脓毒症所致的急性肺损伤发病率和病死率居高不下，探索其机制意义重大。我们前期研究用2D-DIGE技术分离正常和RAGE基因敲除的CLP脓毒症模型组小鼠肺脏组织蛋白，对差异表达蛋白进行鉴定，发现有三个差异蛋白点为同一种蛋白质Krt7，提示Krt7蛋白受RAGE的调控。且运用单层上皮细胞以及整体动物模型初步证实了RAGE和Krt7参与了脓毒症时HMGB1介导的肺上皮细胞通透性的增高。据此提出在脓毒症模型中HMGB1与RAGE结合后通过mDia1引发cdc42/Rac以及p38活化，进而激活Krt7，后者则可通过破坏细胞间连接Desmosomes诱导上皮细胞通透性增高的假说。拟利用敲基因小鼠、原代上皮细胞培养、siRNA、单层上皮细胞通透性及肺的干湿重比等多种手段，从分子、细胞和整体模型层面对RAGE、Krt7和Desmosomes在脓毒症小鼠致肺上皮细胞屏障功能障碍中的作用机制进行探讨。

Sepsis is a systemic inflammatory response syndrome caused by microbial infection, which is one of the serious complications of serious infection. It will lead to septic shock, ALI, ARDS, MODS and so on. Our previous study has demonstrated that Krt7 expression was regulated by RAGE after cecal ligation and puncture (CLP). By utilizing lung epithelial monolayer model, we identified that RAGE and Krt7 were involved in lung epithelial hyperpermeability induced by HMGB1 in septic shock. Based on the results, we assume that HMGB1 binding to RAGE can promote oxidative stress through mDia1 activation, followed by cdc42 activation and p38 phosphorylation, which lead to Krt7 phosphorylation. By promotion cell-cell junction disassembly via Desmosomes, activated Krt7 could lead to lung epithelial barrier dysfunction. We aim to explor the effect and signal mechanism of RAGE, Krt7 and Desmosomes in this process, through a series of techniques including RAGE knockout mice model, primary epithelial cell culture, siRNA, epithelial monolayer permeability assay, and lung dry-wet proportion method et al. The mechanism of lung epithelial hyperpermeability induced by HGB1 can provide therapy target for prevention and cure of ALI in septic shock.