Nf-kappab 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 is associated with the development of necro-inflammatory changes in the liver. Whether activation of NF-kappaB occurs prior to development of liver injury is unknown. We determined whether activation of NF-kappaB 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-kappaB, 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-kappaB was seen in the livers from ethanol-fed rats. In addition, elevated mRNA levels of hepatic pro-inflammatory cytokines (TNF-alpha and IL12), chemokines MIPIalpha and MIP-2) and cyclo-oxygenase-2 were seen in association with activation of NF-kappaB and increased levels of free radicals and endotoxin. Thus, activation of NF-kappaB, associated with elevated mRNA levels of pro-inflammatory stimuli, precedes the histopathological liver changes in experimental alcoholic liver disease in rats.
Jokelainen
K
K
Department of Pathology, Harvard Medical School, Boston, MA, USA.
Reinke
L A
LA
Nanji
A A
AA
D000818:Animals; D018925:Chemokines / Q000378:metabolism; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D019446:Endotoxemia / Q000378:metabolism* / Q000473:pathology; D004731:Endotoxins / Q000097:blood; D004750:Enteral Nutrition; D000431:Ethanol / Q000378:metabolism; D005395:Fish Oils; D005609:Free Radicals / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D018925:Chemokines; D016207:Cytokines; D004731:Endotoxins; D005395:Fish Oils; D005609:Free Radicals; D020672:I-kappa B Proteins; D007527:Isoenzymes; D016328:NF-kappa B; C065424:1-hydroxyethyl radical; D000431:Ethanol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases