CD40L诱导严重烧伤后肺微血管内皮细胞损伤的机理研究

项目名称： CD40L诱导严重烧伤后肺微血管内皮细胞损伤的机理研究

项目编号： No.81471867

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： 郇京宁

作者单位： 上海交通大学

项目金额： 72万元

中文摘要： 严重烧伤所致的急性肺损伤（ALI）治疗棘手且死亡率高，因而以肺微血管内皮细胞（PMVECs）为靶目标的防治研究具有重要的临床应用价值。严重创伤后循环中CD40L水平异常增高，但CD40L与伤后ALI是否存在内在关系尚不清楚。我们前期研究发现GEF-H1/RhoA信号通路的活化是血管内皮细胞炎症因子表达以及通透性增加的重要因素之一，而CD40L不仅能上调PMVECs内GEF-H1的表达和cleaved caspase-3水平，而且明显减少细胞表面Syndecan-1和VE-cadherin的表达。因此本研究推测CD40L与CD40结合后，活化胞内GEF-H1/RhoA信号通路，造成PMVECs屏障完整性和功能损伤，激活炎症和凋亡反应，从而探讨CD40L诱导烧伤后ALI的病理生理机制，并调控CD40L功能，以期改善PMVECs损伤，为严重烧伤后ALI的防治提供一种新的、潜在的临床治疗手段。

中文关键词： CD40L；血管通透性；急性肺损伤；严重烧伤；肺微血管内皮细胞

英文摘要： High mortality rate and thorny treatment of post-burn patients with acute lung injury (ALI) challenged burn clinic, thus explore of underling mechanisms of post-burn ALI and protection approach is important. Pulmonary microvascular endothelial cells (PMVECs) play a critical role in pathophysiology of ALI after severe burns, so researchers pay more and more attention to how to protect PMVECs in ALI. Abnormally high circulating level of CD40L was found in severe trauma, but the inherent relationship between CD40L and ALI is still unclear. Our previous studies showed that GEF-H1/RhoA signaling pathway activation is an important factor in production of inflammatory cytokines and hyperpermeability of vascular endothelial cells. In the present study, CD40L not only could significantly upregulate GEF-H1 and cleaved caspase-3 expression in PMVECs, but also could significantly reduce the expression of Syndecan-1 and VE-cadherin on the surface of PMVECs. The present study try to improve the hypothesis that CD40L-CD40 signal activates GEF-H1/RhoA signaling pathway, causing PMVECs barrier dysfunction and inflammatory and apoptotic cascades. The research results are benefit to understand mechanisms of the damage of PMVECs in post-burn ALI, and to explore potential strategies to prohibit CD40L-related post-burn ALI.

英文关键词： CD40L;Vascular permeability;Acute lung injury;Sever burn;Pulmonary microvascular endothelial cell