Procoagulant signalling in acute lung injury.

急性肺损伤中的促凝血信号传导。

• 批准号: G0800265/1
• 负责人: Rachel Chambers
• 金额: $ 50.45万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0800265%2F1
• 关键词: Procoagulant; signalling; acute; lung; injury.

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.

急性肺损伤(ALI)及其更严重的形式--急性呼吸窘迫综合征(ARDS)是由感染、创伤、肺部毒物暴露和药物不良反应引起的毁灭性的、往往是致命的临床综合征。肺部对损伤的反应是发炎，积累液体，激活凝血蛋白系统(凝血因子)，以暂时堵塞受损的血管。除了在凝血方面的作用外，这些凝血因子中的许多也可以直接影响炎症。在某些情况下，他们的行动可能会引发夸大的炎症反应，导致肺损伤升级，在许多情况下，受影响的人会死亡。目前治疗ALI/ARDS的有效方法很少，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，一种细胞表面受体，即蛋白酶激活受体-1(PAR1)，在这种情况下的动物模型中介导了凝血酶的细胞效应，并可能成为一种新的治疗靶点。该项目将开始确定PAR1拮抗剂在临床前研究中的潜力，并将使用一种涉及肺损伤实验模型、培养细胞以及患者活检和肺灌洗样本的综合实验方法，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毁灭性疾病的具体和有效的治疗方法。