Acute alcohol produces hypoxia directly in rat liver tissue in vivo: role of Kupffer cells

Abstract

Previous studies using liver slices and isolated perfused rat liver have suggested that ethanol causes hypoxia by increasing oxygen consumption. However, ethanol also increases blood flow to the liver, a phenomenon that may counteract the effects of hypermetabolism by increasing oxygen delivery. Thus whether ethanol causes hypoxia in vivo remains unclear. To clarify this important point, female Sprague-Dawley rats (100-125 g) simultaneously received pimonidazole (120 mg/kg ip), a 2-nitroimidazole hypoxia marker, and one large dose of ethanol (5 g/kg ig), which increase hepatic oxygen uptake dramatically and elevate ethanol metabolism (swift increase in alcohol metabolism) in 2-3 h. After 2 h, ethanol significantly increased the accumulation of bound pimonidazole in pericentral regions of the liver lobule. Treatment of animals with the Kupffer cell-specific toxicant, GdCl3 (10 mg/kg iv, 24 h before experiment), blocked ethanol-induced increases in pimonidazole binding. It is concluded that one large dose of ethanol causes pericentral hypoxia in rat liver tissue in vivo and that Kupffer cells are involved.

Mechanisms of alcohol-induced hepatotoxicity studies in rats

“…Recently, it was reported that high doses of ethanol impair hepatic microcirculation (19) by producing endothelin-1, (20) and we recently detected hypoxia directly in rats on the Tsukamoto-French protocol (21) and in the perfused liver after acute exposure to ethanol in vivo (22). These findings support the idea that hypoxia directly contributes to alcohol-induced liver injury.…”

Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease

“…This may also have the effect of changing oxygen gradients in tissues. Indeed, this is precisely the series of events that we propose occurs with NO in alcohol hepatotoxicity [49] , which has been shown to be associated with tissue hypoxia [53,54] . Several studies have clearly demonstrated that acute alcohol exposure "steepens" the hepatic oxygen gradient as a consequence of ethanol oxidation [55,56] , thus rendering the pericentral regions of the liver lobule hypoxic [53] .…”

“…Indeed, this is precisely the series of events that we propose occurs with NO in alcohol hepatotoxicity [49] , which has been shown to be associated with tissue hypoxia [53,54] . Several studies have clearly demonstrated that acute alcohol exposure "steepens" the hepatic oxygen gradient as a consequence of ethanol oxidation [55,56] , thus rendering the pericentral regions of the liver lobule hypoxic [53] . Thus, the effect of acute hypoxia in an individual actively drinking is proposed to be exaggerated in the chronic alcohol consumer as a consequence of the alcohol dependent increase in inhibition of mitochondrial respiration by NO [14] .…”

Viral gene delivery of superoxide dismutase attenuates experimental cholestasis-induced liver fibrosis in the rat

“…Apoptotic cells were assessed morphologically by identifying Gene Therapy condensed and fragmented nuclei from 2000 cells in H& E slides using methods described elsewhere, 42 and areas in sections stained for collagens by Sirius red F2BA or trichrome were quantified by image analysis. 43 An Image-1/AT image acquisition and analysis system (Universal Imaging, Chester, PA, USA) incorporating an Axioskop 50 microscope (Carl Zeiss, Thornwood, NY, USA) was used to capture and analyze Sirius red-and trichrome-stained tissue sections at ×40 magnification. Detection thresholds were set for the appropriate color of stained collagen based on an intensely labeled point and a default color threshold range was assigned.…”