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26 March 2015 : Original article  

Preconditioning by Cilostazol Protects against Cold Hepatic Ischemia-Reperfusion Injury

Maximilian von HeesenABCDEF, Simon MüllerBC, Ulrich KepplerBE, Moritz J. StrowitzkiBE, Claudia ScheuerC, Martin K. SchillingADG, Michael D. MengerADEF, Mohammed R. MoussavianACDG

DOI: 10.12659/AOT.893031

Ann Transplant 2015; 20:160-168

Abstract

BACKGROUND: In liver transplantation, prolonged cold storage and post-transplant reperfusion are associated with endothelial inflammation, organ dysfunction, and graft failure. We herein studied whether cilostazol, a phosphodiesterase-3-inhibitor, attenuates post-ischemic liver injury after prolonged cold storage.

MATERIAL AND METHODS: Sprague-Dawley rats were assigned to 5 groups (n=6 each): sham animals (cold storage time (CST): 1 h), vehicle-treated (NaCl 0.9%) controls (CST: 24 h), and animals receiving 0.1, 1.0, or 10.0 mg/kg body weight (BW) cilostazol pre-treatment (CST: 24 h). After organ explantation, all livers were stored at 4°C in HTK solution, followed by 60 min of reperfusion with 37°C Krebs Henseleit buffer in a non-recirculating ex situ system. Bile flow was measured to evaluate liver function. To analyze inflammation and morphology, liver tissue samples were taken and histology, immunohistochemistry, and Western blotting were conducted.

RESULTS: In vehicle-treated controls, prolonged cold storage and warm reperfusion induced inflammation, organ dysfunction, and cell death. This was indicated by an increase of hepatocellular vacuolization, endothelial ICAM-1 expression, and apoptotic cell death compared to sham animals. Cilostazol pre-treatment protected against cold hepatic ischemia-reperfusion injury by preventing hepatocellular disintegration, ICAM-1-associated endothelial inflammation, and apoptotic death.

CONCLUSIONS: Inhibition of PDE3 reduces endothelial cell activation and hepatocellular injury in cold ischemia/reperfusion of the liver.

Keywords: Cyclic AMP, Microcirculation, Organ Preservation, Reperfusion Injury

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Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358