Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model

• Published in: The Journal of thoracic and cardiovascular surgery Vol. 137; no. 5; pp. 1249 - 1257
• Main Authors: Weiss, Eric S., MD, Champion, Hunter C., MD, PhD, Williams, Jason A., MD, Baumgartner, William A., MD, Shah, Ashish S., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.05.2009; AATS/WTSA; Elsevier
• Subjects: Administration, Oral; Analysis of Variance; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Carbolines - pharmacology; Cardiology. Vascular system; Cardiothoracic Surgery; Cyclic GMP - metabolism; Delayed-Action Preparations - pharmacology; Disease Models, Animal; Graft Rejection; Graft Survival; Immunohistochemistry; Lung Transplantation - adverse effects; Lung Transplantation - methods; Medical sciences; Phosphodiesterase Inhibitors - pharmacology; Pneumology; Preoperative Care; Probability; Rabbits; Random Allocation; Reactive Oxygen Species - metabolism; Reference Values; Reperfusion Injury - drug therapy; Reperfusion Injury - prevention & control; Tadalafil; Tissue and Organ Harvesting - methods; NO; eNOS; pulmonary artery; P o 2; repeated-measures analysis of variance; partial pressure of carbon dioxide; generalized estimating equation; inducible nitric oxide synthase; PDE; reactive oxygen species; endothelial nitric oxide synthase; iNOS; protein kinase G; nitric oxide synthase; pulmonary artery pressure; primary graft dysfunction; partial pressure of oxygen; 12; nitric oxide; GEE; IR; GMP; PGD; PKG; PA; NOS; ischemia and reperfusion; ROS; 9; RM-ANOVA; P co 2; phosphodiesterase; guanosine monophosphate; PAP; Injury; Lung; Oral administration; Transplantation; Experimental study; Homotransplantation; Oral cavity; Reperfusion; Treatment; Surgery; Graft; Anesthesia; Models; Circulatory system; Inhibition; Lesion; Cardiology
• ISSN: 0022-5223; 1097-685X
• DOI: 10.1016/j.jtcvs.2008.12.040

Objectives Ischemia–reperfusion injury remains a devastating complication of lung transplantation. Phosphodiesterase inhibitors have been shown to precondition tissues against ischemia–reperfusion injury. Little is known, however, about the utility of phosphodiesterase inhibition in reperfusion injury after lung transplantation. We evaluated the long-acting phosphodiesterase-5 inhibitor, tadalafil, in an ex vivo lung transplant model. Methods New Zealand White rabbits (4 kg), were given oral tadalafil (n = 11) 24 hours before lung harvest and compared with rabbits given oral vehicle alone (n = 11). Lungs were recovered with Perfadex solution (Vitrolife, Kungsbacka, Sweden) and cold stored for 18 hours. After storage, lung blocks were reperfused with donor rabbit blood in an ex vivo apparatus. Pulmonary artery pressures were recorded with serial arterial and venous blood gas sampling and animals served as their own controls. Phosphodiesterase-5 and protein kinase G tissue activity assays confirmed drug effects. Luminol chemiluminescence assay was used to measure reactive oxygen species and levels of endothelial and inducible nitric oxide synthase were measured. Results Extended cold storage, followed by reperfusion produced a consistent reproducible decrease in oxygenation and increase in pulmonary pressure. Tadalafil-treated animals exhibited greater Pa o2 throughout the course of reperfusion ( P = .001) Mean pulmonary artery pressure was lower in tadalafil-treated animals (22 vs 40 mm Hg; P = .04). Phosphodiesterase-5 activity was decreased (143 ± 8 vs 205 ± 32 mP; P < .001) with protein kinase G activity increased (25 ± 12 vs 12 ± 2.4 fU/μg; P = .01) in the experimental group confirming that oral pretreatment resulted in active phosphodiesterase inhibition in the lung tissue. Reactive oxygen species (as measured by luminol activity) were decreased in tadalafil-treated animals (7.8 ± 1.5 vs 10.2 ± 1.2 relative light units; P = .003). Conclusions Our experimental model demonstrates that oral donor pretreatment with a long-acting phosphodiesterase inhibitor is an effective strategy for improving pulmonary performance after reperfusion. Importantly, phosphodiesterase enzymes and their downstream effectors may play a critical role in reperfusion injury after lung transplantation.