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Role of TRPV4 channel signaling in lung ischemia-reperfusion injury

TRPV4通道信号在肺缺血再灌注损伤中的作用

基本信息

批准号：
10586084
负责人：
Victor E Laubach
金额：
$ 70.49万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586084
关键词：
Acute Acute Lung Injury Affect Alveolar Animals Arteries Attenuated Bone Marrow Bronchiolitis Obliterans Calcium Calcium Channel Cations Cells Chronic Clinical Trials Coupled Coupling Data Edema Endothelial Cells Endothelium Epithelial Cells Epithelium Exposure to Family suidae Fibroblasts Functional disorder Graft Rejection Heart Heart failure Hypoxia Immune In Vitro Inflammation Inflammation Mediators Inflammatory Kidney Knockout Mice Left Leucocytic infiltrate Lung Lung Transplantation Macrophage Mediating Mediator Membrane Molecular Morbidity - disease rate Mus NADPH Oxidase Oxidative Stress P2Y2 receptor Patients Pattern Permeability Phosphorylation Prevention Preventive therapy Proteins Pulmonary Edema Pulmonary artery structure Reactive Oxygen Species Receptor Signaling Reperfusion Injury Reporting Risk Factors Role Sepsis Signal Transduction Source Sum Testing Therapeutic Translating Transplant Recipients Transplantation Vanilloid Vascular Endothelial Cell Vascular Permeabilities Wild Type Mouse alveolar epithelium antagonist cell type clinically relevant driving force extracellular graft dysfunction improved in vivo inflammatory lung disease inhibitor insight lung allograft lung ischemia lung microvascular endothelial cells migration monolayer mortality neutrophil new therapeutic target novel pharmacologic prevent prophylactic pulmonary function receptor success therapeutic target therapeutically effective transplant model uptake vascular inflammation

项目摘要

Project Summary The success of lung transplantation is limited by high rates of primary graft dysfunction due to ischemia-reperfusion injury (IRI) characterized by robust inflammation, vascular permeability, and alveolar damage. IRI is also a risk factor for late graft rejection (bronchiolitis obliterans), the major cause of mortality beyond one year of transplant. TRPV4 is a transmembrane calcium channel expressed in numerous cell types including vascular endothelial cells (ECs), alveolar epithelial cells, macrophages, and neutrophils. TRPV4 activation can induce lung endothelial/epithelial barrier dysfunction, a critical feature of IRI, and our data suggests that TRPV4 activity in endothelial cells (ECs) is a significant mediator of lung IRI and that inhibition of TRPV4 activity is significantly protective. We also show that TRPV4 activity may be affected by ATP released by pannexin (Panx1) channels on ECs. Thus, our proposal will test the overall hypothesis that endothelial TRPV4 channel signaling is a critical mediator of lung IRI by inducing endothelial barrier disruption, vascular permeability and leukocyte infiltration. Aim 1 will determine if TRPV4 activity on ECs mediates lung IRI leading to endothelial/epithelial barrier dysfunction, vascular inflammation, and leukocyte infiltration. A potential role for TRPV4 in alveolar epithelial cells, macrophages, and neutrophils will also be evaluated during lung IRI. Aim 2 will define mechanisms for a Panx1/TRPV4 axis in ECs that mediates lung IRI by testing the hypothesis that TRPV4 is activated by ATP released by Panx1 channels after IR. We will also determine if TRPV4 activity is induced by NADPH oxidase-derived reactive oxygen species after IR. Aim 3 will utilize a murine orthotopic lung transplant model to decipher the role of TRPV4 in donor versus recipient cells as well as in ECs after transplantation. In addition, a clinically relevant, large animal porcine lung transplant model will be used to determine if pharmacologic inhibition of Panx1 will prevent lung IRI after transplantation. There currently are no preventative therapies for IRI, and our studies will provide novel insight into mechanisms of lung IRI and will define TRPV4 channels as a novel therapeutic target for the prevention of IRI after lung transplantation.

项目摘要肺移植的成功受到原发性移植物功能障碍的高发生率的限制，缺血再灌注损伤（IRI）的特征在于强烈的炎症，血管通透性，和肺泡损伤IRI也是晚期移植物排斥反应（闭塞性细支气管炎）的危险因素，移植一年后死亡的主要原因。TRPV 4是一种跨膜钙离子，通道在许多细胞类型中表达，包括血管内皮细胞（EC）、肺泡上皮细胞、巨噬细胞和嗜中性粒细胞。TRPV 4激活可诱导肺内皮/上皮屏障功能障碍是IRI的一个重要特征，我们的数据表明，内皮细胞（EC）中TRPV 4活性是肺IRI的重要介质， TRPV 4的活性具有显著的保护作用。我们还表明，TRPV 4活性可能会受到影响，通过内皮细胞上的泛连接蛋白（Panx 1）通道释放ATP。因此，我们的建议将测试整体假设内皮TRPV 4通道信号传导是肺IRI的关键介质，诱导内皮屏障破坏、血管渗透性和白细胞浸润。目标1将确定EC上的TRPV 4活性是否介导肺IRI，导致内皮/上皮屏障功能障碍、血管炎症和白细胞浸润。TRPV 4在以下方面的潜在作用：肺泡上皮细胞、巨噬细胞和中性粒细胞也将在肺IRI期间进行评价。目的2将通过测试来定义EC中Panx 1/TRPV 4轴介导肺IRI的机制假设TRPV 4被IR后Panx 1通道释放的ATP激活。我们将还确定TRPV 4活性是否由NADPH氧化酶衍生的活性氧物质诱导 Aim 3将利用小鼠原位肺移植模型来解释 TRPV 4在供体与受体细胞以及移植后EC中的表达。另外还有按将使用临床相关的大型动物猪肺移植模型来确定 Panx 1的药理学抑制将防止移植后的肺IRI。目前有没有预防性治疗IRI，我们的研究将提供新的见解，并将TRPV 4通道定义为预防IRI的新治疗靶点肺移植后