Lung Injury Protection by Coagulation Blockade

这是一个修改后的应用程序，旨在研究肺的凝血系统在急性肺损伤(ALL)中的作用。在急性呼吸窘迫综合征(ARDS)尤其是脓毒症的发病机制中，组织因子(TF)启动凝血和持续促凝血状态是非常重要的。转铁蛋白和其他凝血蛋白与炎症因素沟通，增强肺的损伤反应。此外，纤溶酶原激活物抑制物(PAI-1和-2)和抗纤溶酶的激活抑制了纤溶，促进了纤维蛋白的堆积，导致毛细血管闭塞、透明膜形成、气体交换障碍和肺纤维化。我们在动物实验中发现，在内毒素引起的肺损伤和革兰氏阴性脓毒症的肺损伤中，转铁蛋白拮抗剂可以消除炎症。虽然凝血与ARDS的发病机制密切相关，但凝血级联反应的不同成分如何与炎症和纤溶途径相互作用促进或解决急性肺损伤尚不清楚。为了解决这个问题，我们将验证这样的假设：阻断凝血启动是一种最佳的肺保护策略，它通过防止过度的炎症介质释放和细胞内流，从而降低ALI的结构、功能，并延迟ALI的解决。我们进一步提出，凝血因子以外的其他凝血因子，特别是凝血酶和纤维蛋白，通过独立和协调的细胞因子信号事件调节肺部炎症的特定方面及其在脓毒症中的消退。提出了三个目标：目的1.确定TF如何与影响急性肺损伤中白细胞募集和炎症消退的特定细胞因子/趋化因子的产生相互作用。目的2.研究凝血酶受体-1(PAR-1)如何与特异性细胞因子/趋化因子产生相互作用，从而影响急性肺损伤中白细胞的募集和炎症的消退。目的3.研究纤溶酶原激活物-1(PAI-1)与特异性细胞因子-趋化因子的相互作用，从而影响急性肺损伤中白细胞的募集和炎症的消退。提高对凝血蛋白在急性肺损伤中作用的机制洞察的意义在于提供新的机会，通过针对这些活动的干预来预防异常炎症和紊乱的修复。一个成功的优化策略可以极大地减轻肺部炎症的持久性，并促进人类ARDS的解决。

This is an amended application designed to investigate the role of the lung's coagulation system in acute lung injury (All). Initiation of coagulation by tissue factor (TF) and persistence of the pro-coagulant state are important in the pathogenesis of acute respiratory distress syndrome (ARDS), especially in sepsis. TF and other coagulation proteins communicate with inflammatory elements that enhance the lung's injury response. In addition, fibrinolysis is inhibited by activation of plasminogen activator inhibitors (PAI-1 and -2) and antiplasmins, which promotes fibrin accumulation and contributes to capillary obliteration, hyaline membrane formation, gas exchange impairment, and lung fibrosis. We show in animals that TF blockade abrogates inflammation in lung injury by lipopolysaccharide (LPS) and lung injury in Gram-negative sepsis. Although coagulation is integrally involved in the pathogenesis of ARDS, it is not clear how the different components of the coagulation cascade interact with inflammatory and fibrinolytic pathways to promote or resolve acute lung injury. To address this issue, we will test the hypothesis: blockade of coagulation initiation is an optimal strategy for lung protection by preventing excessive inflammatory mediator release and cell influx that degrades structure, function, and delays resolution of ALI. We further propose that coagulation factors other than TF, especially thrombin and fibrin, regulate specific aspects of lung inflammation and its resolution in sepsis through independent and coordinate cytokine-signaling events. Three aims are proposed: Aim 1. Determine how TF interacts with specific cytokine/chemokine production that influences leukocyte recruitment and resolution of inflammation in acute lung injury. Aim 2. Determine how thrombin receptor-1 (PAR-1) interacts with specific cytokine/chemokine production that influences leukocyte recruitment and resolution of inflammation in acute lung injury. Aim 3. Determine how plasminogen activator-1 (PAI-1) interacts with specific cytokine-chemokine production that influences leukocyte recruitment and resolution of inflammation in acute lung injury. The implications of improved mechanistic insight into the role of coagulation proteins in acute lung injury are to provide new opportunities to prevent abnormal inflammation and disordered repair through interventions directed at these activities. A successfully optimized strategy could greatly attenuate persistence of pulmonary inflammation and facilitate the resolution of human ARDS.