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J Thorac Cardiovasc Surg 2010;139:474-482
© 2010 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

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

^a Department of Surgery, University of Virginia Health System, Charlottesville, Va
^b Department of Medicine, University of Virginia Health System, Charlottesville, Va
^c Department of Public Health Sciences, University of Virginia Health System, Charlottesville, Va

Received for publication April 3, 2009; revisions received June 15, 2009; accepted for publication August 9, 2009.

^_* Address for reprints: Victor E. Laubach, PhD, University of Virginia Health System Department of Surgery, PO Box 801359, Charlottesville, VA 22908. (Email: laubach{at}virginia.edu).

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-, 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.

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