The role of gut‐derived bacterial toxins and free radicals in alcohol‐induced liver injury

Journal of Gastroenterology and Hepatology (Australia) - Tập 13 Số S1 - 1998
Ronald G. Thurman1, Blair U. Bradford1, Yuji Iimuro1, Kathryn T. Knecht1, Gavin E. Arteel1, Ming Yin1, Henry D. Connor1,2, C. A. Wall1, James A. Raleigh3, Moritz von Frankenberg1, Yukito Adachi1, Donald T. Forman4, David A. Brenner5, Maria B. Kadiiska2, Ronald P. Mason2
1Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
2Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
3Department of Radiation Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
4Department of Pathology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Tóm tắt

Previous research from this laboratory using a continuous enteral ethanol (EtOH) administration model demonstrated that Kupffer cells are pivotal in the development of EtOH‐induced liver injury. When Kupffer cells were destroyed using gadolinium chloride (GdCl3) or the gut was sterilized with polymyxin B and neomycin, early inflammation due to EtOH was blocked. Anti‐tumour necrosis factor (TNF)‐α antibody markedly decreased EtOH‐induced liver injury and increased TNF‐mRNA. These findings led to the hypothesis that EtOH‐induced liver injury involves increases in circulating endotoxin leading to activation of Kupffer cells. 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 lobule, which was diminished with GdCl3. Enteral EtOH increased free radical generation detected with electron spin resonance (ESR). These radical species had coupling constants matching α‐hydroxyethyl radical and were shown conclusively to arise from EtOH based on a doubling of the ESR lines when 13C‐EtOH was given. α‐Hydroxyethyl radical production was also blocked by the destruction of Kupffer cells with GdCl3. It is known that females develop more severe EtOH‐induced liver injury more rapidly and with less EtOH than males. Female rats on the enteral protocol exhibited more rapid injury and more widespread fatty changes over a larger portion of the liver lobule than males. Plasma endotoxin, ICAM‐1, free radical adducts, infiltrating neutrophils and transcription factor NFκB were approximately two‐fold greater in livers from females than males after 4 weeks of enteral EtOH treatment. Furthermore, oestrogen treatment increased the sensitivity of Kupffer cells to endotoxin. These data are consistent with the hypothesis that Kupffer cells participate in important gender differences in liver injury caused by ethanol.

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Journal of Gastroenterology and Hepatology (Australia)

Tập 13 Số S1

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