Lung Injury Protection by Coagulation Blockade

通过凝血阻断保护肺损伤

• 批准号: 7121628
• 负责人: CLAUDE A PIANTADOSI
• 金额: $ 37.96万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121628
• 关键词: Escherichia coli infections; adult respiratory distress syndrome; anticoagulants; baboons; blood coagulation; chemokine; chemoprevention; coagulation factor VII; cytokine; disease /disorder model; fibrin; fibrinolysis; genetically modified animals; inflammation; laboratory mouse; leukocyte activation /transformation; lung injury; plasminogen activator inhibitors; protein localization; septicemia; thrombin; thrombin receptor; thromboplastin

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.

这是一个修改后的应用程序，旨在研究肺凝血系统在急性肺损伤中的作用（全部）。组织因子（TF）引发的凝血和促凝血状态的持续在急性呼吸窘迫综合征（ARDS）的发病机制中很重要，尤其是在脓毒症中。 TF 和其他凝血蛋白与炎症成分沟通，增强肺部的损伤反应。 此外，纤溶酶原激活剂抑制剂（PAI-1和-2）和抗纤溶酶的激活会抑制纤维蛋白溶解，从而促进纤维蛋白积聚并导致毛细血管闭塞、透明膜形成、气体交换障碍和肺纤维化。 我们在动物身上证明，TF 阻断可消除脂多糖 (LPS) 引起的肺损伤和革兰氏阴性脓毒症肺损伤中的炎症。 尽管凝血与 ARDS 的发病机制密切相关，但尚不清楚凝血级联的不同成分如何与炎症和纤溶途径相互作用以促进或解决急性肺损伤。 为了解决这个问题，我们将检验以下假设：阻断凝血启动是肺保护的最佳策略，可防止炎症介质过度释放和细胞流入，从而降低结构、功能并延迟 ALI 的消退。 我们进一步提出，除 TF 之外的凝血因子，尤其是凝血酶和纤维蛋白，通过独立和协调的细胞因子信号传导事件来调节肺部炎症的特定方面及其在脓毒症中的解决。提出了三个目标： 目标 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/趋化因子产生相互作用。 目标 2. 确定凝血酶受体 1 (PAR-1) 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/趋化因子产生相互作用。 目标 3. 确定纤溶酶原激活剂 1 (PAI-1) 如何与特定细胞因子趋化因子的产生相互作用，从而影响急性肺损伤中白细胞的募集和炎症的消退。 对凝血蛋白在急性肺损伤中的作用的机制深入了解的意义在于，通过针对这些活动的干预措施来预防异常炎症和紊乱修复提供新的机会。 成功优化的策略可以大大减轻肺部炎症的持续性，并促进人类 ARDS 的解决。