ROLES OF OXIDATIVE STRESS IN ACTIVATION OF KUPFFER AND ITO CELLS IN LIVER FIBROGENESIS

An increasing body of experimental evidence is emerging to incriminate oxidative stress as a pivotal signal for liver fibrogenesis. This paper reviews the results from our studies testing this hypothesis. In the rat model of alcoholic liver disease, the importance of oxidative stress was supported by marked accentuation of liver fibrosis by dietary supplementation of iron, a pro-oxidant, and the significant correlation of the liver malondialdehyde (MDA) and 4-hydroxynonenal (4HNE) levels with the hepatic collagen accumulation. Both MDA and 4HNE adduct epitopes were detected intensely and diffusely in close association with collagen deposition. The direct cause and effect relationship between MDA/4HNE and Ito cell stimulation was indicated by the demonstration of Ito cell collagen gene induction by these aldehydes in culture. In primary cultures of rat Kupffer cells (KC), addition of antioxidants such as alpha-tocopherol acetate and succinate suppressed mRNA expression and the release of interleukin (IL)-6 and tumour necrosis factor alpha (TNF alpha). In rats with biliary fibrosis, an increase in the liver MDA level was accompanied by enhanced mRNA expression of procollagen alpha 1(I) and transforming growth factor beta 1 in Ito cells; and that of TNF alpha and IL-6 in KC. Furthermore, the gel shift assay of KC nuclear extracts showed enhanced NF-kB DNA binding activity. These results support the proposal that enhanced oxidative stress constitutes an important signal for activation of Kupffer and Ito cells in experimental liver fibrogenesis.