基于MIF/CD74通路探讨肺泡巨噬细胞极化在肝移植围术期急性肺损伤中的作用

项目名称： 基于MIF/CD74通路探讨肺泡巨噬细胞极化在肝移植围术期急性肺损伤中的作用

项目编号： No.81471892

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 池信锦

作者单位： 中山大学

项目金额： 72万元

中文摘要： 急性肺损伤(ALI)是肝移植术后早期死亡的主要原因，机制未完全阐明,缺乏有效防治方法。虽肺泡巨噬细胞(AM)在ALI中的作用得到确认，但缺乏干预手段。我们前期研究发现肝移植围术期ALI显著的肺组织中MIF表达上调，AM主要以促炎活性的M1存在,且MIF表达量、M1/M2比例与ALI严重程度一致。MIF/CD74通路激活促进巨噬细胞在炎症局部的聚集、活化和细胞因子分泌，影响巨噬细胞极化。据此，我们提出假设MIF/CD74调控AM向M1表型分化是肝移植围术期ALI发生的关键所在。本课题拟用大鼠肝移植模型、CD11c-DRT转基因小鼠剔除M1巨噬细胞后自体肝移植模型、离体肺灌注模型，结合CD74基因敲除鼠及CD74激动剂/拮抗剂等干预，通过在体实验和体外细胞学研究，阐明MIF/CD74通路调控AM极化在移植肝围术期ALI发生、发展中的作用及机制，为防治肝移植围术期ALI提供理论及实验依据。

中文关键词： 巨噬细胞移动抑制因子；肺泡巨噬细胞；肝移植；急性肺损伤

英文摘要： Acute lung injury(ALI) is a major cause of early death after liver transplantation, the mechanism is still not fully elucidated and there's a lack of effective prevention and treatment. Despite that the role of the alveolar macrophages (AM) in the development of ALI is confirmed, the effective intervention has not been found all over the world. Our previous studies have found that the expression of macrophage migration inhibition factor(MIF) is significantly increased in the lung tissue following liver transplantation which is coincident with perioperative acute lung injury, and AM mainly exists as the M1 phenotype having pro-inflammatory activity. The MIF expression quantity and the proportion of M1/M2 are in accordance with the severity of post-operative ALI. The activation of MIF/CD74 pathways promote macrophages to recruit、activate and secret cytokines in inflammatory area, then impact the polarization of macrophages. In view of the above, we put forward the hypothesis that MIF/CD74 signaling pathway plays a key role in regulating the differentiation of AM toward M1 phenotype and the subsequent perioperative ALI following liver transplantation. This study will illuminate the function and mechanism of the MIF/CD74 pathways regulating AM polarization on the occurrence and development of perioperative acute lung injury following liver transplantation by using the rats liver transplantation model, CD11c-DRT transgenic mice autologous transplantation model which have been excluded M1 macrophages and isolated lung perfusion model,combining with CD74 knockout mice and the drug interventions, such as CD74 agonist/antagonist, through in vivo experiments in animals and in vitro experiments in cultured cells. This study will provide theoretical insights for the prevention of perioperative acute lung injury following liver transplantation.

英文关键词： macrophage migration inhibition factor(MIF);alveolar macrophages(AM);liver transplantation(LT);acute lung injury(ALI)