PARP-1调控急性肺损伤中中性粒细胞浸润和活化的作用及其分子机制研究

在急性肺损伤中，中性粒细胞的活化和组织浸润是重要参与因素之一。研究表明，PARP-1与组织炎症反应密切相关。前期实验发现，抑制PARP-1活性可减少脂多糖引起的肺组织中浸润的中性粒细胞，并有效缓解了肺组织损伤；阻断PARP-1直接影响中性粒细胞ROS的释放和IL-8诱导的细胞迁移，表明PARP-1与中性粒细胞的活化和浸润有重要关系。本项目拟对PARP-1调控中性粒细胞迁移和活化的分子机制进行研究，以加深对急性肺损伤中中性粒细胞作用机制的了解。. 研究包括：（1）PARP-1调控中性粒细胞浸润和活化参与急性肺损伤的研究；（2）PARP-1对中性粒细胞迁移的调控作用及分子机制，检测细胞表面受体、黏附分子和细胞迁移重要分子的表达和活化；（3）PARP-1对中性粒细胞活化的影响，检测脱粒作用、细胞因子、反应活性氧。本研究将为急性肺损伤的治疗提供理论依据，也将为相关药物研发提供参考。

The activation and infiltration of neutrophils play a critical role in the progress and exacerbation of acute lung injury (ALI). Increasing evidences indicate that poly(ADP-ribose) polymerase-1(PARP-1) was involved in the inflammation responses in several animal models. In the previous study, inhibition of PARP-1 decreased the infiltration of neutrophils in lung tissue and attenuated the inflammation responses in a LPS-induced ALI model, suggesting that PARP-1 may modulate neutrophil migration and activation. Preliminary results found that inhibition of PARP-1 blocked neutrophil ROS production and decreased IL-8-induced neutrophil chemotaxis. In this proposal, we would like to explore the molecular mechanisms of PARP-1-mediated neutrophil migration and activation, which is beneficial for understanding the roles of neutrophils in the pathogenesis of ALI. . This study is divided into 3 parts: (1) the role of activation and infiltration of neutrophil modulated by PARP-1 in ALI. (2) the mechanism of PARP-1-mediated neutrophil migration, including the detection of the expression and activation of receptors, adhesion molecules and key neutrophil migration regulators. (3) the function of PARP-1 in regulating neutrophil activation, such as degranulation, secretion of cytokines and chemokines, ROS generation. Our studies will provide new mechanisms and pharmacological target for treatment of ALI.