Hypoxia-reoxygenation is as damaging as ischemia-reperfusion in the rat liver

OBJECTIVE: We hypothesized that the extent of injury and release of xanthine oxidase, an oxidant generator, into the circulation would be less in normal-flow hypoxia-reoxygenation than in equal duration no-flow ischemia-reperfusion. DESIGN: Randomized study. SETTING: University-based animal research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: The livers were isolated, perfused, and then randomly subjected to 2 hrs of hypoxia (normal flow, low oxygen) or ischemia (no flow, no oxygen), and 2 hrs of reperfusion. Hepatocytes were also isolated, and were subjected to either: a) hypoxia (0, 2, 4, and 6 hrs); or b) hypoxia (2 and 4 hrs) with reoxygenation (2 hrs). MEASUREMENTS AND MAIN RESULTS: The extent of liver injury (as assessed by release of hepatocellular enzymes) and the release of xanthine oxidase were measured from isolated-perfused rat livers and cultured hepatocytes. The pattern of release of xanthine oxidase in isolated-perfused liver effluent was different in hypoxia-reoxygenation compared with ischemia-reperfusion. During hypoxia, xanthine oxidase gradually increased in the effluent; then, the xanthine oxidase decreased to low concentrations during reoxygenation. After ischemia, there was a sharp spike in xanthine oxidase at 1 min of reperfusion, with a rapid decrease to low concentrations. The total release of xanthine oxidase during hypoxia-reoxygenation was similar to that during ischemia-reperfusion. Lactate dehydrogenase and other markers of liver injury showed a pattern of release that was similar to that of xanthine oxidase, but the total release of markers was not different between the two groups. In hepatocytes, most of the release of enzymes occurred in hypoxia, and the rate of release was not different between hypoxia and hypoxia-reoxygenation. CONCLUSIONS: Hypoxia-reoxygenation results in as much damage to the liver as ischemia-reperfusion, and results in the release of a similar amount of oxidant-producing xanthine oxidase into the circulation.