CROSS-TOLERANCE BETWEEN ACUTE ALCOHOL-INTOXICATION AND ENDOTOXEMIA

This study tests two hypotheses: (1) prior exposure to LPS induces cro ss-tolerance for the hepatic effects of subsequent short-term alcohol intoxication; and (2) short-term alcohol intoxication renders the live r resistant to the effects of acute endotoxemia, resulting in reduced production of superoxide and tumor necrosis factor. In the first group of experiments, male Sprague-Dawley rats were treated intravenously w ith E. coli lipopolysaccharide (LPS) (0.5 mg/kg) 48 hr before they wer e given an intravenous bolus of ethanol (1.75 g/kg), followed by 250-3 00 mg/kg/hr) for 3-5 hr. Superoxide release in the perfused liver was measured after the 3-hr ethanol infusion. Pretreatment with LPS attenu ated ethanol-mediated superoxide anion release by the perfused liver. The stimulatory effect of phorbol myristate acetate on hepatic release of superoxide was also decreased. In the second group of experiments, rats previously treated with ethanol for 5 hr, received an intravenou s injection of LPS (1 mg/kg). At 90 min after LPS, sera were collected for tumor necrosis factor alpha assay. Hepatic release of superoxide anion was determined 3 hr after LPS. Acute ethanol intoxication for 5 hr significantly reduced LPS-induced serum tumor necrosis factor activ ity and free radical release by the perfused liver. LPS-induced mortal ity was also decreased. In both groups of experiments serum corticoste roid levels were reduced during cross-tolerance. These results demonst rate that cross-tolerance develops between acute alcohol intoxication and endotoxemia manifesting in reduced hepatic production of cytotoxic cytokines and superoxide anions.