ALCOHOL-INDUCED DOWN-REGULATION OF SUPEROXIDE ANION RELEASE BY HEPATIC PHAGOCYTES IN ENDOTOXEMIC RATS

Bacterial endotoxins [lipopolysaccharide (LPS)] are potent immunomodulators, and ethanol is known to depress certain immune defense mechanisms. Thus the combined impact of these two agents on the generation of superoxide anion (O2-.) by isolated hepatic phagocytic cells was investigated. Ethanol was infused intravenously into rats for 7 h, and Escherichia coli LPS was injected intravenously at 4 h after ethanol administration. Control groups received an equal volume of saline or ethanol alone. Nonparenchymal cells that were composed of endothelial and Kupffer cells and few polymorphonuclear neutrophils (PMN; < 1%) were obtained after collagenase-pronase digestion. In the LPS-treated rats, the total number of PMN per liver increased significantly. Histological sections of the liver showed PMN infiltration and areas of necrosis after LPS treatment with or without ethanol. In the presence of either phorbol 12-myristate 13-acetate or oposonized zymosan in vitro, Kupffer cells and hepatic PMN from LPS-treated rats generated large amounts of O2-.. Ethanol intoxication in vivo reduced the LPS-induced generation of O2-. in vitro by these cells to 50%. Ethanol alone (without LPS) had no effect on the production of O2-.. These studies demonstrate that ethanol intoxication was associated with the downregulation of the LPS-enhanced in vivo priming of hepatic phagocytes to generate O2-. in vitro and may thus contribute to the enhanced susceptibility of alcoholic subjects to develop an infection.