小鼠脑死亡供体肝移植的补体依赖性损伤与修复机制

Owing to the discrepancy between organ donation and the demand for liver transplantation, expanding the liver donor pool is of vital importance, and marginal donor livers are increasingly considered of being used. However, marginal liver grafts, such as brain death（BD） grafts, are associated with increased incidence of primary graft nonfunction and initial poor graft. The development of novel therapeutic strategies for BD liver graft injury would have significant clinical benefit. The mechanisms responsible for graft dysfunction in BD liver graft are not well understood. In this study we propose to investigate BD liver graft associated with graft survival. The liver is the major site for biosynthesis of 80-90% plasma complement components, and expresses a variety of complement receptors. Recent evidence from several studies suggests that the complement system is involved in the pathogenesis of a variety of liver disorders including liver injury and repair, fibrosis, alcoholic liver disease, and liver ischemia reperfusion injury (IRI). Our working hypothesis is that complement plays a central role in causing IRI to liver grafts, and that BD amplifies complement-dependent hepatic injury. BD and ischemia synergistically active the complement system, then stimulating amount of reactive oxygen (ROS), resulting in proinflammatory responses, increasing IRI and inhibiting liver regeneration (repair), leading to graft failure. Although complement activation products (such as C3, C5) take participate in liver repair procedure and are necessary to regeneration after liver injury, aggravated activation of complement may be harmful to regeneration. Therefore, it is reasonable to assume that complement inhibitory strategies may prove an effective treatment option. We propose to utilize relevant mouse models to determine the role of complement in hepatic injury and regeneration to BD liver graft that occurs at different stages of the transplantation process. We will investigate complement effector mechanisms and develop novel therapeutic strategies.

脑死亡供体（Brain death donor , BDD）肝移植容易出现术后移植肝功能不全甚至原发性无功能（primary no function , PNF），脑死亡引起的损伤（Brain death-induced injury, BDI）以及缺血/再灌注损伤（ischemia reperfusion injury, IRI）是至关重要的风险因素，具体损伤机制不明。我们的工作假设是：BD及I/R过程协同诱发补体的过度激活，过度活化的补体成分在BDI、IRI以及BD与I/R引起的级联性致伤效应中起核心作用，并阻碍移植肝的修复。本研究拟借助小鼠BD及肝移植模型，利用不同补体基因缺失小鼠以及不同靶向性补体抑制剂探讨BDD 肝移植过程中BDI、IRI及级联性损伤中的补体依赖性作用及其相关机制，并验证靶向性补体抑制剂治疗的效应。探讨BDD肝移植中的补体依赖性致损机制并寻求新的治疗策略。

脑死亡供体（Brain death donor , BDD）肝移植容易出现术后移植肝功能不全甚至原发性无功能（primary no function , PNF），脑死亡引起的损伤（Brain death-induced injury, BDI）以及缺血/再灌注损伤（ischemia reperfusion injury, IRI）是至关重要的风险因素，具体损伤机制不明。我们的工作假设是：BD及I/R过程协同诱发补体的过度激活，过度活化的补体成分在BDI、IRI以及BD与I/R引起的级联性致伤效应中起核心作用，并阻碍移植肝的修复。本研究拟借助小鼠BD模型，利用不同补体基因缺失小鼠以及不同靶向性补体抑制剂探讨BDD 肝移植过程中BDI的补体依赖性作用及其相关机制，并进一步验证靶向性补体抑制剂治疗的效应及可行性。通过项目研究，探讨BDD肝移植中的补体依赖性致损机制并寻求新的治疗策略。