抑制剂探索了补体活化参与肝脏衰老的机制，并利用衰老小鼠肝部分切除模型，探讨不同补体成分与衰老肝脏肝切除后肝再生障碍之间的关系，揭示补体系统的过度激活引起肝脏应激性早衰与肝切除术后致命性肝衰的作用及机制，验证靶向性补体调控有效防止老年性肝切除肝脏细胞的应激性衰老触发的致命性肝衰，从而为临床应用提供理论与实验依据。