Adenosine receptor activation in pulmonary ischemia-reperfusion injury

描述(申请人提供)：肺缺血再灌注(IR)损伤是移植后的主要并发症，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。我们的实验室已经证实，早期的急性肺IR损伤依赖于肺泡巨噬细胞的激活和TNF-α的诱导。IR的一个主要抗炎机制是通过释放腺苷来介导的，我们已经证明A2A腺苷受体(AR)的激活可以减轻肺IR损伤。其他受体在肺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。目的2证实肺泡巨噬细胞表面的A2AARs对急性肺缺血再灌注损伤具有保护作用。目的3将确定A2AAR减轻IR损伤的机制是否涉及MAPK、NF-kB和巨噬细胞的凋亡途径。我们的总体假设是，A2AARs在肺泡巨噬细胞上的特异性激活对移植后急性肺IR损伤具有保护作用。公共卫生相关性：肺再灌注损伤是肺移植的主要并发症，会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。这项建议的目的是为了更好地了解再灌注损伤的机制，并潜在地预防这种并发症。如果成功，这将导致肺移植的更成功结果，并可能增加终末期肺部疾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.