Role of Kupffer cells in the ethanol-induced oxidative stress in the liver.
These studies test the hypothesis that acute and chronic alcohol intoxication stimulate the release of oxygen-derived radicals in the liver. Male Sprague-Dawley rats received an intravenous bolus followed by continuous infusion of ethanol to maintain blood alcohol level at about 175 mg/dl for 0-18 hr. They were then allowed to recover from this "alcohol binge" and the release of free radicals during the recovery phase was monitored. In the chronic alcohol intoxication model, rats were fed with 40% ethanol in agar blocks for 16 weeks. Acute ethanol intoxication induced two phases of hepatic superoxide release. The first phase peaked during the first 3 hr of alcohol intoxication, while the second phase reached its maximum at 6 hr of recovery following a 12 hr binge. The recovery period was also associated with elevated serum transaminase activity. Kupffer cells were largely responsible for hepatic superoxide release during the first phase, while both Kupffer and hepatic sinusoidal endothelial cells contributed to the second phase of free radical formation. Acute ethanol intoxication did not induce endotoxemia. During chronic alcohol intoxication, increased levels of serum endotoxin, TNF, IL-1, and transaminase were observed and hepatic superoxide anion release was present. Superoxide release by isolated Kupffer cells, blood and hepatic PMNs of alcoholic rats was also significantly enhanced in the chronic alcoholic rats. These data indicate that acute alcohol intoxication may directly stimulate the release of reactive oxygen intermediates, whereas chronic alcohol may elicit free radical generation through enhanced endotoxin influx and cytokine release. These studies further demonstrate that free radicals produced by hepatic non-parenchymal cells are likely to play an important role in the pathogenesis of hepatic injury in susceptible individuals with alcohol-related liver disorders.
Department of Physiology and Alcohol Research Center, Louisiana State University Medical Center, New Orleans, Louisiana 70112, USA. Barcdav@aol.com
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Bautista
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Spitzer
D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D007728:Kupffer Cells / Q000378:metabolism* / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D013995:Time; D013997:Time Factors
D013481:Superoxides; D000431:Ethanol