Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model
Received 13 May 2008; received in revised form 25 November 2008; accepted 30 December 2008. published online 12 March 2009.
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.
aDivision of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Md
bDivision of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Md
Address for reprints: Ashish S. Shah, MD, Assistant Professor of Surgery, Division of Cardiac Surgery, The Johns Hopkins Hospital, Blalock 618, 600 N. Wolfe St, Baltimore, MD 21287.
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.).
Read at the Eighty-eighth Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif, May 10–14, 2008.
ABSTRACT