IRF-1调控肺泡巨噬细胞焦亡在急性肺损伤中的作用及信号机制

项目名称： IRF-1调控肺泡巨噬细胞焦亡在急性肺损伤中的作用及信号机制

项目编号： No.81470266

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： 潘频华

作者单位： 中南大学

项目金额： 70万元

中文摘要： ALI/ARDS的发病机制还未清楚。本研究在我们以前对IRF-1调控脓毒症发病机制的基础上，研究肺泡巨噬细胞细胞焦亡在ALI/ARDS的作用,以期发现新的治疗靶点。我们前期研究发现IRF-1基因敲除减轻了脓毒症相关性肺损伤和死亡率，并伴有肺组织和肺泡巨噬细胞caspase-1活化下降。但尚不清楚IRF-1是否主要通过调控肺泡巨噬细胞焦亡参与ALI/ARDS的发生。本项目以野生型、IRF-1 基因敲除小鼠为研究对象，分别以LPS气管内滴入和腹腔注射制备肺内和肺外致病因素ALI/ARDS模型，在体阐明IRF-1调控肺泡巨噬细胞焦亡在ALI/ARDS中的作用；并进一步通过原代培养野生型和IRF-1基因敲除小鼠肺泡巨噬细胞和巨噬细胞株RAW264.7，体外证实IRF-1调控肺泡巨噬细胞焦亡致肺损伤的细胞分子机制及其上下游信号调控机制，为ALI/ARDS寻找新的治疗途径打下坚实的理论基础。

中文关键词： 干扰素调节因子-1；肺泡巨噬细胞；细胞焦亡；急性肺损伤；信号通路

英文摘要： The pathogenesis of ALI/ARDS remains unclear. Basing on our previous study on the role of IRF-1 in sepsis, this study focus on the role of alveolar macrophages pyroptosis in the pathogenesis of the ALI/ARDS, aimed to find new therapeutic targets for ALI/ARDS. Our previous study found that IRF-1 gene knockout relieved sepsis-induced lung injury and mortality in mice, accompanied by decreased expression of active caspase-1 in lung tissue and alveolar macrophages. But it is unclear whether IRF-1 involves in the pathogenesis of ALI / ARDS mainly by modulating alveolar macrophages pyroptosis. With wild type, IRF-1 knockout mice as the object,this project uses pulmonary and extrapulmonary pathogenic factors-induced ALI/ ARDS model, prepared by intratracheal instillation or intraperitoneal injection of LPS,to study the role of alveolar macrophages pyroptosis regulated by IRF-1 in the pathogenesis of the ALI/ARDS in vivo.Furthermore, in vitro experiments are performed to clarify the role of IRF-1 in regulation of macrophage pyroptosis and lung injury，and the upstream and downstream signal regulatory mechanism of IRF-1 regulation of alveolar macrophage pyroptosis,by primary culturing alveolar macrophages from wild-type and IRF-1 knockout mice and macrophage cell line RAW264.7,which will lay a solid theoretical basis for new therapeutic approach for ALI/ARDS.

英文关键词： interferon regulatory factor-1;alveolar macrophage;pyroptosis;acute lung injury;signal pathway