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

• 批准号: 10181419
• 负责人: Victor E Laubach
• 金额: $ 65.78万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/10181419
• 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; 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; cell type; clinically relevant; driving force; extracellular; improved; in vivo; inflammatory lung disease; inhibitor/antagonist; insight; lung allograft; lung ischemia; macrophage; monolayer; mortality; neutrophil; new therapeutic target; novel; prevent; prophylactic; pulmonary function; receptor; success; therapeutic target; therapeutically effective; transplant model; uptake; vascular inflammation

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 原发移植物功能障碍发生率高，限制了肺移植的成功。 缺血再灌注损伤(IRI)的特点是强烈的炎症反应，血管通透性， 和肺泡损伤。IRI也是移植物晚期排斥反应(闭塞性细支气管炎)的危险因素。 移植后一年以上死亡的主要原因。TRPV4是一种跨膜钙 通道在多种细胞类型中表达，包括血管内皮细胞、肺泡细胞 上皮细胞、巨噬细胞和中性粒细胞。TRPV4激活可诱发肺损伤 内皮/上皮屏障功能障碍，这是IRI的关键特征，我们的数据表明 内皮细胞内TRPV4活性是肺缺血再灌注损伤的重要介质，其抑制作用 TRPV4活性的一部分具有显著的保护作用。我们还表明，TRPV4的活性可能会受到影响 由内皮细胞上的pAnnexin(Panx1)通道释放的ATP。因此，我们的提案将考验整体 内皮细胞TRPV4通道信号是肺IRI的关键介质的假说 导致内皮屏障破坏、血管通透性和白细胞浸润。目标1将 确定内皮细胞上的TRPV4活性是否介导肺IRI导致内皮/上皮屏障 功能障碍、血管炎症和白细胞渗出。TRPV4在人类基因组中的潜在作用 肺泡上皮细胞、巨噬细胞和中性粒细胞也将在肺IRI期间进行评估。 AIM 2将通过测试确定内皮细胞中Panx1/TRPV4轴介导肺IRI的机制 认为TRPV4是由IR后Panx1通道释放的ATP激活的假说。我们会 还要确定TRPV4活性是否由NADPH氧化酶衍生的活性氧诱导 在IR之后。目标3将利用小鼠原位肺移植模型来破译 TRPV4在供受者细胞和移植后内皮细胞中的表达。此外，a 临床上，大型动物猪肺移植模型将被用来确定 药物抑制Panx1可预防移植后肺IRI。目前有 没有针对IRI的预防性治疗方法，我们的研究将为我们提供新的洞察机制。 并将TRPV4通道定义为预防IRI的新治疗靶点 肺移植后。