FAK抑制剂对ICAM-1介导的炎症反应中的作用

急性肺损伤是肺脏的一种过度炎症反应，严重情况下可发展为急性呼吸窘迫综合征，目前尚缺乏有效的治疗药物和新的治疗手段。中性粒细胞的过度活化是导致失控性炎症反应的主要原因，而中性粒细胞的活化有赖于内皮细胞的黏附作用，其中粘附分子ICAM-1负责中性粒细胞的紧密黏附和跨内皮细胞迁移，ICAM-1还是炎症反应和组织损伤愈合的总调控者。ICAM-1在急性肺损伤中的作用机理尚未完全阐明。FAK是一种黏着斑激酶，前期研究发现FAK会促进小鼠的急性肺损伤并与ICAM-1表达密切相关；肺内皮细胞中的FAK缺失，炎症因子的产生明显减少。本研究拟阐明FAK在调节内皮细胞介导急性肺损伤的机制，通过探明FAK在急性肺损伤中的重要作用，重点探讨ICAM-1调控FAK表达的分子机制，探索FAK抑制剂PF-573228治疗急性肺损伤的分子机制，同时为呼吸窘迫综合症的治疗提供一个潜在的新型药物靶标。

Acute lung injury is an excessive inflammatory reaction in the lungs. In severe cases, it develops into acute respiratory distress syndrome. So far, there are no effective drugs and new treatments. The excessive activation of neutrophils lead to uncontrolled inflammatory response. Activation of neutrophils depends on the adhesion of endothelial cells, in which the adhesion molecule ICAM-1 is responsible for the tight adhesion of neutrophils and transendothelial cell migration. ICAM-1 is a master regulator of inflammatory response and tissue injury healing, but its mechanism of action in acute lung injury haven’t yet been fully elucidated. FAK is focal adhesion kinase. Based on our novel preliminary data that FAK promotes acute lung injury in mice. Deficient of FAK significantly reduce inflammatory factors expression in lung endothelial cells. Therefore, this study intends to clarify the mechanism of FAK regulating endothelial cells to mediate acute lung injury, to explore the important role of FAK in acute lung injury. In addition, this studies will focus on the molecular mechanism of ICAM-1 regulating FAK expression, and evaluate whether FAK inhibitor PF-573228 will be able to alleviate acute lung injury. Taken together, our finding will provide a potential drug target for treating of respiratory distress syndrome.