Procoagulant signalling in acute lung injury.

急性肺损伤（ALI）及其更严重的形式——急性呼吸窘迫综合征（ARDS）是毁灭性的，往往是致命的临床综合征，由感染、创伤、接触肺部毒物和药物不良反应引起。肺部对损伤的反应是发炎、积液和激活凝血蛋白（凝血因子）系统，以便暂时堵塞受损的血管。除了它们在凝血中的作用，许多凝血因子也可以直接影响炎症。在某些条件下，它们的作用可引发夸张的炎症反应，导致肺损伤升级，在许多情况下，受影响的个体死亡。目前ALI/ARDS的有效治疗方法很少，因此迫切需要新的治疗方法。我们对一种新化合物的研究表明，在这种疾病的动物模型中，一种细胞表面受体，蛋白酶激活受体-1 (PAR1)，介导凝血蛋白酶的细胞效应，并可能作为一种新的治疗靶点提供希望。该项目将开始在临床前研究中确定PAR1拮抗剂的潜力，并将利用包括肺损伤实验模型、培养细胞、患者活检和肺灌洗样本在内的综合实验方法，阐明该受体介导肺部炎症和肺液积聚的机制。这些信息将有助于开发针对这些破坏性疾病的具体有效疗法。

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS) are devastating and often fatal clinical syndromes caused as a result of infection, trauma, exposure to lung toxicants and adverse drug reactions. The lungs respond to injury by becoming inflamed, accumulating fluid and activating a system of blood clotting proteins (coagulation factors) in order to temporarily plug damaged blood vessels. Aside from their roles in clotting, many of these coagulation factors can also directly influence inflammation. Under certain conditions their action can trigger an exaggerated inflammatory response, resulting in escalation of lung damage and in many cases, death of affected individuals. There are currently few effective therapies for ALI/ARDS, so that new treatments are urgently required. Our work with a new compound, has shown that a cell surface receptor, proteinase activated receptor-1 (PAR1), mediates the cellular effects of coagulation proteinases in an animal model of this condition and might offer promise as a novel therapeutic target. This project will begin to identify the potential of PAR1 antagonists in pre-clinical studies and will elucidate the mechanisms by which this receptor mediates lung inflammation and lung fluid accumulation, using an integrated experimental approach involving an experimental model of lung injury, cultured cells and patient biopsy and lung lavage samples. This information will help in the development of specific and effective therapies for these devastating conditions.