SCCOR in translational research in Acute Lung Injury

描述（由申请人提供）：这是一份急性肺损伤SCCOR申请，旨在研究早期急性肺损伤的发病机制和治疗。尽管在临床急性肺损伤的研究和治疗方面取得了相当大的进展，但临床肺损伤的发病机制尚不完全清楚，死亡率仍然很高。急性肺损伤（acute lung injury, ALl）是危重患者急性呼吸衰竭的重要原因，需要临床和基础研究来提供关于肺损伤基本机制的新知识，并测试新的治疗方法。项目1提出一项随机、双盲、II期临床试验，评估活化蛋白C （activated protein C， APC）治疗急性肺损伤的潜在疗效。本项目还将探讨凝血和炎症依赖机制对临床肺损伤的机制贡献。项目2是一项临床项目，旨在研究人类遗传学、细菌遗传学和宿主事件在细菌性肺炎急性肺损伤发展中的相互作用。该项目将测试甘露糖结合凝集素基因异常作为严重肺炎和急性肺损伤原因的潜在贡献。该项目还将验证当铜绿假单胞菌菌株表达III型毒力基因时，其定植转化为肺部感染（呼吸机相关性肺炎）的假设。项目3将通过对转基因小鼠的研究，以及对重组小鼠AP - C治疗实验性肺损伤的影响，来检验凝血依赖机制在小鼠实验性肺损伤中的作用。项目4将研究转化生长因子- β 1在早期实验性急性肺损伤中的致病机制，评估tgf - β 1激活的机制，并确定tgf - β 1诱导肺泡上皮液体运输改变的机制。行政和临床核心（核心A和核心B）将支持项目的科学目标。蛋白质组学核心（core C）将提供创新的方法来鉴定急性肺损伤患者和动物的支气管肺泡灌洗液中的新蛋白质，无论是在几种治疗策略之前还是之后。

DESCRIPTION (provided by applicant): This is an Acute Lung Injury SCCOR application designed to study the pathogenesis and treatment of early acute lung injury. Although considerable progress has been made in selected areas of research and treatment of clinical acute lung injury, the pathogenesis of clinical lung injury is incompletely understood and mortality remains too high. Clinical and basic research is needed to provide new knowledge regarding fundamental mechanisms of lung injury as well as to test new therapies for acute lung injury (ALl), an important cause of acute respiratory failure in critically ill patients. Project 1 proposes a randomized, double-blind, phase II clinical trial to evaluate the potential efficacy of activated protein C (APC) for the treatment of acute lung injury. This project will also explore mechanistically the contribution of coagulation and inflammation dependent mechanisms to clinical lung injury. Project 2 is a clinical project to investigate the interactions among human genetics, bacterial genetics, and host events in the development of acute lung injury from bacterial pneumonia. This project will test the potential contribution of Mannose Binding Lectin genetic abnormalities as a cause of severe pneumonia and acute lung injury. This project will also test the hypothesis that P.aeruginosa colonization transforms to lung infection (ventilator-associated pneumonia) when the P.aeruginosa strains express type III virulence genes. Project 3 will examine the contribution of coagulation dependent mechanisms in experimental lung injury in mice by studying genetically modified mice as well as testing the impact of recombinant mouse AP C as therapy for experimental lung injury. Project 4 will examine the role of transforming growth factor-beta1 as a pathogenetic mechanism for early experimental acute lung injury, evaluating the mechanisms for TGF-beta1 activation, and also will identify the mechanisms for responsible for the TGF-beta1 induced alterations in alveolar epithelial fluid transport. The administrative and clinical cores (Cores A & B) will support the scientific objective of the projects. The proteomics core (Core C) will provide innovative methods for identifying novel proteins in the bronchoalveolar lavage fluid from patients and animals with acute lung injury, both before and after several treatment strategies.