title: Adenoviral bcl-2 transfer improves survival and early graft function after ischemia and reperfusion in rat liver transplantation.
abstract: BACKGROUND
  Primary graft dysfunction due to ischemia and reperfusion injury represents a major problem in liver transplantation. The related cell stress may induce apoptosis, which can be suppressed by bcl-2. The purpose of the study was to investigate the effect of adenoviral bcl-2 gene transfer on early graft function and survival in rat liver transplantation.
  
  
  METHODS
  An adenoviral construct that transfers bcl-2 under the control of a tetracycline inducible promoter was generated (advTetOn bcl-2) and used with a second adenovirus that transfers the repressor protein (advCMV Rep). Forty-eight hours before explantation, donor rats were treated with advTetOn bcl-2/ advCMV Rep (n=7) and doxycyclin, with the control adenoviral construct advCMV GFP (n=8) or with doxycyclin alone (n=8). Liver transplantation was performed following 16 hours of cold storage (UW). Bcl-2 expression and intrahepatic apoptosis was assessed. Bile flow was monitored 90 min posttransplantation. The endpoint for survival was 7 days.
  
  
  RESULTS
  Bcl-2 was expressed in hepatocytes and sinusoidal lining cells. This was associated with a significant reduction of apoptotic sinusoidal lining cells and hepatocytes after 24 hours and 7 days. Bile production was significantly higher following bcl-2 pretreatment. Furthermore, bcl-2 transfer resulted in significantly improved survival (100% vs. 50% both control groups).
  
  
  CONCLUSIONS
  Adenoviral bcl-2 transfer results in protein expression in hepatocytes and sinusoidal lining cells resulting in early graft function and survival enhancement after prolonged ischemia and reperfusion injury. The inhibition of apoptosis in the context of liver transplantation might be a reasonable approach in the treatment of graft dysfunction.
authors.affiliation: Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rentsch
authors.forename: Klaus
authors.initials: K
authors.lastname: Kienle
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.forename: Mandy
authors.initials: M
authors.lastname: Vogel
authors.forename: Karl Walter
authors.initials: KW
authors.lastname: Jauch
authors.forename: Kerstin
authors.initials: K
authors.lastname: Püllmann
authors.forename: Aiman
authors.initials: A
authors.lastname: Obed
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Alexander
authors.initials: A
authors.lastname: Beham
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018014:Gene Transfer Techniques; D019254:Genes, bcl-2; D006085:Graft Survival / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D051381:Rats; D015427:Reperfusion Injury / Q000503:physiopathology*