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Sildenafil extends survival and graft function in a large animal lung transplantation model


Korom, S; Hillinger, S; Cardell, M; Zhai, W; Tan, Q; Dutly, A; Leskosek, B; Weder, W (2006). Sildenafil extends survival and graft function in a large animal lung transplantation model. European Journal of Cardio-Thoracic Surgery, 29(3):288-293.

Abstract

Objective: Restoring intracellular cGMP and inducing NO-synthesis attenuates ischemia-associated early pulmonary allograft dysfunction. Phosphodiesterase-5 (PDE), predominantly expressed in lung tissue, plays a pivotal role in modulating the cGMP/NO-synthase pathway in endothelial and epithelial cells. In this study, we evaluate the effect of employing sildenafil (Viagra®), a specific inhibitor of PDE-5, to counteract ischemia/reperfusion (I/R) injury in a single lung transplantation model of extended ischemia. Methods: Donor animals (weight matched outbred pigs, 28-35 kg) in the treatment group (I) (n = 5) were injected with 0.7 mg sildenafil/kg into the pulmonary artery (PA) prior to inflow occlusion. For perfusion, Perfadex®, containing 0.7 mg sildenafil/l was used, and the graft stored at 1 °C in the perfusion solution. After 24 h ischemia, unilateral left lung transplantation was performed. Starting at reperfusion, group I received continuous sildenafil (0.7 mg sildenafil/kg), over 6 h. Except for the sildenafil application, the control group (II) (n = 4) was treated identically (PGE1 was injected into the PA). One hour after reperfusion, the right main bronchus (MB) and right PA were occluded. Over the next 5 h, cardiopulmonary parameters (systemic aterial, PA, central venous, left atrial pressure, pCO2, pO2) were measured, including extravascular lung water (EVLW). Thiobarbituric acid-reactive substance assay (TBARS) and myeloperoxidase (MPO) analysis from lung tissue were run. Results: All recipients of group I survived the 6-h reperfusion period; in contrast, all control animals died within 1-2 h after occlusion of the right side. In comparison to a marked rise in pulmonary vascular resistance (PVR) in group II (>1000 dyne s cm−5), PVR in group I remained stable, moderately elevated from baseline (baseline: 150-180 dyne s cm−5 vs endpoint: 1000 dyne s cm−5). EVLW in group I did not increase during reperfusion (baseline: 6.75 ± 1.4 mg/kg vs endpoint: 6.7 ± 1.0 mg/kg), in contrast to group II, where pulmonary edema at 2-h reperfusion preceded terminal graft failure (group I: 9.7 ± 0.1 mg/kg vs group II: 6.48 ± 1.8 mg/kg). Tissue reactive free radicals at endpoint measurement in group I did not differ significantly from native tissue. Yet, when compared to specimen taken from group II at time of terminal graft failure, a significant increase in free radicals was noted (group I: 13.8 ± 1.6 pmol/g vs group II: 18.5 ± 3.0 pmol/g, p < 0.05). Conclusion: Sildenafil treatment prevents terminal early graft failure, allowing lung transplantation after 24-h ischemia time. Reperfusion edema was strikingly diminished, preserving pulmonary structural and functional integrity while prolonging graft ischemia time. Employing the established PDE-5 inhibitor sildenafil during lung perfusion, storage, and implantation, ischemic tolerance may be extended and early graft function improved

Abstract

Objective: Restoring intracellular cGMP and inducing NO-synthesis attenuates ischemia-associated early pulmonary allograft dysfunction. Phosphodiesterase-5 (PDE), predominantly expressed in lung tissue, plays a pivotal role in modulating the cGMP/NO-synthase pathway in endothelial and epithelial cells. In this study, we evaluate the effect of employing sildenafil (Viagra®), a specific inhibitor of PDE-5, to counteract ischemia/reperfusion (I/R) injury in a single lung transplantation model of extended ischemia. Methods: Donor animals (weight matched outbred pigs, 28-35 kg) in the treatment group (I) (n = 5) were injected with 0.7 mg sildenafil/kg into the pulmonary artery (PA) prior to inflow occlusion. For perfusion, Perfadex®, containing 0.7 mg sildenafil/l was used, and the graft stored at 1 °C in the perfusion solution. After 24 h ischemia, unilateral left lung transplantation was performed. Starting at reperfusion, group I received continuous sildenafil (0.7 mg sildenafil/kg), over 6 h. Except for the sildenafil application, the control group (II) (n = 4) was treated identically (PGE1 was injected into the PA). One hour after reperfusion, the right main bronchus (MB) and right PA were occluded. Over the next 5 h, cardiopulmonary parameters (systemic aterial, PA, central venous, left atrial pressure, pCO2, pO2) were measured, including extravascular lung water (EVLW). Thiobarbituric acid-reactive substance assay (TBARS) and myeloperoxidase (MPO) analysis from lung tissue were run. Results: All recipients of group I survived the 6-h reperfusion period; in contrast, all control animals died within 1-2 h after occlusion of the right side. In comparison to a marked rise in pulmonary vascular resistance (PVR) in group II (>1000 dyne s cm−5), PVR in group I remained stable, moderately elevated from baseline (baseline: 150-180 dyne s cm−5 vs endpoint: 1000 dyne s cm−5). EVLW in group I did not increase during reperfusion (baseline: 6.75 ± 1.4 mg/kg vs endpoint: 6.7 ± 1.0 mg/kg), in contrast to group II, where pulmonary edema at 2-h reperfusion preceded terminal graft failure (group I: 9.7 ± 0.1 mg/kg vs group II: 6.48 ± 1.8 mg/kg). Tissue reactive free radicals at endpoint measurement in group I did not differ significantly from native tissue. Yet, when compared to specimen taken from group II at time of terminal graft failure, a significant increase in free radicals was noted (group I: 13.8 ± 1.6 pmol/g vs group II: 18.5 ± 3.0 pmol/g, p < 0.05). Conclusion: Sildenafil treatment prevents terminal early graft failure, allowing lung transplantation after 24-h ischemia time. Reperfusion edema was strikingly diminished, preserving pulmonary structural and functional integrity while prolonging graft ischemia time. Employing the established PDE-5 inhibitor sildenafil during lung perfusion, storage, and implantation, ischemic tolerance may be extended and early graft function improved

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Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 March 2006
Deposited On:02 Nov 2018 06:42
Last Modified:05 Nov 2018 03:23
Publisher:Oxford University Press
ISSN:1010-7940
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.ejcts.2005.12.023
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicenceoxford101016jejcts200512023 (Library Catalogue)

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