Prostaglandin E1 abrogates early reductive stress and zone-specific paradoxical oxidative injury in hypoperfused rat liver.

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Abstract
This study was designed to investigate the effects of prostaglandin E1 on reductive stress and the subsequent oxidative cell injury in hypoperfused rat liver. The intralobular heterogeneity of hepatocellular redox state, mitochondrial dysfunction, and intracellular hydroperoxide formation were visually monitored by digital microfluorography of pyridine nucleotide autofluorescence, rhodamine 123, and dichlorofluorescein fluorescence, respectively. Under the 25% low flow perfusion, pyridine nucleotide autofluorescence increased time-dependently and reached a steady state at 10 min among the entire lobules. The decrease in mitochondrial membrane potential was > 20 mV in all portions of the lobules at 60 min. The onset of hydroperoxide formation was observed at 40 min in the marginally oxygenated proximal portion of anoxic pericentral regions and the oxidative impact reached a maximum level at 60 min. Sodium (-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazo [1,5-a]-1,3,5-triazine-4-olate monohydrate (BOF 4272), a novel xanthine oxidase inhibitor, suppressed the zone-specific oxidative changes without attenuating the increase in pyridine nucleotide autofluorescence and mitochondrial dysfunction. Pretreatment with prostaglandin E1 not only abrogated an early increase in pyridine nucleotide fluorescence and mitochondrial dysfunction induced by hypoperfusion but also diminished the subsequent midzonal oxidative injury. Since prostaglandin E1 has no oxyradical-scavenging action, the preventive effect of this reagent on the hypoxia-induced oxidative cell injury is attributable to the attenuation of mitochondrial dysfunction. These results suggest that, in low flow hypoxia, early reductive stress plays a key role in the initiation of xanthine oxidase-mediated midzonal oxidative changes, which may lead to subsequent centrilobular necrosis.

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