Adenoviral bcl-2 transfer improves survival and early graft function after ischemia and reperfusion in rat liver transplantation.
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.
Rentsch
Markus
M
Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Kienle
Klaus
K
Mueller
Thomas
T
Vogel
Mandy
M
Jauch
Karl Walter
KW
Püllmann
Kerstin
K
Obed
Aiman
A
Schlitt
Hans J
HJ
Beham
Alexander
A
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*