Fibrinolytic Pathways in Lung Injury and Repair

描述(由申请人提供)：纤溶酶原激活物(PA)途径的异常与急性肺(ALL)和胸膜损伤的发病机制有关。最近的介入试验表明，靶向这些通路可以降低脓毒症的死亡率，并对急性肺或胸膜损伤具有保护作用。这个PPG的项目负责人已经发现证据表明，这些途径可以通过新认识的机制影响ALI和胸膜损伤。然而，将PA通路与ALI和胸膜损伤联系起来的致病机制尚不清楚，可能涉及非蛋白水解性信号转导途径。我们的主题目标是通过确定尿激酶(UPA)及其受体(UPAR)、其他新的uPA受体及其抑制物PAI-1影响ALI和胸膜损伤的炎症、移行基质重塑和加速纤维化的过程的新机制来解决这一差距。在项目1中，将定义在转录后水平上由间皮细胞调节PAI-1和uPAR表达的途径，并将进一步评估一种防止胸膜积液的新型纤溶干预措施。项目2将阐明肺上皮细胞调节uPA和uPAR的新的转录后机制。项目3将定义uPA与细胞表面信号转导分子相互作用的新途径，以调节ALI后的肺血管收缩和肺水肿，并确定防御素在这一过程中的作用。这些互动项目源于有经验的项目负责人指导的积极项目，现在面向我们的主题目标。将采用体外、体内和干预方法。这一PPG将加速获得新的临床相关信息，这些信息将加速开发更好的治疗ALI和/或胸膜损伤的方法。

DESCRIPTION (provided by applicant): Abnormalities in the plasminogen activator (PA) pathways have been implicated in the pathogenesis of acute lung (All) and pleural injury. Recent interventional trials suggest that targeting these pathways can reduce mortality in sepsis and protect against acute lung or pleural injury. The Project Leaders of this PPG have developed evidence that these pathways can influence ALI and pleural injury through newly recognized mechanisms. However the pathogenic mechanisms that link the PA pathways to ALI and pleural injury are poorly understood and are likely to involve non-proteolytic signal-transducing pathways. Our thematic objective is to address this gap by defining novel mechanisms by which urokinase (uPA), its receptor (uPAR), other novel uPA receptors and its inhibitor PAI-1 influence the course of inflammation, remodeling of transitional matrix and accelerated fibrosis in ALI and pleural injury. In Project 1, pathways that regulate PAI-1 and uPAR expression by the.mesothelium at the posttranscriptional level will be defined and a novel fibrinolytic intervention to prevent pleural loculation will be further evaluated. Project 2 will elucidate novel posttranscriptional mechanisms by which uPA and uPAR are regulated by the lung epithelium. Project 3 will define novel pathways by which uPA interacts with cell surface signaling adapter molecules to regulate pulmonary vasoconstriction and lung edema after ALI and ascertain the role of defensin in the process. These interactive projects derive from active programs directed by experienced Project Leaders and are now oriented to our thematic objective. In vitro, in vivo and interventional methods will be used. This PPG will accelerate the acquisition of new, clinically relevant information that will hasten the development of better treatments for ALI and/or pleural injury.