NF-kappa B activation is associated with free radical generation and endotoxemia and precedes pathological liver injury in experimental alcoholic liver disease

Endotoxemia and oxidative stress activate nuclear factor kappa B (NF-kappaB ) in alcoholic liver injury. In alcohol-fed rats, activation of NF-kappaB i s associated with the development of necro-inflammatory changes in the live r. Whether activation of NF-kappaB occurs prior to development of liver inj ury is unknown. We determined whether activation of NF-kappaB preceded hist opathological liver changes. Male Wistar rats were fed a liquid diet contai ning ethanol by continuous infusion through permanently implanted gastric t ubes. Radical intermediates detected by spin trapping were measured in bile prior to killing. After 2 weeks of treatment, samples of liver tissue were obtained for histopathological examination, for evaluation of NF-kappaB, a nd determination of messenger RNA levels of cytokines, chemokines and cyclo -oxygenase-2. No pathological changes in liver were seen after 2 weeks of i ntragastric feeding. However, activation of NF-kappaB was seen in the liver s from ethanol-fed rats. In addition, elevated mRNA levels of hepatic pro-i nflammatory cytokines (TNF-alpha and IL12), chemokines MIPI alpha and MIP-2 ) and cyclo-oxygenase-2 were seen in association with activation of NF-kapp aB and increased levels of free radicals and endotoxin. Thus, activation of NF-kappaB, associated with elevated mRNA levels of pro-inflammatory stimul i, precedes the histopathological liver changes in experimental alcoholic l iver disease in rats. (C) 2001 Academic Press.