血管内皮细胞通透性增高是脓毒症脏器功能损伤的重要原因，机体对其保护机制尚不清楚。我们前期研究发现肾上腺髓质应激激素蛋白CGA衍生多肽CHR能阻断炎症介质TNF-α引起血管内皮细胞高渗透性。已知Rho/ROCK和p38MAPK信号通路是调控内皮细胞渗透性重要途径。我们假设CHR通过这2条路径改善脓毒症时TNF-α引起血管内皮细胞高通透性。 本课题拟以EA.Hy926细胞，LPS脓毒症小鼠模型为研究对象，利用合成CHR、Rho/ROCK和p38MAPK信号通路特异拮抗剂和血管内皮细胞靶向、实时诱导CHR过表达慢病毒载体等技术，观察CHR对TNF-α引起血管内皮细胞高渗透性及Rho/ROCK和p38MAPK信号途径下游各靶分子的影响并初步阐明其作用机理，进一步明确CHR对脓毒症不同病程阶段血管内皮细胞和脏器的保护作用。 本研究将从神经内分泌角度为脓毒症中血管内皮细胞及脏器功能保护提供新的理论依据

The hyperpermeability of vascular endothelium is critical to lead to the dysfunction of the target organs in septic patients. The underlying mechanism by which the body protects the target organs is, however, not clear under such stress. Our previous studies have shown that the adrenal hormone CGA-derived peptide chromofungin (CHR) could ameliorate the TNF-α-induced hyperpermeability in vascular endothelium. The Rho/ROCK and p38MAPK signaling pathways have previously been implicated in the process of hyperpermeability in vascular endothelium by TNF-α. We hypothesize that CHR could execute its protective function in TNF-α-induced hyperpermeability in vascular endothelium through the Rho/ROCK and p38MAPK signaling pathways。 The goal will be achieved by using EA.Hy926 cells and LPS-induced sepsis mice model with the synthetic CHR peptide, the antagonists against the Rho/ROCK and p38MAPK signaling pathways，and an endothelium-specific, real-time inducible CHR overexpression lentiviral system. We plan to investigate the effect of CHR on the hyperpermeability of vascular endothelium and the expression of the components in the Rho/ROCK and p38MAPK signaling pathways. These findings will confirm the protective role of CHR in the target organs and help to understand the mechanism of how CHR plays such a role in different phage of sepsis pathophysiology. The study will elucidate the new protective mechanism in vascular endothelia and the target organs in pathogenesis of sepsis by neuroendocrine-immune system.