SerpinB1对STAT3磷酸化调控在中性粒细胞凋亡延迟及肝移植急性肺损伤炎症消退中的作用研究

Excessive inflammatory response plays a critical role in acute lung injury (ALI) after liver transplantation (LT), but the effects of anti-inflammation therapy were not obvious as expected. Delay of neutrophil apoptosis is closely related to pulmonary inflammation resolution and study focus on regulation of neutrophil apoptosis will help us find out the effectively target against ALI induced by LT. Interestingly, our proteomic study showed that serpinB1 was up-regulated in injured lung tissue after LT. Furthermore, we found STAT3 was a predicted target of serpinB1 by using bioinformatics analysis. Moreover, our preliminary study showed that inhibition of serpinB1 could decrease the phosphorylation of STAT3 and effectively promote neutrophil apoptosis. Based on these, we hypothesize that serpinB1 regulates neutrophil apoptosis via regulating of phosphorylation of STAT3, leading to improve inflammation resolution occurred in ALI induced by LT. We will incorporate the uses of SerpinB1 gene knockout mice and the uses of adenovirus SerpinB1 overexpression as well as SerpinB1, STAT3 genes silences to explore the roles of SerpinB1 and STAT3 and their interplays in affecting lung inflammation resolution post-LT both in vivo and in vitro.

炎症失控在肝移植急性肺损伤（ALI）中起重要作用，ALI的程度和发展取决于炎症消退快慢，中性粒细胞（PMN）凋亡延迟限制炎症消退，而调控PMN凋亡的机制仍不明确。申请人通过蛋白组学研究发现大鼠肝移植ALI时PMN中SerpinB1高表达，与PMN浸润程度一致，生物信息学预测信号转导与转录激活因子（STAT3）为其重要靶点；预实验结果显示抑制SerpinB1可降低PMN中STAT3磷酸化水平并促进PMN凋亡。据此我们设想：SerpinB1通过STAT3调控PMN凋亡在肝移植ALI炎症消退中起着重要作用。本项目拟用野生型和SerpinB1-/-小鼠肝移植模型及细胞学损伤模型，结合基因过表达和沉默等手段，通过检测肺损伤、PMN凋亡、炎症因子及相关蛋白表达等阐明SerpinB1调控PMN凋亡在肝移植ALI炎症消退中的作用机制，为以促炎症消退为手段防治肝移植ALI提供理论依据和新的特异性干预靶点。

炎症失控在肝移植急性肺损伤（ALI）中起重要作用，ALI的程度和发展取决于炎症消退快慢，中性粒细胞（PMN）凋亡延迟限制炎症消退，而调控PMN凋亡的机制仍不明确。申请人通过蛋白组学研究发现大鼠肝移植ALI时PMN中SerpinB1高表达，与PMN浸润程度一致，生物信息学预测信号转导与转录激活因子（STAT3）为其重要靶点；预实验结果显示抑制SerpinB1可降低PMN中STAT3磷酸化水平并促进PMN凋亡。据此我们设想：SerpinB1通过STAT3调控PMN凋亡在肝移植ALI炎症消退中起着重要作用。本项目拟用野生型和SerpinB1-/-小鼠肝移植模型及细胞学损伤模型，结合基因过表达和沉默等手段，通过检测肺损伤、PMN凋亡、炎症因子及相关蛋白表达等阐明SerpinB1调控PMN凋亡在肝移植ALI炎症消退中的作用机制，为以促炎症消退为手段防治肝移植ALI提供理论依据和新的特异性干预靶点。