HMGB1激活血小板NLRP3炎性小体对重症中暑血管内皮损伤的调控机制研究

项目名称： HMGB1激活血小板NLRP3炎性小体对重症中暑血管内皮损伤的调控机制研究

项目编号： No.81471839

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： 童华生

作者单位： 中国人民解放军南部战区总医院

项目金额： 69万元

中文摘要： 基于血管内皮损伤发生的微血栓和炎症反应是重症中暑发病的关键。重症中暑炎症启动与血栓形成之间存在基于血管内皮为媒介的网络关系，血小板在这种网络关系中发挥重要的调控作用。重症中暑血小板以何机制对血管内皮损伤发挥调控作用未见报道。2013年研究发现血小板可基于线粒体ROS激活NLRP3炎性小体促进IL-1β释放的方式诱导血管内皮损伤。HMGB1为一种典型的DAMP分子可诱导线粒体ROS进而激活NLRP3炎性小体。HMGB1诱导血小板线粒体ROS产生可引起血管内皮损伤。基于线粒体ROS与重症中暑发病密切相关，且我们前期发现重症中暑发病早期HMGB1即呈高水平，HMGB1和线粒体ROS特异性抑制可阻止重症中暑血小板NLRP3炎性小体活化并降低血小板诱导的血管内皮损伤。基于此我们提出假设并期探讨其相关机制：重症中暑血小板可基于HMGB1诱导线粒体ROS触发NLRP3炎性小体激活的方式调控血管内皮损伤。

中文关键词： 重症中暑；血管内皮；血小板；炎性小体；损伤

英文摘要： Multiple organ dysfunction is the leading cause of high mortality rate in severe heatstroke, with the essential pathogenesis of microthrombus and inflammatory reaction due to vascular endothelial injury. It is proved that complicated network forms between inflammatory initiation and thrombosis mediated by the vascular endothelium in multiple critical illnesses including severe heatstroke, in which platelet takes key roles. However, it is seldom reported about its mechanisms of the regulatory role of platelet in vascular endothelium injury in heatstroke. It is found that platelet can stimulate NLRP3 inflammasome to release IL-1β through mitochondria ROS activation, which takes roles on regulating vascular endothelium injury in the recent 2013 research report. HMGB1, a typical DMAP molecule, can also act in a similar way to activate NLRP3 inflammasome induced by mitochondria ROS. Platelet mitochondria ROS,initiated by HMGB1, can induce vascualr endothelium injury.Based on the close relationship between mitochondria ROS and severe heatstroke pathogenesis, combined with our previous results that high HMGB1 levels in early stage of severe heatstroke,and specifically inhibiting HMGB1 and mitochondria ROS can prevent the activation of platelet NLRP3 inflammasome and reduce its regulatory effect on vascular endothelium injury.We assumed that platelet can play regulatory roles in vascular endothelium injury through the mitochondria ROS activation of NALP3 inflammasome induced by HMGB1.In the present project,we explore the molecular mechanism of vascular endothelium injury induced by activated platelet based on NLRP3 inflammasom in heatstroke.

英文关键词： Heatstroke;Vascular endothelium;Platelet;Inflammasome;Injury