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: 8854111
• 负责人: Joanne L. Lomas-Neira
• 金额: $ 24.19万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8854111
• 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; Trauma patient; Vascular Endothelial Cell; Vascular remodeling; Vesicle; Weibel-Palade Bodies; blood vessel development; 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.

项目摘要（参见说明）： 内皮细胞 (EC) 屏障功能的丧失对于间接急性肺损伤 (ALI) 的发生至关重要。我们在一种新的出血（休克）小鼠模型中表明，中性粒细胞（PMN）与常驻肺细胞的相互作用是这种病理学的核心，该模型由盲肠结扎和执行（CLP）引起随后的败血症挑战。在 ALI 中，未解决的炎症会引起 EC 屏障完整性丧失和肺功能受损的病理过程。 EC生长因子血管生成素(Ang)-1和2在生理条件下通过与EC上表达的t3T:肌苷激酶受体Tie2的竞争性相互作用维持血管稳态。 Ang-1/Tie2 结合已被证明可以稳定血管并刺激下游促生存/抗炎信号传导，相反，从活化的 EC 存储颗粒中释放的 Ang-2 会破坏血管的稳定。最近的研究结果表明，患有 ALI 的患者血浆 Ang-2 水平显着升高。我们在休克/CLP 模型中发现肺部和血浆有类似的升高，并且我们发现休克前 PMN 的消耗消除了 Ang-2 升高。我们提出以下中心假设：Ang-2 导致 ALI 中由于休克/CLP 导致肺 EC 屏障功能丧失，这是由 EC 与休克引发的 PMN 相互作用引发的。我们提出以下具体目标： 目标 1 将确定 Ang-1:Ang-2 和 Ang-2 表达和再合成的变化动力学及其与炎症指标变化的关系。我们将使用 Ang-2 (si)RNA 抑制肺组织表达、Ang-2 蛋白特异性抑制以及 Ang-1 对 Ang-2/Tie2 结合的竞争性抑制，以评估 Ang-2 释放在 ALI 发展的休克启动中的贡献。目标 2 将确定 Ang-2 响应 ALI/ARDS 小鼠血浆而改变肺 EC 表型/激活的机制。目标 3 将确定 Ang-2 介导与休克引发的 PMN 共培养后培养的小鼠 EC 中 EC 表型/激活变化的机制。本提案中的研究将为 PMN 相关的 Ang-2 介导的 ALI 机制提供新的见解，并将阐明具有治疗干预潜力的途径。