NF-κB 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-κB) in alcoholic liver injury. In alcohol-fed rats, activation of NF-κB is associated with the development of necro-inflammatory changes in the liver. Whether activation of NF-κB occurs prior to development of liver injury is unknown. We determined whether activation of NF-κB preceded histopathological liver changes. Male Wistar rats were fed a liquid diet containing ethanol by continuous infusion through permanently implanted gastric tubes. 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-κB, and determination of messenger RNA levels of cytokines, chemokines and cyclo-oxygenase-2. No pathological changes in liver were seen after 2 weeks of intragastric feeding. However, activation of NF-κB was seen in the livers from ethanol-fed rats. In addition, elevated mRNA levels of hepatic pro-inflammatory cytokines (TNF-α and IL12), chemokines MIPIα and MIP-2) and cyclo-oxygenase-2 were seen in association with activation of NF-κB and increased levels of free radicals and endotoxin. Thus, activation of NF-κB, associated with elevated mRNA levels of pro-inflammatory stimuli, precedes the histopathological liver changes in experimental alcoholic liver disease in rats.