基于血管内皮损伤的胞外组蛋白对脓毒血症进展的分子机制研究

项目名称： 基于血管内皮损伤的胞外组蛋白对脓毒血症进展的分子机制研究

项目编号： No.81201450

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： 曹清

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 血管内皮细胞(EC)活化和功能障碍是脓毒症发展恶化的中心环节。最近研究表明胞外组蛋白是脓毒症关键致死因素，其机制不明，但利用活化蛋白C（APC）酶切组蛋白可显著降低脓毒症小鼠死亡率。我们前期工作发现脓毒症伴多脏器功能障碍综合征(MODS)患儿血清中组蛋白浓度明显增高，且与疾病严重程度正相关；此外，重组组蛋白与EC共同孵育，可引起炎症因子释放并诱导EC凋亡。我们推测，组蛋白可能通过激活EC上Toll样受体激活NF-κB信号通路，引起大量炎性因子释放并诱导EC凋亡；同时下调血栓调节素表达、降低APC含量进而干扰组蛋白的正常代谢、致使大量组蛋白累积促发MODS发生。为验证本推断，我们将首先探索组蛋白对EC的作用及其机制；然后阐明组蛋白/APC表达水平差异与脓毒症严重程度的相关性。本研究的完成将丰富脓毒症及MODS致病的分子机制，也为组蛋白作为脓毒症疾病进展的分子生物学标记物的可能性提供理论依据。

中文关键词： 脓毒症；胞外组蛋白；内皮细胞；细胞毒性；肝素

英文摘要： Activation and dysfunction of endothelial cells (EC) play pivotal roles in sepsis progression . Recent studies have shown that extracellular histones are major mediators of death in sepsis, but the underlying mechanism is unknown. Treatment of the mice with activated protein C (APC) could significantly decrease the mortality. Our previous study showed that when compared with the control group，the levels of peripheral histones in children with multiple organ dysfunction syndrome (MODS) were significantly higher, and positively correlated with disease severity. Co-incubation of recombinant histone proteins with EC could induce production of cytokines and EC apoptosis, suggesting that extracellular histones might be a key factor in the pathogenesis of MODS. Therefore, we hypothesize that extracellular histones might activate EC by interacting with Toll-like receptors, leading to activation of NF-κB pathway, which cause production of a large number of inflammatory cytokines, and consequently EC apoptosis; at the same time reduce thrombomodulin expression and APC concentration which interferes with the extracellular histones metabolism, Such accumulation of extracellular histones might further exacerbate the inflammatory response-induced incidence of MODS. In order to demonstrate our hypothesis, we will first explore

英文关键词： sepsis；extracellular histones；endothelial cells；cytotoxicity；heparin