Pretreatment strategy with adenosine A2A receptor agonist attenuates reperfusion injury in a preclinical porcine lung transplantation model.

摘要

OBJECTIVE: Adenosine A(2A) receptor activation after lung transplantation attenuates ischemia-reperfusion injury by reducing inflammation. However, the effect of adenosine A(2A) receptor activation in donor lungs before transplant remains ill defined. This study compares the efficacy of 3 different treatment strategies for adenosine A(2A) receptor agonist in a clinically relevant porcine lung transplantation model. METHODS: Mature porcine lungs underwent 6 hours of cold ischemia before allotransplantation and 4 hours of reperfusion. Five groups (n = 6/group) were evaluated on the basis of treatment with ATL-1223, a selective adenosine A(2A) receptor agonist: thoracotomy alone (sham), transplant alone (ischemia-reperfusion), donor pretreatment via ATL-1223 bolus (ATL-D), recipient treatment via ATL-1223 infusion (ATL-R), and a combination of both ATL-1223 treatments (ATL-D/R). Lung function and injury were compared. RESULTS: Blood oxygenation was significantly higher among ATL-D, ATL-R, and ATL-D/R groups versus ischemia-reperfusion (392.0 +/- 52.5, 428.9 +/- 25.5, and 509.4 +/- 25.1 vs 77.2 +/- 17.0 mm Hg, respectively, P < .001). ATL-1223-treated groups had lower pulmonary artery pressures (ATL-D = 30.5 +/- 1.8, ATL-R = 30.2 +/- 3.3, and ATL-D/R = 29.3 +/- 4.5 vs IR = 45.2 +/- 2.1 mm Hg, P < .001) and lower mean airway pressures versus ischemia-reperfusion (ATL-D = 9.1 +/- 0.8, ATL-R = 9.1 +/- 2.6, and ATL-D/R = 9.6 +/- 1.3 vs IR = 21.1 mm Hg, P < .001). Likewise, ATL-1223-treated groups had significantly lower lung wet/dry weight, proinflammatory cytokine expression, and lung injury scores by histology compared with ischemia-reperfusion. All parameters of lung function and injury in ATL-1223-treated groups were similar to sham (all P > .05). CONCLUSIONS: Pretreatment of donor lungs with ATL-1223 was as efficacious as other treatment strategies in protecting against ischemia-reperfusion injury. If necessary, supplemental treatment of recipients with ATL-1223 may provide additional protection. These results support the development of pharmacologic A(2A)R agonists for use in human clinical trials for lung transplantation.