肺巨噬细胞S1P3在脓毒症致急性肺损伤发生发展中的作用及分子机制

项目名称： 肺巨噬细胞S1P3在脓毒症致急性肺损伤发生发展中的作用及分子机制

项目编号： No.81201495

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学四处

项目作者： 谢郭豪

作者单位： 浙江大学

项目金额： 23万元

中文摘要： 肺脏是脓毒症中受累的首位靶器官。肺巨噬细胞过度活化可直接造成肺部炎症反应增强和脓毒症致急性肺损伤的发生、发展。S1P3组成型表达于巨噬细胞，在介导巨噬细胞向炎症病灶募集、趋化因子的产生中发挥重要作用。我们前期研究发现：脓毒症致急性肺损伤小鼠肺巨噬细胞S1P3蛋白表达水平明显上调；离体实验S1P3在LPS 刺激后转录水平显著升高，炎性因子转录水平变化与S1P3一致。使用S1P3拮抗剂处理可下调炎性因子转录水平。因此我们推测：S1P3通过调节肺巨噬细胞活化，促发炎症反应，参与脓毒症致 ALI的发生发展。本项目拟从整体、细胞、分子水平，分析肺巨噬细胞S1P3与脓毒症致急性肺损伤发生、发展的相关性，明确S1P3介导巨噬细胞活化及其对炎症反应的调控的作用，探讨S1P3调控巨噬细胞活化的分子机制。最终，阐明S1P3在脓毒症致急性肺损伤发生、发展中的作用及分子机制，并为急性肺损伤防治提供新思路、新靶向。

中文关键词： 脓毒症；肺损伤；S1PR2；S1PR3；巨噬细胞

英文摘要： The lungs are the most vulnerable organs in sepsis. Over-activated pulmonary macrophages would directly exacerbate the pulmonary inflammation and mediate the initiation and development of sepsis induced acute lung injury (ALI). Sphingosine-1 phosphate receptor 3 (S1P3), which is constitutively expressed on macrophages, plays a pivotal role in chemokine production of macrophages as well as its recruitment into the inflammatory lesion. In our pilot studies, it was demonstrated that S1P3 protein level was remarkably elevated in pulmonary macrophages in rat model of sepsis induced ALI. Our in vitro expriments showed that transcriptional level of S1P3 was significantly up-regulated in LPS-stimulated macrophages, which paralleled with the expression of pro-inflammatory cytokines. And administration of S1P3 antagonist could down-regulate these pro-inflammatory mediators. Therefore, we hypothesize that S1P3 will be involved in the pathogenesis of sepsis induced ALI via modulating pulmonary macrophage activation and promoting inflammatory response. The present project will, from the systemic, cellular and molecular levels, analyze the correlation between pulmonary macrophage S1P3 level and lung injury score, inflammation inducced by sepsis, to clarify the roles of S1P3 in pulmonary macrophage activation and inflammation

英文关键词： sepsis；lung injury；S1PR2；S1PR3；macrophage