Selective adenosine-A(2A) activation reduces lung reperfusion injury following transplantation

Background: The adenosine-A(2A) receptor on the neutrophil is responsible f or several anti-inflammatory actions. We hypothesized that DWH-146e, a sele ctive adenosine-A(2A) agonist, would reduce lung reperfusion injury followi ng transplantation. Methods: We used an isolated, whole blood-perfused, ventilated rabbit lung model. Donor rabbits underwent lung harvest after pulmonary arterial PGE(1) injection and Euro-Collins preservation solution hush, and lungs were pres erved for 18 hours at 4 degrees C. Group I lungs (n = 9) served as control subjects. Group II lungs (n = 9) were reperfused with whole blood that was first passed through a leukocyte-depleting filter. In group III (n = 9), DW H-146e was added to the blood reperfusate (25 mu g/kg) immediately before r eperfusion and was administered throughout the reperfusion period (1 mu g/k g/min). All lungs were reperfused for 30 minutes. Results: Arterial oxygenation in group II and group III was significantly h igher than that of group I after 30 minutes of reperfusion (514.27 +/- 35.8 0 and 461.12 +/- 43.77 vs 91.41 +/- 20.58 mm Hg, p < .001). Pulmonary vascu lar resistance was significantly reduced in group III (22,783 +/- 357 dynes . s . cm(-5)) compared to both group II and group I: (31,057 +/- 1743 and 36,911 +/- 2173 dynes . s . cm(-5), p < .001). Airway compliance was improv ed in groups II and III when compared to group I (1.68 +/- 0.08 and 1.65 +/ - 0.05 vs 1.36 +/- 0.13, p = .03). Microvascular permeability in group III was reduced to 106.82 +/- 17.09 compared with 165.70 +/- 21.83 ng Evans blu e dye per gram of tissue in group I (p = .05). Group III myeloperoxidase ac tivity was 39.88 +/- 4.87 compared with 88.70 +/- 18.69 Delta OD/g/min in g roup I (p = .03); group II myeloperoxidase activity was 56.06 +/- 7.46. Conclusions: DWH-146e reduced lung neutrophil sequestration and dramaticall y improved pulmonary graft function. Neutrophils are important components o f the inflammatory cascade of reperfusion injury and their source may inclu de both the circulating blood and the lung graft itself. Selective adensosi ne-A(2A) activation interrupts the neutrophil-mediated inflammatory respons e and reduces lung reperfusion injury following transplantation.