Role of Adenosine Receptors in Lung Ischemia-Reperfusion Injury
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 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, which mediates its effects through four subtypes of the G protein-coupled adenosine receptor family which includes A1, A2A, A2B, and A3. We have showed that specific activation of the adenosine A2A receptor largely attenuates lung IR injury. Little is known about the role of other adenosine receptors in lung IR injury. Thus this project tests the role of each adenosine receptor in lung IR injury using various adenosine receptor gene knockout mice and potent and specific receptor agonists and antagonists. In addition, we are testing the hypothesis that adenosine A2A receptors specifically on alveolar macrophages confer protection from acute lung IR injury. Finally, we are determining if mechanisms of adenosine A2A receptor attenuation of IR injury involve MAPK, NF-kB, and apoptosis pathways in macrophages. Our overall hypothesis is that specific activation of adenosine A2A receptors on alveolar macrophages provides protection from post-transplant acute lung IR injury.
The average number of CD4+ T cells per high power field (HPF),
assessed via immunohistochemical staining of peripheral lung sections
is significantly increased after IR compared to Sham and is
significantly reduced after IR by ATL313 treatment (IR+ATL313).