Comparison of the effect of adenoviral delivery of three superoxide dismutase genes against hepatic ischemiareperfusion injury. Hum Gene Ther 2001;12:2167-2177. Reprinted with permission.
AbstractThe purpose of this study was to investigate the effectiveness of superoxide dismutase (SOD) overexpression in an acute model of hepatic oxidative stress. Oxidative stress was established using a warm ischemia-reperfusion model, where nearly 70% of the liver was made hypoxic by clamping the hepatic artery and a branch of the portal vein for 1 hr followed by restoration of blood flow. Animals were infected i.v. with 1 ؋ 10(9) plaque-forming units (PFU) of adenovirus containing the transgene for cytosolic Cu/Zn-SOD (Ad.SOD1), mitochondrial Mn-SOD (Ad.SOD2), extracellular Cu/Zn-SOD (Ad.SOD3), or the bacterial reporter gene for betagalactosidase (Ad.lacZ) 3 days prior to experiments. Ad.SOD1 and Ad.SOD2 caused a three-fold increase in SOD expression and activity in liver compared to Ad.lacZ-treated control animals. Intravenous administration of Ad.SOD3 increased SOD activity slightly in serum but not in liver. Increases in serum transaminases and pathology due to ischemia-reperfusion were blunted by Ad.SOD1 and Ad.SOD2; however, extracellular SOD had no significant effect. Moreover, lipid-derived free radical adducts (a(N) ؍ 15.65 G and a(H)(beta) ؍ 2.78 G) were increased by ischemia-reperfusion. This effect was blunted by about 60% in Ad.SOD1-and Ad-.SOD2-infected animals, but was unaffected by Ad-.SOD3. However, when high doses of Ad.SOD3 (3 ؋ 10(10) PFU) were administered. serum SOD activity was elevated three-fold and was protective against hepatic ischemia-reperfusion injury under these conditions. These data demonstrate that adenoviral delivery of superoxide dismutase can effectively reduce hepatic oxidative stress.
CommentsDuring tissue resection (Pringle maneuver) or transplantation, the liver is subjected to ischemia and reperfusion, which cause liver dysfunction or may even trigger organ failure during reperfusion. The injury sustained during the initial reperfusion period can impair the longterm recovery of the liver, cause remote organ dysfunction, and enhance the patient's susceptibility to infection and multiple organ failure. 1 Despite improved organ preservation and surgical techniques, ischemia-reperfusion injury remains a significant clinical problem. In particular, organ shortage may force the use of marginal grafts, which have a lower tolerance for ischemic stress and suffer more severe injury during reperfusion. 1 Thus, novel therapeutic approaches are necessary to minimize complications after transplantation and liver resections.Extensive research into the pathophysiology of reperfusion injury in the liver clearly documented the importance of reactive oxygen species. 2 Therefore, enhancing the antioxidant capacity of the liver is a promising therapeutic strategy. 3 Initial approaches using vitamin E and iron chelators were minimally protective, 4 mainly because lipid peroxidation is of limited rele...