Delivery of Cu/Zn-superoxide dismutase genes with a viral vector minimizes liver injury and improves survival after liver transplantation in the rat.
BACKGROUND
Oxygen-derived free radicals play a central role in pathomechanisms of reperfusion injury after organ transplantation. Endogenous radical scavenger systems such as superoxide dismutase (SOD) degrade toxic radicals; however, SOD is degraded rapidly when given exogenously. Therefore, the hypothesis that treatment of the donor liver with an adenoviral vector encoding the Cu/Zn-SOD gene (Ad-SOD1) would lead to permanent gene expression and therefore protect the organ against injury and increase survival in a rat model of liver transplantation was tested.


METHODS
Some donors were infected with Ad-SOD1, whereas untreated grafts and livers infected with the indicator gene lacZ encoding bacterial beta-galactosidase (Ad-lacZ) served as controls. After orthotopic liver transplantation, survival, serum transaminases, and histopathology were evaluated.


RESULTS
Approximately 80% of hepatocytes expressed beta-galactosidase 72 hr after injection of Ad-lacZ. Moreover, SOD1 gene expression and activity were increased 3- and 10-fold in the Ad-SOD1 group, respectively. After transplantation, 20-25% of rats treated with Ad-lacZ survived. In contrast, all SOD1-treated animals survived. Transaminases measured 8 hr after transplantation in Ad-SOD1 rats were only 40% of those in controls, which increased 40-fold above normal values. Approximately 20% of hepatocytes in untreated and Ad-lacZ-infected organs were necrotic 8 hr after reperfusion, whereas necrosis was nearly undetectable in grafts from rats treated with Ad-SOD1.


CONCLUSIONS
This study provides clear evidence for the first time that gene therapy with Ad-SOD1 increases survival and decreases hepatic injury after liver transplantation. Genetic modification of the liver represents a future approach to protect organs against injury where oxygen-derived free radicals are involved.
Lehmann
T G
TG
Department of Pharmacology, University of North Carolina, Chapel Hill 27599, USA. thorsten_lehmann@med.unc.edu
Wheeler
M D
MD
Schoonhoven
R
R
Bunzendahl
H
H
Samulski
R J
RJ
Thurman
R G
RG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006085:Graft Survival / Q000235:genetics; D007763:Lac Operon; D008099:Liver / Q000098:blood supply / Q000166:cytology; D016031:Liver Transplantation / Q000009:adverse effects / Q000276:immunology*; D051381:Rats; D015427:Reperfusion Injury / Q000201:enzymology / Q000209:etiology; D013482:Superoxide Dismutase / Q000235:genetics*; D000637:Transaminases / Q000032:analysis; D019076:Transgenes / Q000235:genetics
D013482:Superoxide Dismutase; D000637:Transaminases