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：
10391559
负责人：
Victor E Laubach
金额：
$ 66.23万
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/10391559
关键词：
Acute Acute Lung Injury Affect Agonist Alveolar Animals Arteries Attenuated Bone Marrow Bronchiolitis Obliterans Calcium Calcium Channel Cations Cells Chronic Clinical Trials Coupled Coupling Data Edema Endothelial Cells Endothelium Epithelial Epithelial Cells Exposure to Family suidae Functional disorder Graft Rejection Heart failure Hypoxia Immune In Vitro Infiltration Inflammation Inflammation Mediators Inflammatory Kidney Knockout Mice Left Leukocytes Lung Lung Transplantation Mediating Mediator of activation protein Molecular Morbidity - disease rate Mus NADPH Oxidase Oxidative Stress P2Y2 receptor Patients Pattern Permeability Pharmacology Phosphorylation Prevention Preventive therapy Proteins Pulmonary Edema Pulmonary artery structure Reactive Oxygen Species Receptor Signaling Reperfusion Injury Reporting Risk Factors Role 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 macrophage monolayer mortality neutrophil new therapeutic target novel 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.

项目概要肺移植的成功受到原发性移植物功能障碍高发生率的限制。缺血再灌注损伤（IRI），其特征是强烈的炎症、血管通透性、和肺泡损伤。 IRI 也是晚期移植物排斥（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。 TRPV4是一种跨膜钙该通道在多种细胞类型中表达，包括血管内皮细胞 (EC)、肺泡细胞上皮细胞、巨噬细胞和中性粒细胞。 TRPV4激活可诱导肺内皮/上皮屏障功能障碍是 IRI 的一个关键特征，我们的数据表明内皮细胞 (EC) 中的 TRPV4 活性是肺 IRI 的重要介质，并且抑制 TRPV4 活性具有显着的保护作用。我们还表明 TRPV4 活性可能受到影响由 EC 上的 pannexin (Panx1) 通道释放的 ATP 产生。因此，我们的建议将测试整体假设内皮 TRPV4 通道信号传导是肺 IRI 的关键介质诱导内皮屏障破坏、血管通透性和白细胞浸润。目标1将确定 EC 上的 TRPV4 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。 TRPV4 的潜在作用肺 IRI 期间还将评估肺泡上皮细胞、巨噬细胞和中性粒细胞。目标 2 将通过测试定义 EC 中 Panx1/TRPV4 轴介导肺 IRI 的机制 TRPV4 是由 IR 后 Panx1 通道释放的 ATP 激活的假设。我们将还确定 TRPV4 活性是否由 NADPH 氧化酶衍生的活性氧诱导红外后。目标 3 将利用小鼠原位肺移植模型来破译供体细胞与受体细胞以及移植后 EC 中的 TRPV4。此外，还有一个临床相关的大型动物猪肺移植模型将用于确定是否 Panx1 的药物抑制可预防移植后肺 IRI。目前有 IRI 没有预防性疗法，我们的研究将为 IRI 的机制提供新的见解肺 IRI 并将定义 TRPV4 通道作为预防 IRI 的新治疗靶点肺移植后。