Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines

To better understand how gut-derived endotoxins influence alcohol-induced l iver injury and the expression of inflammatory cytokines a new animal model was developed, After 2 weeks on a modified ethanol-containing liquid diet, some rats also were infused with endotoxin via osmotic minipumps for 4 add itional weeks. Ethanol diet alone increased plasma endotoxin threefold to 9 .3 pg/mL. Endotoxin infusion increased the levels to 388 and 513 pg/mL in c ontrols and ethanol-fed animals, respectively. Panlobular macrovesicular an d microvesicular steatosis and inflammatory foci were observed in livers fr om both ethanol- and ethanol-endotoxin-treated animals, but there was no si gnificant potentiation by endotoxin. Only minor changes, mainly polymorphon uclear infiltration, were seen in animals treated with endotoxin alone alth ough the messenger RNA (mRNA) expression of both proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and anti-inflammatory cytokines IL-4 and IL-10 were markedly increased, as sho wn by competitive polymerase chain reaction (PCR) analysis using cyclophili n as standard. The effect of endotoxin infusion on cytokine mRNA expression in ethanol-fed animals was not significantly different. Expression of tran sforming growth factor beta(1) (TGF-beta(1)) mRNA was increased twofold by ethanol, eightfold by endotoxin, but only threefold by ethanol-endotoxin tr eatment. The mRNA expression of lipopolysaccharide binding protein (LBP) an d CD14 endotoxin receptor was not significantly increased by chronic endoto xin treatment, contrasting with the marked elevation observed after acute e ndotoxin challenge. These results suggest that the tolerance observed despi te sustained hepatic expression of proinflammatory cytokines is counteracte d by the antiinflammatory cytokines and by down-regulation of CD14 and LBP Furthermore, a similar adaptation may occur in alcoholics with continuous e ndotoxemia.