title: Multidrug donor preconditioning protects steatotic liver grafts against ischemia-reperfusion injury.
abstract: BACKGROUND
  Graft dysfunction of steatotic livers (SL) still remains a major challenge in liver transplantation. Different mechanisms are thought to be involved in the impaired tolerance of SL to ischemia-reperfusion injury. Thus, different pharmacologic strategies may need to be combined to effectively protect SL and to reduce graft dysfunction after transplantation. Therefore, we analyzed the effectiveness of a multidrug donor preconditioning (MDDP) procedure to protect SL from cold ischemia-reperfusion injury.
  
  
  METHODS
  Liver steatosis was induced by a high-carbohydrate, fat-free diet. A total of 24 Sprague-Dawley rats were divided into 3 groups (n = 8 each), including a control group with nonsteatotic livers (Con), a vehicle-treated SL group (SL-Con), and a SL group undergoing MDDP (SL-MDDP), including pentoxyphylline, glycine, deferoxamine, N-acetylcysteine, erythropoietin, melatonin, and simvastatin. MDDP was applied before liver perfusion with 4°C histidine-tryptophan-ketoglutarate (HTK) solution and organ harvest. After 24 hours of cold storage in HTK, postischemic reperfusion was performed in an isolated liver reperfusion model using 37°C Krebs-Henseleit bicarbonate buffer.
  
  
  RESULTS
  After 60 minutes of reperfusion, SL showed a significant reduction of bile flow as well as a marked increase of liver enzyme levels and apoptotic cell death compared with Con. This was associated with an increased malondialdehyde formation, interleukin-1 production, and leukocytic tissue infiltration. MDDP completely abolished the inflammatory response and was capable of significantly reducing parenchymal dysfunction and injury.
  
  
  CONCLUSIONS
  MDDP decreases SL injury after cold storage and reperfusion. The concept of MDDP as a simple and safe preoperative regime, thus may be of interest in clinical use, expanding the donor pool from marginal donors.
authors.affiliation: Department of General, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: von Heesen
authors.forename: Katharina
authors.initials: K
authors.lastname: Seibert
authors.forename: Matthias
authors.initials: M
authors.lastname: Hülser
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.forename: Mathias
authors.initials: M
authors.lastname: Wagner
authors.forename: Michael Dieter
authors.initials: MD
authors.lastname: Menger
authors.forename: Martin Karl
authors.initials: MK
authors.lastname: Schilling
authors.forename: Mohammed Reza
authors.initials: MR
authors.lastname: Moussavian
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D050377:Cold Ischemia; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000627:therapeutic use; D005234:Fatty Liver; D005260:Female; D018684:Glycine Agents / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D055031:Primary Graft Dysfunction / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017262:Siderophores / Q000627:therapeutic use; D014019:Tissue Donors
chemical_list: D000975:Antioxidants; D018684:Glycine Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017262:Siderophores; D004921:Erythropoietin