Conclusion: Age per se does not potentiate liver fibrosis development. By contrast, previous exposure to a pro-fibrotic stimulus enhances the fibrotic response to a given stimuli later in life. Disclosures: Yves J. Horsmans – Consulting: helssinn, johnson&johnson, roche, merck, ipsen, helssinn, johnson&johnson, roche, merck, ipsen, helssinn, johnson&johnson, roche, merck, ipsen, helssinn, johnson&johnson, roche, merck, ipsen; Grant/Research Support: gsk, astra-zeneca, gsk, astra-zeneca, gsk, astra-zeneca, gsk, astra-zeneca; Speaking and Teaching: bms, bms, bms, bms The following people have nothing to disclose:
Charlotte Selvais, Valérie Lebrun, Isabelle A. Leclercq Background & Aims: Oxidative stress check details is considered to play a key role in the progression of chronic BAY 80-6946 ic50 liver diseases such as hepatitis C and non-alcoholic steatohepatitis. However, since both the production of oxidative stress and liver fibrosis may merely represent the consequences of cell damage caused by the primary disease, it is virtually unknown whether oxidative stress is linked directly to fibrogenesis. Here we examined the direct effects of oxidative stress on hepatic fibrogenesis by using “Tet-mev-1 mouse”, in which mitochondrial reactive oxygen species can be induced by doxycycline (Dox)-regulable expression of mutant succinate dehydrogenase.
Methods: Hepatocytes obtained from wild type or Tet-mev-1 mice were treated with different Dox concentrations. Production of reactive oxygen species and decreased membrane potential of mitochondria were examined by using dichlorofluoresceine diacetate (DCFDA) and tetramethyl rhodamine methyl ester (TMRM), respectively. Both wild type and Tet-mev-1 mice IKBKE were administered 0.4 mg/mL of Dox for 1 year, and subsequently fed either normal diet chow or high fat/high sucrose
(HFHS) diet. Liver tissues obtained from these mice were subjected to histopatho-logical examination and microarray gene expression analyses. Hepatocytes isolated from the same mice were co-cultured with hepatic stellate cells (HSC) prepared from transgenic col1a2 luciferase reporter mice (COL/LUC). Results: DCFDA fluorescent intensities were significantly increased after 1 and 1 0 μg/mL of Dox treatment of hepatocytes from Tet-mev-1 mice, but not control animals. Mitochondrial membrane potential was decreased in Dox-treated Tet-mev-1 hepatocytes as compared with untreated cells. Histopathological examination revealed considerable infiltration of inflammatory cells around the portal tracts, but no apparent cell damage, in Dox-treated Tet-mev-1 mouse liver. Microarray analyses indicated that c-JUN/c-fos expression was markedly elevated in liver tissues from Dox-treated Tet-mev-1 mice as compared with control animals.