Adenosine receptor activation in pulmonary ischemia-reperfusion injury

肺缺血再灌注损伤中腺苷受体的激活

• 批准号: 7824330
• 负责人: Irving L. Kron
• 金额: $ 1.86万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7824330
• 关键词: ADORA3 gene; Acute; Adenosine; Adenosine A2A Receptor; Affect; Agonist; Alveolar; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Bone Marrow; Bone Marrow Transplantation; Buffers; Cells; Chronic; Complication; Epithelial Cells; Hilar; ITGAX gene; Ischemia; Knockout Mice; Laboratories; Lead; Leukocytes; Lung; Lung Transplantation; Lung diseases; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Macrophage Activation; Measures; Mediating; Modeling; Mus; Myeloid Cells; NF-kappa B; Organ; Outcome; Pathway interactions; Patients; Population; Postoperative Period; Property; Purinergic P1 Receptors; Reperfusion Injury; Reperfusion Therapy; Role; Source; Staging; Testing; Time; Transgenic Mice; Transplant Recipients; Transplantation; Tumor Necrosis Factor-alpha; Wild Type Mouse; adenosine receptor activation; attenuation; diphtheria toxin receptor; human TNF protein; in vivo; inhibitor/antagonist; lung ischemia; macrophage; mortality; mouse model; prevent; protective effect; public health relevance; receptor; reconstitution

DESCRIPTION (provided by applicant): Lung ischemia-reperfusion (IR) injury is a major complication after transplantation leading to higher post-operative mortality and late complications including chronic rejection. Our laboratory has established that early, acute lung IR injury is dependent on alveolar macrophage activation and TNF-alpha induction. One major anti-inflammatory mechanism in IR is mediated through the release of adenosine, and we have showed that activation of the A2A adenosine receptor (AR) reduces lung IR injury. Little is known about the role of other ARs in lung IR injury. Thus Aim 1 will determine the role of each AR in a mouse model of acute lung IR. Aim 2 will establish that A2AARs specifically on alveolar macrophages confer protection from acute lung IR injury. Aim 3 will determine if mechanisms of A2AAR attenuation of IR injury involve MAPK, NF-kB, and apoptosis pathways in macrophages. Our overall hypothesis is that specific activation of A2AARs on alveolar macrophages provides protection from post-transplant acute lung IR injury. PUBLIC HEALTH RELEVANCE: Lung reperfusion injury is a major complication of lung transplantation leading to higher post-operative mortality and late complications including chronic rejection. The objective of this proposal is to better understand the mechanisms of reperfusion injury and potentially prevent this complication. If successful, this will lead to more successful outcomes in lung transplantations and potentially increase the number of organs available to patients with end-stage lung disease.

描述（由申请人提供）：肺缺血再灌注（IR）损伤是移植后的主要并发症，导致较高的术后死亡率和晚期并发症，包括慢性排斥反应。我们的实验室已经确定，早期急性肺 IR 损伤依赖于肺泡巨噬细胞的激活和 TNF-α 的诱导。 IR 的一种主要抗炎机制是通过腺苷的释放介导的，我们已经证明 A2A 腺苷受体 (AR) 的激活可减少肺 IR 损伤。关于其他 AR 在肺 IR 损伤中的作用知之甚少。因此，目标 1 将确定每种 AR 在急性肺 IR 小鼠模型中的作用。目标 2 将确定专门作用于肺泡巨噬细胞的 A2AAR 可提供针对急性肺 IR 损伤的保护。目标 3 将确定 A2AAR 减轻 IR 损伤的机制是否涉及巨噬细胞中的 MAPK、NF-kB 和凋亡途径。我们的总体假设是，肺泡巨噬细胞上 A2AAR 的特异性激活可提供针对移植后急性肺 IR 损伤的保护。公共卫生相关性：肺再灌注损伤是肺移植的主要并发症，导致较高的术后死亡率和晚期并发症，包括慢性排斥反应。该提案的目的是更好地了解再灌注损伤的机制并可能预防这种并发症。如果成功，这将带来更成功的肺移植结果，并可能增加终末期肺病患者可用的器官数量。