Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model
| Autor: | Hunter C. Champion, Ashish S. Shah, William A. Baumgartner, Jason A. Williams, Eric S. Weiss |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Pulmonary and Respiratory Medicine
Graft Rejection Phosphodiesterase Inhibitors medicine.medical_treatment Cold storage Administration Oral 030204 cardiovascular system & hematology Pharmacology Nitric oxide Tadalafil 03 medical and health sciences chemistry.chemical_compound Random Allocation 0302 clinical medicine Reference Values Preoperative Care medicine Lung transplantation Animals Phosphodiesterase inhibitor Cyclic GMP Probability Analysis of Variance Lung business.industry Graft Survival Phosphodiesterase medicine.disease Immunohistochemistry 3. Good health Transplantation Disease Models Animal medicine.anatomical_structure 030228 respiratory system chemistry Anesthesia Delayed-Action Preparations Reperfusion Injury Tissue and Organ Harvesting Surgery Rabbits Cardiology and Cardiovascular Medicine business Reactive Oxygen Species Reperfusion injury Carbolines Lung Transplantation |
| Zdroj: | The Journal of thoracic and cardiovascular surgery. 137(5) |
| ISSN: | 1097-685X |
| Popis: | ObjectivesIschemia–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.MethodsNew 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.ResultsExtended cold storage, followed by reperfusion produced a consistent reproducible decrease in oxygenation and increase in pulmonary pressure. Tadalafil-treated animals exhibited greater Pao2 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).ConclusionsOur 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|