Ex vivo lung perfusion with adenosine A2A receptor agonist allows prolonged cold preservation of lungs donated after cardiac death

Abstract

Objective: Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an adenosine A2A receptor agonist during ex vivo lung perfusion.

Methods: Porcine DCD donor lungs were preserved at 4°C for 12 hours and underwent ex vivo lung perfusion for 4 hours. Left lungs were then transplanted and reperfused for 4 hours. Three groups (n = 4/group) were randomized according to treatment with the adenosine A2A receptor agonist ATL-1223 or the dimethyl sulfoxide vehicle: Infusion of dimethyl sulfoxide during ex vivo lung perfusion and reperfusion (DMSO), infusion of ATL-1223 during ex vivo lung perfusion and dimethyl sulfoxide during reperfusion (ATL-E), and infusion of ATL-1223 during ex vivo lung perfusion and reperfusion (ATL-E/R). Final Pao2/Fio2 ratios (arterial oxygen partial pressure/fraction of inspired oxygen) were determined from samples obtained from the left superior and inferior pulmonary veins.

Results: Final Pao2/Fio2 ratios in the ATL-E/R group (430.1 ± 26.4 mm Hg) were similar to final Pao2/Fio2 ratios in the ATL-E group (413.6 ± 18.8 mm Hg), but both treated groups had significantly higher final Pao2/Fio2 ratios compared with the dimethyl sulfoxide group (84.8 ± 17.7 mm Hg). Low oxygenation gradients during ex vivo lung perfusion did not preclude superior oxygenation capacity during reperfusion.

Conclusions: After prolonged cold preservation, treatment of DCD donor lungs with an adenosine A2A receptor agonist during ex vivo lung perfusion enabled Pao2/Fio2 ratios greater than 400 mm Hg after transplantation in a preclinical porcine model. Pulmonary function during ex vivo lung perfusion was not predictive of outcomes after transplantation.

Keywords: adenosine A2A receptor agonist; donation after cardiac death; ex vivo lung perfusion; lung transplantation; prolonged cold preservation.

Figure 1

Comparison of initial and final PaO2/FiO2 ratios among groups. Initial donor PaO2/FiO2 ratios were obtained before procurement. Final PaO2/FiO2 ratios of donor lungs were determined from samples obtained from the left superior and inferior pulmonary veins after 4 hours of reperfusion. *p < 0.0001 vs. DMSO.

Figure 2

Trends in PO2 gradients throughout 4 hours of EVLP in DMSO, ATL-E, and ATL-E/R groups. The red line represents the 350 mmHg threshold for clinical lung transplantation.

Figure 3

Changes in physiologic parameters throughout 4 hours of EVLP. Peak airway pressure, dynamic compliance, and pulmonary vascular resistance in the DMSO, ATL-E, and ATL-E/R groups.

Figure 4

Percent change in peak airway pressure, dynamic compliance, and pulmonary vascular resistance between the 1^st hour and the 4^th hour of EVLP among groups. The red line represents the 15% threshold for clinical lung transplantation.

Figure 5

Proinflammatory cytokine levels in lung tissue after 4 hours of reperfusion.

Figure 6

Pulmonary edema after 4 hours of reperfusion as measured by total protein concentration in BAL fluid and lung wet-to-dry weight ratios.

Figure 7

(Top) Representative lung histology (hematoxylin and eosin stain at 20X magnification) after 4 hours of reperfusion in DMSO, ATL-E, and ATL-E/R groups. (Bottom) Comparison of mean lung injury severity scores among groups as determined from histology.