Long Acting Oral Phophodiesterase Inhibition Preconditions Against Reperfusion Injury ln An Experimental Lung Transplantation Model
Eric S. Weiss1, Jason A. Williams1, William M. Baldwin2, William A. Baumgartner1, Hunter C. Champion3, Ashish S. Shah1; 1Cardiac Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD; 2Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD; 3Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD
Comment on this Abstract
Objective: Ischemia-reperfusion (IR) injury remains a devastating complication of Lung Transplantation (LTx). Phosphodiesterase (PDE) inhibitors have been shown to precondition tissues against IR injury. Little is known, however, about the utility of PDE inhibition in reperfusion injury after LTx. We evaluated the long acting PDE-5 inhibitor, tadalafil, in an ex-vivo LTx model.
Methods: New Zealand White rabbits (4Kg), were given oral tadalafil (n=6) 24 hours prior to lung harvest and compared to rabbits given oral vehicle alone (n=8). Lungs were recovered with Perfadex, and cold stored for 18 hours. Following storage, lung blocs were reperfused with donor rabbit blood in an ex vivo apparatus. Pulmonary artery pressures (PAP) were recorded with serial arterial and venous blood gas sampling and animals served as their own controls. PDE-5 and protein kinase G (PKG) tissue activity assays confirmed drug effects. Luminol chemoluminescence assay was used to measure reactive oxygen species (ROS).
Results: Extended cold storage, followed by reperfusion produced a consistent reproducible decrease in oxygenation and increase in pulmonary pressure. Tadalafil treated animals exhibited greater initial PaO2 levels (563 vs. 470 mmHg, p=0.07) and at each subsequent time point post reperfusion (p=0.04) (Figure-1). Mean PAP was lower in tadalafil treated animals (26 vs. 39 mmHg, p=0.04). PDE-5 activity was decreased (143 ± 8 vs. 205 ± 32 mP, p<0.001) with PKG activity increased (25 ± 12 vs. 12 ± 2.4 fU/microgram, p=0.01) in the experimental group confirming that oral pretreatment resulted in active PDE inhibition in the lung tissue. ROS (as measured by luminol activity) were decreased in tadalafil treated animals (7.8 ± 1.5 vs. 15.5 ±1.2 RLU, p=0.002).
Conclusion: Our experimental model demonstrates that oral donor pretreatment with a long acting PDE inhibitor is an effective strategy for improving pulmonary performance following reperfusion. Importantly, PDE enzymes and their downstream effectors may play a critical role in reperfusion injury after LTx.
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