Ahr转录激活CYP1下调Wnt信号通路在高压氧导致的急性肺损伤中的作用研究

潜水是经济、国防建设及军事行动中不可缺少的技术。氧气是维持潜水员生命的必备元素，但在水下等高压环境下呼吸高浓度的氧气（高压氧）,会导致急性肺损伤（ALI）。目前对于高压氧导致的ALI缺乏有效防治措施。细胞色素（CYP）450是肺组织中代谢氧气的主要激酶。课题组前期研究发现高压氧可诱导CYP1及其转录因子Ahr在肝肺表达，CYP1活化对高压氧导致的ALI具有保护作用，转录组芯片结果显示CYP1活化下调Wnt通路。Wnt通路介导的生理过程参于维持肺血管内皮屏障的完整性和介导肺纤维化。本项目拟通过体内外实验证实Ahr转录激活CYP1可减轻高压氧导致的ALI，明确Wnt信号通路下调及其下游效应通路的改变在CYP1保护效应中的关键作用，并从调控转录激活及蛋白质泛素化降解两方面，阐明两者之间的调控机制，最后采用基因敲除鼠体内验证。从而加深对高压氧致ALI的发病机制的认识，为临床防治提供新的靶点。

Diving is an indispensable technology in economy, national defense and military operations. Oxygen is a necessary element to maintain the life of divers, but breathing high concentration of oxygen under high pressure environment (hyperbaric oxygen, HBO) such as underwater can lead to acute lung injury (ALI). Currently, there is no effective treatment strategy for HBO-induced ALI. Cytochrome P450 (CYP) is the major kinase that metabolizes oxygen in lung tissue. Our previous studies have shown that CYP1 and its transcription factor Ahr can be induced by HBO in liver and lung. CYP1 activation has protective effect on ALI caused by HBO. Results of transcriptome microarray showed that CYP1 activation can down-regulate Wnt pathway. Wnt pathway plays an important role in regulating cell-cell adhesion and epithelial cell proliferation. These physiological processes are involved in maintaining the integrity of the pulmonary vascular endothelial barrier and mediating pulmonary fibrosis. This project aims to observe the effect of Ahr transcriptional activation of CYP1 on HBO-induced ALI, to explore if down-regulation of Wnt signaling pathway and its downstream effector pathway play critical role in CYP1 protective effect, and to clarify the regulatory mechanism. With the results of this project, we will have a better understanding of the pathogenesis of HBO-induced ALI and find new therapeutic targets for clinic treatment.