title: Preconditioning by cilostazol protects against cold hepatic ischemia-reperfusion injury.
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.
  
  
  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.
authors: Department of General, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.
authors: Maximilian
authors: M
authors: von Heesen
authors: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors: Simon
authors: S
authors: Müller
authors: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors: Ulrich
authors: U
authors: Keppler
authors: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors: Moritz J
authors: MJ
authors: Strowitzki
authors: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors: Claudia
authors: C
authors: Scheuer
authors: Department of General, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.
authors: Martin K
authors: MK
authors: Schilling
authors: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors: Michael D
authors: MD
authors: Menger
authors: Department of General, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.
authors: Mohammed R
authors: MR
authors: Moussavian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077407:Cilostazol; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D018799:Intercellular Adhesion Molecule-1; D000077407:Cilostazol