Adenosine A2A receptor activation on CD4+ T lymphocytes and neutrophils attenuates lung ischemia-reperfusion injury

Objective: Adenosine A_2A receptor activation potently attenuates lung ischemia-reperfusion injury. This study tests the hypothesis that adenosine A_2A receptor activation attenuates ischemia-reperfusion injury by inhibiting CD4+ T cell activation and subsequent neutrophil infiltration. Methods: An in vivo model of lung ischemia-reperfusion injury was used. C57BL/6 mice were assigned to either sham group (left thoracotomy) or 7 study groups that underwent ischemia-reperfusion (1 hour of left hilar occlusion plus 2 hours of reperfusion). ATL313, a selective adenosine A_2A receptor agonist, was administered 5 minutes before reperfusion with or without antibody depletion of neutrophils or CD4+ T cells. After reperfusion, the following was measured: pulmonary function using an isolated, buffer-perfused lung system, T cell infiltration by immunohistochemistry, myeloperoxidase and proinflammatory cytokine/chemokine levels in bronchoalveolar lavage fluid, lung wet/dry weight, and microvascular permeability. Results: ATL313 significantly improved pulmonary function and reduced edema and microvascular permeability after ischemia-reperfusion compared with control. Immunohistochemistry and myeloperoxidase content demonstrated significantly reduced infiltration of neutrophils and CD4+ T cells after ischemia-reperfusion in ATL313-treated mice. Although CD4+ T cell-depleted and neutrophil-depleted mice displayed significantly reduced lung injury, no additional protection occurred when ATL313 was administered to these mice. Expression of tumor necrosis factor-α, interleukin 17, KC, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and RANTES were significantly reduced in neutrophil- and CD4+ T cell-depleted mice and reduced further by ATL313 only in neutrophil-depleted mice. Conclusions: These results demonstrate that CD4+ T cells play a key role in mediating lung inflammation after ischemia-reperfusion. ATL313 likely exerts its protective effect largely through activation of adenosine A_2A receptors on CD4+ T cells and neutrophils.