Activation of A3 Adenosine Receptor Provides Lung Protection Against Ischemia‐Reperfusion Injury Associated with Reduction in Apoptosis

Apoptosis has been described in various models of ischemia‐reperfusion (IR) injury, including lung transplantation. A3 adenosine receptor (AR) has been linked to a variety of apoptotic processes. The effect of A3AR activation on lung injury and apoptosis, following IR, has not been reported to date. In a spontaneously breathing cat model, in which the left lower lobe of the lung was isolated and subjected to 2 h of ischemia and 3 h of reperfusion, we tested the effect of IB‐MECA, a selective A3AR agonist, on lung apoptosis and injury. Significant increase in the extent of apoptosis was observed following lung reperfusion. IB‐MECA, administered before IR, and before or with reperfusion, markedly (p < 0.01) attenuated indices of injury and apoptosis including the percentage of injured alveoli, wet/dry weight ratio, myeloperoxidase activity, in situ terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end‐labeling (TUNEL) positive cells, and caspase 3 activity and expression. The protective effects of IB‐MECA were completely blocked by pretreatment with the selective A3AR antagonist MRS‐1191. In summary, even when given after the onset of ischemia, the A3AR agonist IB‐MECA conferred a powerful protection against reperfusion lung injury, which was associated with decreased apoptosis. This suggests a potentially important role for A3AR in lung IR injury.