肠黏膜PD-L1/PD-1 通路在脓毒症肠免疫功能障碍中的作用及机制研究

项目名称： 肠黏膜PD-L1/PD-1 通路在脓毒症肠免疫功能障碍中的作用及机制研究

项目编号： No.81501647

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 吴友平

作者单位： 中国人民解放军南部战区总医院

项目金额： 18万元

中文摘要： 淋巴细胞功能失调是导致脓毒症免疫功能障碍的重要因素，肠粘膜淋巴组织功能失调诱发或加重肠屏障功能障碍，在脓毒症进程中起重要作用。共抑制分子PD-L1/PD-1通路抑制淋巴细胞活化及功能，是导致脓毒症淋巴细胞无能的原因之一。研究发现PD-L1/PD-1通路在胃肠道炎症性疾病模型中具有调控作用，我们前期研究也发现肠上皮细胞表达PD-L1，而且基因敲除PD-L1对脓毒症小鼠肠通透性具有保护作用，PD-L1/PD-1通路是否在脓毒症肠粘膜淋巴组织功能失调中起作用尚不清楚。本课题拟通过研究肠黏膜内PD-L1及PD-1表达及定位；体外及在体阻断PD-L1/PD-1通路对肠粘膜淋巴细胞增殖、凋亡及功能的影响，旨在阐明肠黏膜PD-L1/PD-1通路在脓毒症肠免疫屏障功能障碍中的作用及机制，为以PD-L1/PD-1通路为靶点治疗脓毒症提供基础。

中文关键词： 脓毒症；肠屏障功能；免疫失衡；共刺激分子；细胞凋亡

英文摘要： Lymphocytes dysfunction is one of the important factors in sepsis-induced immunosuppression. Dysfunction of intestinal mucosal lymphoid tissue induces or aggravates the intestinal barrier dysfunction, play an important role in the process of sepsis. Increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles in T cell incompetence. Study found that PD-L1 / PD-1 pathway regulating gastrointestinal inflammatory disease. Our previous study has also proved that intestinal epithelial cell (IEC) express PD-L1, gene deficiency of PD-L1 protected mice intestinal barrier function during sepsis. Whether PD-L1 on IEC interaction with PD-1 on intestinal mucosa lymphocyte presented in intestine and whether this interaction is the cause of intestinal immune barrier dysfunction is not defined. In this study we will investigate the expression pattern of PD-L1 and its receptor PD-1 in the small intestine of mice during sepsis, the effect of anti-PD-L1 antibody on mice intestinal immune barrier function during sepsis, explore the mechanisms of PD-L1 regulating intestinal immune barrier function in vitro. The results of our study will provide the theoretical foundation for PD-L1/PD-1 pathway as the target for the treatment of sepsis.

英文关键词： sepsis;intestinal barrier function;immune inbalance;co-inhibitary molecule;cell apoptosis