肝移植胆道周围血管丛缺血性损伤中的MAC作用机制及对缺血型胆道病变的影响研究

项目名称： 肝移植胆道周围血管丛缺血性损伤中的MAC作用机制及对缺血型胆道病变的影响研究

项目编号： No.81200328

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 张金彦

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 缺血型胆道病变(ITBL)主要病理表现为胆管周围血管丛（PVP）损伤所致胆管微循环障碍,内皮细胞是损伤的主要靶点，肝脏缺血再灌注(IR)的是其发生的重要原因。我们已报导，肝脏IR激活补体使血管内皮损伤因子增加，通过CD59抑制补体活化终末产物MAC可改善此病理变化。已知MAC主要通过改变[Ca2+]i浓度攻击细胞。由此推测,肝脏IR可通过激活补体生成MAC,后者与PVP内皮细胞结合,在细胞膜形成跨膜通道改变细胞内外Ca2+浓度使细胞损伤,导致胆管微循环障碍形成ITBL。本研究拟用mCd59ab-/-小鼠肝IR及肝移植模型,观察MAC对PVP损伤作用;在单个细胞水平观测MAC诱导血管内皮细胞[Ca2+]i动态变化，探讨MAC对PVP损伤机制;用内皮细胞表达人类CD59的ThCd59End-/-转基因小鼠,探讨人类CD59对缺血胆道损伤保护作用。最终为改善胆道微循环，预防ITBL提供新思路。

中文关键词： 肝移植；缺血再灌注；CD59；；

英文摘要： Ischemic type biliary lesion (ITBL) is mainly characterized by the presence of biliary microcirculatory disorders caused by the injury of peribiliary vascular plexus (PVP). Hepatic ischemia reperfusion (IR) is one of significant reason of the ITBL occurrence. Recently, we reported that hepatic IR during the liver transplantation also results in excessive activation of the complement system, which leads to increase of vascular endothelial damage factors. However, inhibition of membrane attack complex (MAC), a terminal product of complement activation, by the complement regulator CD59 improved the pathological lesion. As we known, MAC attacks the cell by changing the intracellular calcium [Ca2+]i. Therefore, we speculate that, the excessive activation of complement system generates MAC during liver IR. MAC combined with endothelia cells of PVP causes a rapid increase in [Ca 2+]i which is dependent on transmembrane channel change, leading to the disorder of bile duct microcirculation， and results in the formation of ITBL. In this project, firstly, we are going to use mCd59ab-/- mouse and rat liver IR model to observe the effect of MAC on PVP; Secondly, to study the injury mechanism of MAC PVP, we will observe the effect of MAC on the induction vascular endothelial cells [Ca2+]i dynamic change in a single cell l

英文关键词： liver transplantion；ischemia reperfusion；CD59；；