Ischemia–reperfusion injury after lung transplantation remains a major source of morbidity and mortality. Adenosine receptors have been implicated in both pro- and anti-inflammatory roles in ischemia–reperfusion injury. This study tests the hypothesis that the adenosine A_2B receptor exacerbates the proinflammatory response to lung ischemia–reperfusion injury.

An in vivo left lung hilar clamp model of ischemia–reperfusion was used in wild-type C57BL6 and adenosine A_2B receptor knockout mice, and in chimeras created by bone marrow transplantation between wild-type and adenosine A_2B receptor knockout mice. Mice underwent sham surgery or lung ischemia–reperfusion (1 hour ischemia and 2 hours reperfusion). At the end of reperfusion, lung function was assessed using an isolated buffer-perfused lung system. Lung inflammation was assessed by measuring proinflammatory cytokine levels in bronchoalveolar lavage fluid, and neutrophil infiltration was assessed via myeloperoxidase levels in lung tissue.

Compared with wild-type mice, lungs of adenosine A_2B receptor knockout mice were significantly protected after ischemia–reperfusion, as evidenced by significantly reduced pulmonary artery pressure, increased lung compliance, decreased myeloperoxidase, and reduced proinflammatory cytokine levels (tumor necrosis factor-α; interleukin-6; keratinocyte chemoattractant; regulated on activation, normal T-cell expressed and secreted; and monocyte chemotactic protein-1). Adenosine A_2B receptor knockout→adenosine A_2B receptor knockout (donor→recipient) and wild-type→ adenosine A_2B receptor knockout, but not adenosine A_2B receptor knockout→wild-type, chimeras showed significantly improved lung function after ischemia–reperfusion.

These results suggest that the adenosine A_2B receptor plays an important role in mediating lung inflammation after ischemia–reperfusion by stimulating cytokine production and neutrophil chemotaxis. The proinflammatory effects of adenosine A_2B receptor seem to be derived by adenosine A_2B receptor activation primarily on resident pulmonary cells and not bone marrow-derived cells. Adenosine A_2B receptor may provide a therapeutic target for prevention of ischemia–reperfusion-related graft dysfunction in lung transplant recipients.