FAK信号通路在严重烧伤早期肝素结合蛋白介导血管内皮细胞损伤中的作用机制

严重烧伤早期，血浆肝素结合蛋白（HBP）的水平已证实与炎症因子产生和毛细血管通透性的增加等密切相关。我们前期研究结果表明GEF-H1/RhoA信号通路的活化是血管内皮细胞炎症因子的产生与释放以及内皮细胞通透性增加的重要因素之一。然而微血管内皮屏障的变化不仅取决于细胞间紧密粘附连接，而且还取决于内皮细胞与周围基质之间的接触位点黏着斑的变化。黏着斑的调控却有赖于黏着斑激酶（FAK）的活性。本项目的预实验结果提示HBP可在短时间内激活内皮细胞中FAK，通过FAK的活化不仅细胞内GEF-H1和 p-MYPT-1活性显著增加，而且p65的磷酸化水平以及MCP-1和VCAM-1 的表达均明显升高。因此，我们推测严重烧伤早期，HBP通过激活内皮细胞FAK信号通路，介导炎症因子的表达和内皮细胞通透性的改变。从而更加全面地理解严重烧伤早期烧伤休克的细胞和分子生物学机制，为临床防治提供新的思路。

In the early severe burns, increasing level of Heparin-binding protein (HBP) in plasma is closely associated with expression of cytokines and dysfunction of systemic vascular permeability. Our previous studies confirmed that GEF-H1/RhoA signaling pathway mediated endotoxin-induced expression of inflammatory cytokines and permeability dysfunction in endothelial cells. However, changes of microvascular vascular permeability not only depend on intercellular adhesion, but also depend on changes of focal adhesion through which the cytoskeleton of endothelial cells connect to the extracellular matrix. Focal adhesion is regulated by focal adhesion kinase (FAK). In the present study, we found HBP could activate FAK within a short time in microvascular endothelial cells. HBP not only increased significantly activity of GEF-H1 and p-MYPT-1, but also upregulated significantly expression of p-p65, MCP-1, VCAM-1 in endothelial cells. Taken together, we assume that HBP regulates expression of inflammatory cytokines and vascular permeability compromise through activation of FAK signaling pathway in the early severe burns. The purpose of study is to fully illustrate the cellular and molecular biological mechanisms of burn shock during the early stage after severe burns, and to provide strategical methods for clinical treatments.