Sildenafil extends survival and graft function in a large animal lung transplantation model

Objective: Restoring intracellular cGMP and inducing NO-synthesis attenuates ischemia-associated early pulmonary allograft dysfunction. Phosphodiesterase-5 (PDE), predominantly expressed in lung tissue, plays a pivotal role in modulating the cGMP/NO-synthase pathway in endothelial and epithelial cells. In this study, we evaluate the effect of employing sildenafil (Viagra 1 ), a specific inhibitor of PDE-5, to counteract ischemia/reperfusion (I/R) injury in a single lung transplantation model of extended ischemia. Methods:Donor animals (weight matched outbred pigs, 28—35 kg) in the treatment group (I) (n = 5) were injected with 0.7 mg sildenafil/kg into the pulmonary artery (PA) prior to inflow occlusion. For perfusion, Perfadex 1 , containing 0.7 mg sildenafil/l was used, and the graft stored at 1 8C in the perfusion solution. After 24 h ischemia, unilateral left lung transplantation was performed. Starting at reperfusion, group I received continuous sildenafil (0.7 mg sildenafil/kg), over 6 h. Except for the sildenafil application, the control group (II) (n = 4) was treated identically (PGE1 was injected into the PA). One hour after reperfusion, the right main bronchus (MB) and right PA were occluded. Over the next 5 h, cardiopulmonary parameters (systemic aterial, PA, central venous, left atrial pressure, pCO2, pO2) were measured, including extravascular lung water (EVLW). Thiobarbituric acid-reactive substance assay (TBARS) and myeloperoxidase (MPO) analysis from lung tissue were run. Results: All recipients of group I survived the 6-h reperfusionperiod;in contrast,all control animalsdied within1—2 h after occlusionof the rightside. In comparison to a markedrise inpulmonary vascular resistance (PVR) in group II (>1000 dyne s cm � 5 ), PVR in group I remained stable, moderately elevated from baseline (baseline: 150— 180 dyne s cm � 5 vs endpoint: 1000 dyne s cm � 5 ). EVLW in group I did not increase during reperfusion (baseline: 6.75 � 1.4 mg/kg vs endpoint: 6.7 � 1.0 mg/kg), in contrast to group II, where pulmonary edema at 2-h reperfusion preceded terminal graft failure (group I: 9.7 � 0.1 mg/kg vs group II: 6.48 � 1.8 mg/kg). Tissue reactive free radicals at endpoint measurement in group I did not differ significantly from native tissue. Yet, when compared to specimen taken from group II at time of terminal graft failure, a significant increase in free radicals was noted (group I: 13.8 � 1.6 pmol/g vs group II: 18.5 � 3.0 pmol/g,p < 0.05). Conclusion:Sildenafil treatment prevents terminal early graft failure, allowinglung transplantation after 24-h ischemia time. Reperfusion edema was strikingly diminished, preserving pulmonary structural and functional integrity while prolonging graft ischemia time. Employing the established PDE-5 inhibitor sildenafil during lung perfusion, storage, and implantation, ischemic tolerance may be extended and early graft function improved.