Urokinase, Neutrophil Activation and Acute Lung Injury.

尿激酶、中性粒细胞激活和急性肺损伤。

• 批准号: 8212041
• 负责人: Gang Liu
• 金额: $ 36.23万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212041
• 关键词: Acute Lung Injury; Affect; Apoptosis; Apoptotic; Bacteria; Binding; CD47 gene; Chemosensitization; Chemotaxis; Coagulation Process; Collectins; Data; Development; Eating; Fibrinolysis; Funding; Goals; Incidence; Integrins; Kringles; Laboratories; Ligands; Lung; Neutrophil Activation; Opsonin; PECAM1 gene; Pathway interactions; Patients; Perfusion; Phagocytosis; Plasminogen Activator Inhibitor 1; Property; Research; Role; Severities; Signal Pathway; Signal Transduction; TLR2 gene; TLR4 gene; Thrombosis; Tissues; Urokinase; Vitronectin; calreticulin; improved; in vivo; macrophage; neutrophil; novel; novel therapeutic intervention; public health relevance; receptor; receptor expression

DESCRIPTION (provided by applicant): Alterations in coagulation and fibrinolytic pathways, associated with increases in circulating and pulmonary concentrations of urokinase (uPA), plasminogen activator inhibitor 1 (PAI-1), and vitronectin, are present in almost all patients with acute lung injury (ALI). Our recent findings suggest two novel mechanisms through which uPA, PAI-1, and vitronectin can contribute to the development of ALI independently of their effects on coagulation and fibrinolytic pathways: 1) by enhancing neutrophil activation and 2) by decreasing phagocytosis and clearance of neutrophils in the lungs. Our hypothesis is that: uPA, PAI-1, and vitronectin, through actions that directly affect neutrophil activation, accumulation, and clearance in the lungs, are centrally involved in determining the development, perpetuation, and severity of ALI. Our specific aims are: 1) To define the mechanisms through which uPA and PAI-1 potentiate neutrophil activation by identifying the receptors and ligands involved, examining how interactions between uPA, PAI-1, and vitronectin modulate the proinflammatory properties of uPA and PAI-1, and determining the intracellular signaling pathways that are affected by combinations of uPA, PAI-1, and vitronectin in neutrophils stimulated through TLR4 and by whole bacteria; 2) To determine the mechanisms through which PAI-1 and vitronectin modulate phagocytosis and clearance of neutrophils by delineating the roles of neutrophil and macrophage associated PAI-1 and vitronectin, identifying the receptors engaged by PAI-1 and vitronectin on neutrophils and macrophages that participate in modulating phagocytosis of viable and apoptotic neutrophils, and delineating the effects of PAI-1 and vitronectin in modifying the expression of receptors and ligands involved in phagocytosis of neutrophils, including calreticulin (CRT), CD47, CD31, integrins, mer, axl, and LRP, as well as in affecting the binding of opsonins to PtdSer and of collectins to CRT and CD91; and 3) To determine the mechanisms through which PAI-1 and vitronectin contribute to the development and severity of ALI by delineating the in vivo roles of PAI-1 and vitronectin in modulating phagocytosis of apoptotic neutrophils in the lungs during ALI, and examining the importance of interactions between PAI-1 and vitronectin in contributing to the severity of ALI. The proposed studies should not only improve understanding of cellular mechanisms leading to ALI, but also are likely to suggest novel therapeutic interventions aimed at decreasing the incidence and/or severity of ALI. PUBLIC HEALTH RELEVANCE: Urokinase, plasminogen activator inhibitor 1 (PAI-1), and vitronectin have well described roles in modulating coagulation and fibrinolysis. However, our recent results suggest two novel mechanisms through which urokinase, PAI-1, and vitronectin can contribute to the development of acute lung injury independently of their effects on coagulation and fibrinolytic pathways: 1) by enhancing neutrophil activation and 2) by decreasing phagocytosis and clearance of neutrophils in the lungs. The studies proposed in this application should not only improve understanding of cellular mechanisms leading to acute lung injury, but also are likely to suggest novel therapeutic interventions aimed at decreasing the incidence and/or severity of acute lung injury.

描述（由申请人提供）：凝血和纤溶途径的改变，与尿激酶（uPA）、纤溶酶原激活剂抑制剂1（PAI-1）和玻连蛋白的循环和肺部浓度增加相关，几乎存在于所有急性肺病患者中损伤（ALI）。我们最近的研究结果表明，uPA、PAI-1 和玻连蛋白可通过两种新机制促进 ALI 的发展，而与它们对凝血和纤溶途径的影响无关：1) 通过增强中性粒细胞活化，2) 通过减少中性粒细胞的吞噬和清除在肺部。我们的假设是：uPA、PAI-1 和玻连蛋白通过直接影响肺部中性粒细胞活化、积聚和清除的作用，在决定 ALI 的发生、持续和严重程度方面发挥重要作用。我们的具体目标是：1) 通过识别相关受体和配体，研究 uPA、PAI-1 和玻连蛋白之间的相互作用如何调节 uPA 和 PAI 的促炎特性，确定 uPA 和 PAI-1 增强中性粒细胞激活的机制。 1、确定通过TLR4刺激的中性粒细胞和整个细菌中uPA、PAI-1和玻连蛋白组合影响的细胞内信号传导途径； 2) 通过描述与 PAI-1 和玻连蛋白相关的中性粒细胞和巨噬细胞的作用，确定 PAI-1 和玻连蛋白调节中性粒细胞吞噬和清除的机制，确定参与参与的中性粒细胞和巨噬细胞上 PAI-1 和玻连蛋白参与的受体调节活的和凋亡的中性粒细胞的吞噬作用，并描述 PAI-1 和玻连蛋白在修饰参与中性粒细胞吞噬作用的受体和配体的表达，包括钙网蛋白 (CRT)、CD47、CD31、整合素、mer、axl 和 LRP，以及影响调理素与 PtdSer 的结合以及集合素与 CRT 和 CD91 的结合; 3) 通过描述 PAI-1 和玻连蛋白在 ALI 期间调节肺部凋亡中性粒细胞吞噬作用的体内作用，并检查其重要性，确定 PAI-1 和玻连蛋白导致 ALI 发生和严重程度的机制PAI-1 和玻连蛋白之间的相互作用导致 ALI 的严重程度。拟议的研究不仅应该增进对导致 ALI 的细胞机制的理解，而且还可能提出旨在降低 ALI 发生率和/或严重程度的新治疗干预措施。 公共健康相关性：尿激酶、纤溶酶原激活剂抑制剂 1 (PAI-1) 和玻连蛋白在调节凝血和纤维蛋白溶解方面的作用已得到充分描述。然而，我们最近的结果表明，尿激酶、PAI-1 和玻连蛋白可通过两种新机制促进急性肺损伤的发生，而与它们对凝血和纤溶途径的影响无关：1）通过增强中性粒细胞活化，2）通过减少吞噬作用和肺部中性粒细胞的清除。本申请中提出的研究不仅应提高对导致急性肺损伤的细胞机制的理解，而且还可能提出旨在降低急性肺损伤的发生率和/或严重程度的新的治疗干预措施。