Fibrinolytic Pathways in Lung Injury and Repair

肺损伤和修复中的纤溶途径

• 批准号: 7173688
• 负责人: Steven Idell
• 金额: $ 0.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173688
• 关键词: Fibrinolytic; Pathways; Lung; Injury; Repair

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 ALl and pleural injury through newly recognized mechanisms. However the pathogenic mechanisms that link the PA pathways to ALl and pleural injury are poody 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, its inhibitor PAl-l, and plasmin influence the course of inflammation, remodeling of transitional matrix and accelerated fibrosis in ALl and pleural injury. In Project 1, expression of PAl-1 and uPAR by the mesothelium will be studied with a focus on posttranscriptional regulation and a mechanistically based intervention to prevent pleural Ioculation 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 regulates pulmonary vasoconstriction and lung edema after ALl and the role of defensin in the process. Proiect 4 will elucidate novel mechanisms by which plasmin may influence remodeling during evolving ALl or pleural injury. 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. Based on reported recent clinical and preclinical trials, this PPG will accelerate the acquisition of new, clinically relevant information that will hasten the development of better treatments for ALl and/or pleural injury.

描述（由申请人提供）： 纤溶酶原激活物（PA）通路的异常参与了急性肺（AL 1）和胸膜损伤的发病机制。最近的干预性试验表明，靶向这些途径可以降低脓毒症的死亡率，并防止急性肺或胸膜损伤。本PPG的项目负责人已经开发出证据，证明这些途径可以通过新认识的机制影响ALl和胸膜损伤。然而，将PA途径与AL 1和胸膜损伤联系起来的致病机制尚不清楚，并且可能涉及非蛋白水解信号转导途径。我们的主题目标是通过定义尿激酶（uPA）、其受体（uPAR）、其他新的uPA受体、其抑制剂PA 1 - 1和纤溶酶影响炎症过程、过渡基质的重塑和AL 1和胸膜损伤中的加速纤维化的新机制来解决这一差距。在项目1中，将研究间皮细胞的PAI-1和uPAR表达，重点是转录后调节，并将进一步评估预防胸膜炎的机制性干预。项目2将阐明新的转录后机制，uPA和uPAR的调节肺上皮细胞。 项目3将确定新的途径，通过该途径，uPA调节肺血管收缩和急性肺损伤后肺水肿以及防御素在该过程中的作用。项目4将阐明纤溶酶可影响进展中的AL 1或胸膜损伤期间的重塑的新机制。这些互动项目源自经验丰富的项目领导者指导的活动计划，现在面向我们的主题目标。将使用体外、体内和介入方法。 基于最近报道的临床和临床前试验，该PPG将加速获得新的临床相关信息，这将加速开发更好的AL 1和/或胸膜损伤治疗。