Pannexin-1 Signaling in Lung Ischemia-Reperfusion Injury

肺缺血再灌注损伤中的 Pannexin-1 信号转导

基本信息

批准号：
9898429
负责人：
Victor E Laubach
金额：
$ 55.85万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898429
关键词：
ATP Receptors ATP phosphohydrolase Acute Acute Lung Injury Adhesions Aftercare Alveolar Alveolar Macrophages Apyrase Attenuated Autocrine Communication Bone Marrow Bronchiolitis Bronchiolitis Obliterans Catabolism Cells Coculture Techniques Data Emigrations Endothelial Cells Endothelium Exposure to Functional disorder Graft Rejection HMGB1 gene Hypoxia IL2 gene Immune In Vitro Infiltration Inflammasome Inflammation Inflammation Mediators Inflammatory Injury Knock-out Leukocytes Lung Lung Transplantation Macrophage Activation Measures Mediating Mediator of activation protein Modeling Molecular Mus Neutrophil Infiltration Nucleotides Oxidative Stress P2X-receptor P2Y2 receptor Peptides Pharmacology Prevention Preventive therapy Probenecid Purinoceptor Reperfusion Injury Reporting Risk Factors Role Signal Transduction Source Sum TNF gene Testing Transplant Recipients Transplantation Treatment Efficacy Vascular Permeabilities Venous cytokine driving force ectoATPase extracellular inhibitor/antagonist innovation insight leukocyte activation lung injury lung ischemia macrophage migration mortality neutrophil new therapeutic target novel prevent receptor reconstitution response success therapeutic target transplant model trovafloxacin 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, alveolar damage, and vascular permeability. IRI is also a risk factor for late graft rejection (bronchiolitis obliterans), the major cause of mortality beyond one year of transplant. ATP is a nucleotide released in large amounts after acute lung injury such as IRI and serves as a “danger signal” to mediate inflammation. Recent studies reveal that cells can actively release ATP in a controlled manner through pannexin 1 (Panx1) channels to signal through purinergic P2X or P2Y receptors. Our data suggest that Panx1 on endothelial cells (ECs) is an important mediator of lung injury and vascular inflammation after IR and may be a major source of extracellular ATP after IR. Thus this proposal will test the overall hypothesis that EC Panx1 signaling is a major, early inflammatory mediator of lung IRI via release of ATP resulting in endothelial barrier dysfunction, vascular inflammation and leukocyte infiltration. Specific Aim 1 will determine if EC Panx1 signaling mediates lung IRI via ATP release and whether the P2X7 receptor is a major determinant of IRI. Specific Aim 2 will determine if Panx1 signaling mediates leukocyte activation and infiltration during lung IRI. The role of Panx1 and specific purinergic receptors on alveolar macrophages will be deciphered as well as whether Panx1 mediates neutrophil transendothelial migration. Specific Aim 3 will determine if pharmacologic inhibition of Panx1 will prevent IRI after lung transplantation using a murine orthotopic lung transplant model. This transplant model will also be utilized to decipher the role of Panx1 signaling in donor versus recipient cells as well as in ECs and alveolar macrophages after transplantation. There currently are no preventative therapies for IRI, and our studies will provide novel insight into mechanisms or lung IRI and will define Panx1 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、肺泡损伤和 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是大量释放的 ATP。急性肺损伤（如 IRI）后的量，可作为调节的“危险信号” 最近的研究表明，细胞可以以受控的方式主动释放 ATP。通过 pannexin 1 (Panx1) 通道通过嘌呤能 P2X 或 P2Y 受体发出信号。数据表明，内皮细胞（EC）上的 Panx1 是肺损伤和肺损伤的重要介质。 IR 后的血管炎症可能是 IR 后细胞外 ATP 的主要来源。该提案将测试 EC Panx1 信号传导是主要的早期信号传导的总体假设通过释放 ATP 导致肺 IRI 的炎症介质，导致内皮屏障功能障碍，血管炎症和白细胞浸润特定目标 1 将确定 EC Panx1 是否有效。信号传导通过 ATP 释放介导肺 IRI，无论 P2X7 受体是否是主要的 IRI 的决定因素将确定 Panx1 信号传导是否介导白细胞。 Panx1 和特定嘌呤受体对肺 IRI 过程中的激活和浸润的作用。将破译肺泡巨噬细胞以及 Panx1 是否介导中性粒细胞特定目标 3 将确定 Panx1 的药物抑制是否会发生。使用小鼠原位肺移植模型预防肺移植后 IRI。移植模型还将用于破译 Panx1 信号在供体与移植中的作用目前存在于受体细胞以及移植后的 EC 和肺泡巨噬细胞中。没有 IRI 的预防性疗法，我们的研究将为机制提供新的见解或肺 IRI 并将将 Panx1 定义为预防肺损伤后 IRI 的新治疗靶点移植。