Ha. Jarvelainen et al., Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines, HEPATOLOGY, 29(5), 1999, pp. 1503-1510
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.