Fibrinolytic Pathways in Lung Injury and Repair

肺损伤和修复中的纤溶途径

• 批准号: 7671772
• 负责人: Steven Idell
• 金额: $ 1.85万
• 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/7671772
• 关键词: Accounting; Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Alveolar; Alveolar Macrophages; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulation; Antiplasmin; Architecture; Area; Attenuated; Binding; Biology; Blood; Blood Clot; Blood Coagulation Disorders; Blood Vessels; Blood coagulation; Cell Proliferation; Cell physiology; Cells; Clinical; Coagulation Process; Collaborations; Complement; Defect; Defensins; Deposition; Development; Diffuse; Disease; Embolism; Endopeptidases; Epithelial Cells; Epithelium; Event; Fibrin; Fibrinogen; Fibrinolysis; Fibroblasts; Fibrosis; Foundations; Funding; Hemostatic function; Hyperoxia; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Kinins; Laboratories; Lead; Learning; Link; Liquid substance; Literature; Lower respiratory tract structure; Lung; Medical; Mesothelial Cell; Mesothelium; Methods; Mission; Modeling; Modification; Mus; Papio; Pathogenesis; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Plasmin; Plasminogen Activator; Plasminogen Activator Inhibitor 1; Play; Pleural; Pleural Diseases; Pleural Mesothelial Cell; Pleurisy; Pleurodesis; Positioning Attribute; Primates; Process; Program Reviews; Protein Overexpression; Proteolysis; Publishing; Pulmonary Edema; Pulmonary Fibrosis; Range; Regulation; Relative (related person); Reporting; Research Personnel; Research Project Grants; Role; Science; Sepsis; Signal Transduction; Structure; Structure of parenchyma of lung; Surface; System; Therapeutic; Thrombosis; Tissues; Transgenic Animals; United States National Institutes of Health; Universities; Up-Regulation; Urokinase; Urokinase Plasminogen Activator Receptor; Weight; Work; activated Protein C; atherogenesis; base; career; cell motility; clinically relevant; concept; cytokine; design; editorial; experience; improved; in vivo; indium-bleomycin; inhibitor/antagonist; injured; injury and repair; interest; lung injury; mortality; novel; pre-clinical; preclinical study; prevent; programs; receptor; repaired; response; skills; success; vasoconstriction

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 Proiect 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. Proiect 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.

纤溶酶原激活物（PA）通路的异常参与了急性心肌梗死的发病机制。 肺（AL 1）和胸膜损伤。最近的干预性试验表明，针对这些途径可以减少 败血症的死亡率，并防止急性肺或胸膜损伤。本PPG的项目负责人有 这些途径可以通过新认识到的途径影响ALl和胸膜损伤 机制等然而，将PA途径与AL 1和胸膜损伤联系起来的致病机制是 poody理解并可能涉及非蛋白水解信号转导途径。我们专题 目的是通过定义尿激酶（uPA）及其受体 （uPAR）、其它新型uPA受体、其抑制剂PA 1 - 1和纤溶酶影响炎症过程， AL 1和胸膜损伤中过渡基质的重塑和加速的纤维化。在项目1中， PAI-1和uPAR的间皮细胞将研究的重点是转录后调控和 将进一步评估预防胸膜闭合的机械性干预。项目2将 阐明肺调节uPA和uPAR的新的转录后机制 上皮项目3将确定uPA调节肺血管收缩的新途径， 急性肺损伤后肺水肿及防御素在此过程中的作用项目4将阐明新的机制， 所述纤溶酶可影响进展中的AL 1或胸膜损伤期间的重塑。这些互动项目 源自经验丰富的项目负责人指导的活动计划，现在面向我们的主题 objective.将使用体外、体内和介入方法。根据最近报告的临床和 通过临床前试验，PPG将加速获得新的临床相关信息， 开发更好的治疗AL 1和/或胸膜损伤的方法。