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), 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, containing 0.7 mg sildenafil/l was used, and the graft stored at 1 degrees C in the perfusion solution. After 24h ischemia, unilateral left lung transplantation was performed. Starting at reperfusion, group I received continuous sildenafil (0.7 mg sildenafil/kg), over 6h. 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 5h, cardiopulmonary parameters (systemic atrial, PA, central venous, left atrial pressure, pCO(2), pO(2)) 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 reperfusion period; in contrast, all control animals died within 1-2h after occlusion of the right side. In comparison to a marked rise in pulmonary vascular resistance (PVR) in group II (>1000 dynescm(-5)), PVR in group I remained stable, moderately elevated from baseline (baseline: 150-180 dynescm(-5) vs endpoint: 1000 dynescm(-5)). EVLW in group I did not increase during reperfusion (baseline: 6.75+/-1.4 mg/kg vs endpoint: 6.7+/-1.0mg/kg), in contrast to group II, where pulmonary edema at 2-h reperfusion preceded terminal graft failure (group I: 9.7+/-0.1mg/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).


CONCLUSIONS
Sildenafil treatment prevents terminal early graft failure, allowing lung 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.
Korom
Stephan
S
Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland.
Hillinger
Sven
S
Cardell
Markus
M
Zhai
Wei
W
Tan
Qiang
Q
Dutly
André
A
Leskosek
Boris
B
Weder
Walter
W
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015633:Extravascular Lung Water / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D016040:Lung Transplantation; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology; D010879:Piperazines / Q000627:therapeutic use*; D011652:Pulmonary Circulation / Q000187:drug effects; D011687:Purines; D015427:Reperfusion Injury / Q000517:prevention & control; D000068677:Sildenafil Citrate; D013450:Sulfones; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D009195:Peroxidase; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5