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iron chelators, lipid peroxidation, liver, oxidative stress, reperfusion injury


To examine the role of iron in mediating hepatocellular damage during reperfusion after hemorrhagic shock, we studied five groups of n=4 or 5 dogs, bled to reduce mean arterial pressure to 35 mmHg (± 5mrnHg) for three hours and subsequently treated 20 minutes prior to reinfusion of shed blood with either 0.9% saline, 5 ml/kg; deferoxamine, 50 μg/kg in 0.9% saline; 6% pentastarch solution, 5 ml/kg; deferoxamine covalently bound to 6% pentastarch, 50 μg/kg; or iron loaded deferoxamine in 0.9% saline. Saturation of iron binding capacity increased during hemorrhagic shock and remained high in all but the def eroxamine pentastarch treated group. Serum iron levels were significantly lower in animals treated with saline or iron loaded deferoxamine. Serum alanine aminotransferase (ALT), a specific marker for hepatocellular injury in the dog, was measured as an indicator of hepatic reperfusion injury. During shock, ALT did not change significantly from the normal in any group. After reperfusion, however, ALT rose sharply in animals reperfused without iron chelators, from a mean baseline value of less than 36 U /L to a post-reperfusion plateau of 5509 ± 2260 U /L at four hours, a pattern suggesting hepatic reperfusion injury. Iron loaded deferoxamine control dogs, also showed a substantial rise in ALT activity to 6287 ± 2134 U/L four hours after reperfusion. However, dogs treated with free deferoxamine showed significantly smaller elevations in ALT to only 655 ± 139 U /L (P <0.05). Histologic evaluation of liver sections showed significantly smaller areas of necrosis in both of the deferoxamine treated groups compared to other groups. These findings suggest that deferoxamine preventable reperfusion injury of the liver, perhaps involving the iron catalyzed Haber-Weiss reaction, may play a role in the pathophysiology of hemorrhagic shock.