Effects of Angiopoietins on Shock-Induced Acute Lung Injury

血管生成素对休克引起的急性肺损伤的影响

• 批准号: 8465678
• 负责人: Joanne L. Lomas-Neira
• 金额: $ 25.79万
• 依托单位: OCEAN STATE RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8465678
• 关键词: Acute Lung Injury; Address; Adhesions; Adult Respiratory Distress Syndrome; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biology; Blood Vessels; Cardiopulmonary; Cell Adhesion Molecules; Cell Communication; Cell physiology; Cells; Centers of Research Excellence; Coculture Techniques; Complication; Cytoplasmic Granules; Development; Edema; Endothelial Cells; Endothelial Growth Factors; Environment; Extracellular Matrix; Face; Fibroblast Growth Factor; Fibroblasts; Functional disorder; Gases; Hemorrhage; Hemorrhagic Shock; Homeostasis; Host Defense; Inflammation; Inflammatory; Instruction; Kinetics; Laboratories; Ligation; Liquid substance; Lung; Mediating; Mediator of activation protein; Microvascular Permeability; Modeling; Multiple Organ Failure; Mus; Pathogenesis; Pathologic Processes; Pathology; Pathway interactions; Patients; Pericytes; Permeability; Phenotype; Phosphotransferases; Physiological; Plasma; Play; Proteins; Pulmonary Edema; RNA; Receptor Protein-Tyrosine Kinases; Regulation; Relative (related person); Reporting; Respiratory physiology; Risk; Role; Sepsis; Shock; Signal Transduction; Smooth Muscle Myocytes; Stream; Structure of parenchyma of lung; Supportive care; Syndrome; TIE-2 Receptor; Testing; Therapeutic Intervention; Trauma; Vascular Endothelial Cell; Vascular remodeling; Vesicle; Weibel-Palade Bodies; effective therapy; indexing; injury and repair; insight; migration; mortality; mouse development; neutrophil; novel; receptor; response; septic

PROJECT SUMMARY (See instructions): Loss of endothelial cell (EC) barrier function is important in the development of indirect acute lung injury (ALI). We have shown, in a novel murine model of hemorrhage (shock) with a subsequent septic challenge caused by cecal ligation and performation (CLP), that neutrophil (PMN) interactions with resident pulmonary cells are central to this pathology. In ALI, unresolved inflammation elicits a pathological process with loss of EC barrier integrity and impaired lung function. EC growth factors, Angiopoietin (Ang)-i and 2, under physiological conditions, maintain vascular homeostasis through competitive interactions wdth the t3T:osine kinase receptor, Tie2, expressed on ECs. Ang-1/Tie2 binding has been shown to stabilize vessels and stimulate down stream pro-survival/anti-inflammatory signaling, in contrast, Ang-2, released from storage granules of activated ECs, destabilizes vessels. Recent findings report that plasma Ang-2 levels are significantly elevated in patients that develop ALI. We find similar elevation in the lungs and plasma in our shock/CLP model, and we have found that depletion of PMNs prior to shock abrogates Ang-2 elevation. We propose the following central hypothesis: Ang-2 causes loss of pulmonary EC barrier function in ALI due to shock/CLP, initiated by EC interaction with shock-primed PMNs. We propose the following specific aims: Aim 1 will determine the kinetics of change in Ang-1:Ang-2 and Ang-2 expression and re-synthesis as well as its relationship to changes in indices of inflammation. We will use Ang-2 (si)RNA to suppress lung tissue expression, Ang-2 protein specific inhibition, and Ang-1 competitive inhibition of Ang-2/Tie2 binding to assess the contribution of Ang-2 release in shock priming for the development of ALI. Aim 2 will determine mechanisms by which Ang-2 changes pulmonary EC phenotype/activation in response to plasma from mice with ALI/ARDS. Aim 3 will determine mechanisms by which Ang-2 mediates changes in EC phenotype /activation in cultured mouse ECs following co-culture with shock-primed PMNs. The studies in this proposal will provide novel insights into the mechanisms of PMN associated, Ang-2 mediated ALI and will elucidate pathways that hold potential for therapeutic intervention.

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