Adenosine receptor activation in pulmonary ischemia-reperfusion injury

描述（申请人提供）：肺缺血再灌注（IR）损伤是移植术后的主要并发症，导致较高的术后死亡率和晚期并发症，包括慢性排斥反应。我们的实验室已经证实，早期急性肺IR损伤依赖于肺泡巨噬细胞激活和tnf - α诱导。IR的一个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）的激活可以减少肺IR损伤。其他ARs在肺IR损伤中的作用尚不清楚。因此，Aim 1将确定每种AR在小鼠急性肺IR模型中的作用。目的2将确定A2AARs特异性作用于肺泡巨噬细胞，对急性肺IR损伤具有保护作用。目的3将确定A2AAR抑制IR损伤的机制是否涉及巨噬细胞的MAPK、NF-kB和凋亡途径。我们的总体假设是，A2AARs对肺泡巨噬细胞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。这项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，这将导致更多成功的肺移植结果，并可能增加终末期肺病患者可用器官的数量。

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.