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

Eric S. Weiss, Hunter C. Champion, Jason A. Williams, William A Baumgartner, Ashish S. Shah

Research output: Contribution to journalArticle

Abstract

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 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). 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.

Original languageEnglish (US)
Pages (from-to)1249-1257
Number of pages9
JournalJournal of Thoracic and Cardiovascular Surgery
Volume137
Issue number5
DOIs
StatePublished - May 2009

Fingerprint

Lung Transplantation
Phosphoric Diester Hydrolases
Reperfusion Injury
Lung
Type 5 Cyclic Nucleotide Phosphodiesterases
Reperfusion
Cyclic GMP-Dependent Protein Kinases
Luminol
Phosphodiesterase Inhibitors
Rabbits
Pressure
Pulmonary Artery
Reactive Oxygen Species
Phosphodiesterase 5 Inhibitors
Nitric Oxide Synthase Type III
Nitric Oxide Synthase Type II
Luminescence
Blood Donors
Sweden
Theoretical Models

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Pulmonary and Respiratory Medicine

Cite this

Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model. / Weiss, Eric S.; Champion, Hunter C.; Williams, Jason A.; Baumgartner, William A; Shah, Ashish S.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 137, No. 5, 05.2009, p. 1249-1257.

Research output: Contribution to journalArticle

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abstract = "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 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). 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.",
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AU - Champion, Hunter C.

AU - Williams, Jason A.

AU - Baumgartner, William A

AU - Shah, Ashish S.

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N2 - 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 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). 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.

AB - 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 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). 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.

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