Background: Reperfusion injury continues to significantly affect lung transplantation patients. Isolated lung models have demonstrated that adenosine A_2A receptor activation preserves function while decreasing inflammation. We hypothesized the adenosine A_2A receptor activation by ATL-146e during the initial reperfusion period preserves pulmonary function and attenuates inflammation in a porcine model of lung transplantation.
Methods: Mature pig lungs preserved with Viaspan underwent 6hrs of cold ischemia before transplantation and 4hrs of reperfusion. Animals were treated with (ATL+, n=7) and without (ATL-, n=7) ATL-146e (0.04 mg/kg/min ATL-146e IV for 3hrs). With occlusion of the opposite pulmonary artery, the animal was maintained for the final 30min on the allograft alone. Recipient lung physiology was monitored before tissue evaluation of pulmonary edema (wet-to-dry ratio), myeloperoxidase assay (MPO), and tissue TNF-α by ELISA.
Results: When ATL+ was compared to ATL-, ATL+ had better PCO₂ (43.8± 4.1 vs. 68.9±6.3 mmHg, p<0.01) and PO₂ (100.1±21.4 vs. 272.3±132.7 mmHg, p<0.01). ATL+ animals exhibited lower pulmonary artery pressures in (33.6±2.1 vs. 47.9±3.5 mm Hg, p<0.01) and mean airway pressures in mmHg (16.25±0.08 vs. 16.64±0.15, p=0.04). ATL+ treated lungs had lower wet-to-dry ratios (5.9±0.39 vs. 7.3±0.38, p<0.02), MPO (DOD/mg/min) (0.03±0.04 vs.13±0.01, p=0.03), and a trend towards decreased lung TNF-α (pg/ml) (96±15 vs. 57±12, p=0.06). ATL+ also demonstrated significantly less inflammation on histology.
Conclusion: Adenosine A_2A activation during the early reperfusion attenuated lung inflammation and preserved pulmonary function in this in vivo model of lung transplantation. ATL-146e and similar compounds could play a significant role in improving outcomes of pulmonary transplantation.

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