Superoxide anion release into the hepatic sinusoid after an acute ethanol challenge and its attenuation by Kupffer cell depletion

Superoxide anion release into the hepatic sinusoids and subsequent damage to the endothelial cells of the hepatic sinusoids after ethanol challenge was examined. A 250 mg/kg body weight/hr dose of ethanol was given to rats for 3 hr, and superoxide anion release into the hepatic sinusoids was examined in a liver perfusion model using the cytochrome e method. Ethanol treatment resulted in superoxide anion release into the hepatic sinusoids (0.20 ± 0.01 vs. 0.12 ± 0.02 o.d., p < 0.05) and an increase in the purine nucleoside phosphorylase/alanine aminotransferase ratio in the liver perfusate, a marker of damage to the endothelial cells of the hepatic sinusoids (0.003 ± 0.002 vs. 0.008 ± 0.002; p < 0.05). Tumor necrosis factor-alpha was not detectable in either group, and there were no significant differences in the population of hepatic macrophages, leukocytes, or Kupffer cells between the two groups. To clarify the role of Kupffer cells in the mechanism, 10 mg/kg of body weight of gadolinium chloride was given to rats twice, 24 hr apart, resulting in depletion of ED2-positive cells from the hepatic lobules. The superoxide anion release after the ethanol challenge was significantly attenuated in the Kupffer cell-depleted rats, compared with the controls (0.14 ± 0.02; p < 0.05, compared with ethanol alone). The change was associated with a significant decrease in the purine nucleoside phosphorylase/alanine aminotransferase ratio in the liver perfusate (0.004 ± 0.002; p < 0.05, compared with ethanol alone). Ethanol causes superoxide anion release into the hepatic sinusoid and subsequent damage to the sinusoidal endothelial cells. These changes were reduced by Kupffer cell depletion. This supports the view that Kupffer cell depletion has a protective effect on ethanol-induced liver injury.