TY - JOUR
T1 - Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model
AU - Weiss, Eric S.
AU - Champion, Hunter C.
AU - Williams, Jason A.
AU - Baumgartner, William A.
AU - Shah, Ashish S.
N1 - Funding Information:
Supported by the Mildred and Carmont Blitz Cardiac Research Fund, the Joyce Koons Family Cardiac Endowment Fund, the American Medical Association Foundation (AMA seed grant, E.S.W.), and the National Institutes of Health (NIH 2T32DK007713-12 ESW). Eric Weiss and Jason Williams are Irene Piccinini Investigators in Cardiac Surgery. The study was also supported in part by an American Heart Association Scientist Development Grant, a grant from the W.W.Smith Charitable Trust, a Shih-Chun Wang Young Investigator Award; a Giles F. Filley Award of the American Physiological Society; the Bernard Family Foundation, and NIHP50HL084946 (H.C.C.).
PY - 2009/5
Y1 - 2009/5
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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U2 - 10.1016/j.jtcvs.2008.12.040
DO - 10.1016/j.jtcvs.2008.12.040
M3 - Article
C2 - 19379999
AN - SCOPUS:64649098038
SN - 0022-5223
VL - 137
SP - 1249
EP - 1257
JO - Journal of Thoracic and Cardiovascular Surgery
JF - Journal of Thoracic and Cardiovascular Surgery
IS - 5
ER -