THE ROLE OF GUT-DERIVED BACTERIAL TOXINS AND FREE-RADICALS IN ALCOHOL-INDUCED LIVER-INJURY

Previous research from this laboratory using a continuous enteral etha nol (EtOH) administration model demonstrated that Kupffer cells are pi votal in the development of EtOH-induced liver injury. When Kupffer ce lls were destroyed using gadolinium chloride (GdCl3) or the gut was st erilized with polymyxin B and neomycin, early inflammation due to EtOH was blocked. Anti-tumour necrosis factor (TNF)-alpha antibody markedl y decreased EtOH-induced liver injury and increased TNF-mRNA. These fi ndings led to the hypothesis that EtOH-induced liver injury involves i ncreases in circulating endotoxin leading to activation of Kupffer cel ls. Pimonidazole, a nitro-imidazole marker, was used to detect hypoxia in downstream pericentral regions of the lobule. Following one large dose of EtOH or chronic enteral EtOH for 1 month, pimonidazole binding was increased significantly in pericentral regions of the liver lobul e, which was diminished with GdCl3. Enteral EtOH increased free radica l generation detected with electron spin resonance (ESR). These radica l species had coupling constants matching alpha-hydroxyethyl radical a nd were shown conclusively to arise from EtOH based on a doubling of t he ESR lines when C-13-EtOH was given. alpha-Hydroxyethyl radical prod uction was also blocked by the destruction of Kupffer cells with GdCl3 . It is known that females develop more severe EtOH-induced liver inju ry more rapidly and with less EtOH than males. Female rats on the ente ral protocol exhibited more rapid injury and more widespread fatty cha nges over a larger portion of the liver lobule than males. Plasma endo toxin, ICAM-1, free radical adducts, infiltrating neutrophils and tran scription factor NF kappa B were approximately two-fold greater in liv ers from females than males after 4 weeks of enteral EtOH treatment. F urthermore, oestrogen treatment increased the sensitivity of Kupffer c ells to endotoxin. These data are consistent with the hypothesis that Kupffer cells participate in important gender differences in liver inj ury caused by ethanol.