炎症失控是肝移植急性肺损伤（ALI）的重要机制，随着损伤因素撤除，炎症消退障碍成为肺损伤持续发展和恶化的关键因素。既往我们在国自然基金支持下筛选出SerpinB1为炎症消退调控新靶点，介导中性粒细胞凋亡。预实验发现SerpinB1表达具节律性，生物信息学提示其受时钟蛋白REV-ERBα调节，并发现损伤肺组织REV-ERBα表达减少，SerpinB1表达节律受抑制及中性粒细胞凋亡延迟，提示SerpinB1介导的炎症消退受节律调控。据此提出“REV-ERBα钟控节律失振荡负调控SerpinB1合成，导致肝移植早期肺组织炎症消退障碍，加重ALI”的科学假想。本项目拟构建REV-ERBα敲除小鼠肝移植及细胞损伤模型，结合基因过表达和沉默手段，通过检测SerpinB1及炎症消退相关指标等阐明REV-ERBα调控SerpinB1在肝移植ALI中的作用机制，为防治肝移植ALI提供理论依据和新的干预靶点。

Uncontrolled inflammatory response is an important mechanism of acute lung injury (ALI) in liver transplantation. Removal of injury factors does not constrain inflammation effectively that its resolution appears to be hindered. Previously with the support of National Natural Fund, we found SerpinB1 as a new target in regulating the resolution of inflammation, which mediates neutrophil apoptosis. Preliminary experiments showed that SerpinB1 expressed according to circadian rhythm. Bioinformatics suggested that it is regulated by the circadian clock component REV-ERBα. It was also found that in the injured lung tissue, the expression of REV-ERBα decreased, the expression rhythm of SerpinB1 was inhibited, and the apoptosis of neutrophils was delayed, suggesting that SerpinB1-mediated inflammation resolution was regulated by circadian rhythm. Therefore, we hypothesize that the loss of circadian oscillation of REV-ERBα suppresses the synthesis of SerpinB1, which leads to failed resolution of pulmonary inflammation in the early stage of liver transplantation, aggravating ALI. This project plans to establish liver transplantation model in REV-ERBα-knockout mice as well as cell injury model to evaluate SerpinB1 and markers of inflammation resolution, using gene overexpression and silencing tools. Through this design, we aim to illustrate the role of SerpinB1 regulation by REV-ERBα in ALI during liver transplantation in hope to provide theoretical basis and novel therapeutic targets for ALI prevention and treatment in liver transplantation.