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Transplantation. 2003 Jul 15;76(1):28-37.

Effects of three superoxide dismutase genes delivered with an adenovirus on graft function after transplantation of fatty livers in the rat.

Author information

1
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7038, USA.

Abstract

BACKGROUND:

Oxygen-derived free radicals play a central role in ischemia/reperfusion injury after organ transplantation and are degraded by endogenous radical scavengers such as superoxide dismutase (SOD). Overexpression of SOD by delivery of the cytosolic SOD gene with an adenovirus (Ad.SOD1) decreases organ injury and increases survival in a rat model of liver transplantation. However, it is unclear which of the three isoforms of SOD provides the most protective effect. The purpose of this study was to identify the isoform with the highest effectiveness against ischemia/reperfusion injury after transplantation of fatty livers, which are particularly susceptible.

METHODS:

Donor rats were given ethanol by gavage before harvest to induce steatotic livers. Some of the donors were infected with adenoviruses expressing either the gene lacZ encoding bacterial beta-galactosidase (Ad.lacZ), Ad.SOD1, Ad.SOD2 (mitochondrial isoform), or Ad.SOD3 (extracellular isoform). After transplantation, SOD activity in liver, survival, histopathology, transaminases, and activation of nuclear factor (NF)-kappaB, IkappaB kinase, Jun-N-terminal kinase (JNK), and tumor necrosis factor (TNF)-alpha were evaluated.

RESULTS:

Ad.SOD1 treatment increased survival, blunted transaminase release, and reduced necrosis, whereas Ad.SOD3 had no protective effect. Ad.SOD2 was not as protective as Ad.SOD1. Ad.SOD1 reduced the activation of NF-kappaB, blunted JNK activity, and reduced TNF-alpha activity. Ad.SOD2 treatment resulted in lower kinase, TNF-alpha, and NF-kappaB activities but was not as effective as Ad.SOD1. IkappaB kinase activity was not affected.

CONCLUSION:

This study demonstrates that cytosolic SOD represents the most effective isoform of SOD to protect transplanted livers from failure; this may be related to lowered NF-kappaB and JNK activities because of reduced oxygen-derived radical production.

[Indexed for MEDLINE]

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