Adenosine receptor activation in pulmonary ischemia-reperfusion injury

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活化和TNF-α诱导。IR中的一个主要抗炎机制是通过腺苷的释放介导的，并且我们已经表明A2 A腺苷受体（AR）的激活减少肺IR损伤。关于其他AR在肺IR损伤中的作用知之甚少。因此，目的1将确定每种AR在急性肺IR小鼠模型中的作用。目的2将确定肺泡巨噬细胞上特异性的A2 AAR赋予急性肺IR损伤的保护作用。目的3探讨A2 AAR减轻IR损伤的机制是否涉及MAPK、NF-κ B和巨噬细胞凋亡途径。我们的总体假设是，肺泡巨噬细胞上A2 AAR的特异性激活提供了对移植后急性肺IR损伤的保护。公共卫生相关性：肺再灌注损伤是肺移植术后的主要并发症之一，可导致较高的术后死亡率和包括慢性排斥反应在内的晚期并发症。该建议的目的是更好地了解再灌注损伤的机制，并有可能预防这种并发症。如果成功，这将导致肺移植的更成功的结果，并可能增加终末期肺病患者可用的器官数量。

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.