Adenosine A2A receptor activation reduces inflammation and preserves pulmonary function in an in vivo model of lung transplantation

Abstract

BackgroundReperfusion injury continues to significantly affect patients undergoing lung transplantation. Isolated lung models have demonstrated that adenosine A2A receptor activation preserves function while decreasing inflammation. We hypothesized that adenosine A2A receptor activation by ATL-146e during the initial reperfusion period preserves pulmonary function and attenuates inflammation in a porcine model of lung transplantation.MethodsMature pig lungs preserved with Viaspan (Barr Laboratories, Pomona, NY) underwent 6 hours of cold ischemia before transplantation and 4 hours of reperfusion. Animals were treated with (ATL group, n = 7) and without (IR group, n = 7) ATL-146e (0.05 μg kg−1 · min−1 ATL-146e administered intravenously for 3 hours). With occlusion of the opposite pulmonary artery, the animal was maintained for the final 30 minutes on the allograft alone. Recipient lung physiology was monitored before tissue evaluation of pulmonary edema (wet-to-dry weight ratio), myeloperoxidase assay, and tissue tumor necrosis factor α by means of enzyme-linked immunosorbent assay.ResultsWhen the ATL group was compared with the IR group, the ATL group had better partial pressure of carbon dioxide (43.8 ± 4.1 vs 68.9 ± 6.3 mm Hg, P < .01) and partial pressure of oxygen (272.3 ± 132.7 vs 100.1 ± 21.4 mm Hg, P < .01). ATL-146e-treated animals exhibited lower pulmonary artery pressures (33.6 ± 2.1 vs 47.9 ± 3.5 mm Hg, P < .01) and mean airway pressures (16.25 ± 0.08 vs 16.64 ± 0.15 mm Hg, P = .04). ATL-146e-treated lungs had lower wet-to-dry ratios (5.9 ± 0.39 vs 7.3 ± 0.38, P < .02), lower myeloperoxidase levels (2.9 × 10−5 ± 1.2 × 10−5 vs 1.3 × 10−4 ± 4.0 × 10−5 ΔOD mg−1 · min−1, P = .03), and a trend toward decreased lung tumor necrosis factor α levels (57 ± 12 vs 96 ± 15 pg/mL, P = .06). The ATL group demonstrated significantly less inflammation on histology.ConclusionAdenosine A2A activation during early reperfusion attenuated lung inflammation and preserved pulmonary function in this model of lung transplantation. ATL-146e and similar compounds could play a significant role in improving outcomes of pulmonary transplantation