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: 8423720
• 负责人: Gang Liu
• 金额: $ 34.49万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423720
• 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.

描述（由申请方提供）：几乎所有急性肺损伤（ALI）患者都存在凝血和纤溶途径的改变，与尿激酶（uPA）、纤溶酶原激活物抑制剂1（派-1）和玻连蛋白的循环和肺浓度增加相关。我们最近的研究结果表明，uPA、派-1和玻连蛋白可以通过两种新的机制促进ALI的发展，而不依赖于它们对凝血和纤溶途径的影响：1）通过增强中性粒细胞活化和2）通过减少肺中中性粒细胞的吞噬和清除。我们的假设是：uPA、派-1和玻连蛋白通过直接影响肺中中性粒细胞活化、积聚和清除的作用，在决定ALI的发展、持续和严重程度中起中心作用。我们的具体目标是：1）通过鉴定所涉及的受体和配体，检查uPA、派-1和玻连蛋白之间的相互作用如何调节uPA和派-1的促炎性质，并确定在通过TLR 4刺激的嗜中性粒细胞中受uPA、派-1和玻连蛋白的组合影响的细胞内信号传导途径，来确定uPA和派-1增强嗜中性粒细胞活化的机制; 2）通过描述中性粒细胞和巨噬细胞相关的派-1和玻连蛋白的作用，鉴定派-1和玻连蛋白在中性粒细胞和巨噬细胞上参与调节活的和凋亡的中性粒细胞的吞噬作用的受体，以及描述派-1和玻连蛋白在修饰参与嗜中性粒细胞吞噬作用的受体和配体的表达中的作用，所述受体和配体包括钙网蛋白（CRT）、CD 47、CD 31、整联蛋白、mer、axl和LRP，以及影响调理素与PtdSer的结合和凝集素与CRT和CD 91的结合;和3）通过描述PAI-1和玻连蛋白的体内作用来确定PAI-1和玻连蛋白促进ALI的发展和严重性的机制。1和玻连蛋白在调节ALI期间肺中凋亡中性粒细胞的吞噬作用中的作用，并检查派-1和玻连蛋白之间的相互作用在促成ALI严重程度中的重要性。拟议的研究不仅应该提高对导致ALI的细胞机制的了解，而且还可能提出旨在降低ALI发生率和/或严重程度的新型治疗干预措施。

项目成果

Vitronectin inhibits efferocytosis through interactions with apoptotic cells as well as with macrophages.

玻染蛋白通过与凋亡细胞以及巨噬细胞的相互作用来抑制胚细胞增多症。

• DOI: 10.4049/jimmunol.1200625
• 发表时间: 2013-03-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Bae HB;Tadie JM;Jiang S;Park DW;Bell CP;Thompson LC;Peterson CB;Thannickal VJ;Abraham E;Zmijewski JW
• 通讯作者: Zmijewski JW

The human long noncoding RNA lnc-IL7R regulates the inflammatory response.

人类长链非编码 RNA lnc-IL7R 调节炎症反应。

• DOI: 10.1002/eji.201344126
• 发表时间: 2014-07
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Cui, Huachun;Xie, Na;Tan, Zheng;Banerjee, Sami;Thannickal, Victor John;Abraham, Edward;Liu, Gang
• 通讯作者: Liu, Gang

Participation of the receptor for advanced glycation end products in efferocytosis.

• DOI: 10.4049/jimmunol.1004134
• 发表时间: 2011-06-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Friggeri A;Banerjee S;Biswas S;de Freitas A;Liu G;Bierhaus A;Abraham E
• 通讯作者: Abraham E

The receptor for urokinase regulates TLR2 mediated inflammatory responses in neutrophils.

尿激酶的受体调节TLR2介导的中性粒细胞中的炎症反应。

• DOI: 10.1371/journal.pone.0025843
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Liu G;Yang Y;Yang S;Banerjee S;De Freitas A;Friggeri A;Davis KI;Abraham E
• 通讯作者: Abraham E

MicroRNA let-7c regulates macrophage polarization.

• DOI: 10.4049/jimmunol.1202496
• 发表时间: 2013-06-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Banerjee S;Xie N;Cui H;Tan Z;Yang S;Icyuz M;Abraham E;Liu G
• 通讯作者: Liu G