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H epatic fibrosis is a major histological finding associated with the progression of chronic liver disease to cirrhosis; it is characterized by increased deposition of components of the extracellular matrix (ECM), in particular fibrillar collagens type I and type III. 1 Hepatic stellate cells (HSC) are currently considered to be one of the major sources of ECM proteins in the liver; expansion of their pool is a key step in the fibrogenic process. 2 Following hepatic injury, HSC develop a myofibroblast-like phenotype, characterized by a reduced content of vitamin A, increased proliferation and migration, enhanced expression of matrix protein, and production of matrix metalloproteinases (MMPs). 3 Evidence from experimental and clinical studies indicates that production of reactive oxygen species (ROS) and lipid peroxidation of cell membranes are often associated with the development of hepatic fibrogenesis and

Hepatic fibrosis is the main histological feature that accomExperimental evidence indicates that the lipid peroxipanies the progression of alcoholic liver injury to cirrhosis dation of biological membranes is often associated with in chronic alcohol abusers. 1,2 Acetaldehyde, a potential prothe development of liver fibrosis. We have studied the oxidant factor linked to ethanol metabolism, has been proeffect of neutrophil-derived reactive oxygen species posed as a mediator of fibrogenesis in alcoholic liver disease. (ROS) on collagen synthesis by human hepatic stellateIn fact, an immunohistochemical association between acetalcells (HSC), the major source of collagen in the liver, in dehyde-protein adducts and extracellular matrix deposition a coculture system. Lipid peroxidation in the cocultures in alcohol-induced liver injury has been reported. of extracellular matrix components in the liver. 6,13-16 When ROS resulted in the early induction of lipid peroxidation isolated and cultured on plastic, they undergo spontaneous and was associated with a marked increase (threefold) transformation into myofibroblast-like cells, thereby mimickof procollagen I mRNA expression and synthesis. The ing in vitro 17 conditions that prevail in vivo after chronic addition of antioxidants, such as vitamin E or superoxalcohol consumption. [18][19][20] However, different mechanisms, ide dismutase (SOD), impaired this stimulation. The other than acetaldehyde-induced fibrogenesis, may be ininhibition of neutrophil NO formation by N G -monovolved in alcoholic hepatic fibrosis. Evidence coming from methyl-L-arginine made the ROS-induced stimulation of either experimental or clinical studies indicates that lipid procollagen I more evident. The addition of xanthine/ peroxidation of biological membranes is often associated with xanthine oxidase X/XO, a superoxide anion donor, to the development of liver fibrosis. [21][22][23][24][25] We have recently shown HSC cultures strongly increased procollagen I synthesis.that the induction of lipid peroxidation phenomena or that This stimulation was hampered by the addition of both treatment with 4-hydroxynonenal (a highly reactive alde-SOD and sodium nitroprusside (an NO donor). The conhydic end-product of lipid peroxidation) stimulates procollatribution of HSC to the production of NO in our coculgen type I synthesis in human HSC by acting at the level ture system was negligible, because inducible NO synof gene expression. 26 Moreover, malondialdehyde has been thase (iNOS) mRNA was almost undetectable in these shown to stimulate collagen production by rat HSC upon acticells, and also because the amount of NO produced by vation in primary culture. 27 HSC stimulated with tumor necrosis factor a (TNF-a)Although alcoholic liver fibrosis may develop in the absence and lipopolysaccharide (LPS) was 500 times less than of evident inflammation, 1,2 the occurrence of alcoholic hepatithat synthesized by neutrophils. In conclusion, these retis may contribute to the increased extracellular matrix deposults ind...

Oxidative stress is associated with liver fibrosis and with hepatic stellate cell (HSC) activation in vivo. However, it remains controversial whether oxidative stress contributes to HSC activation either directly or through a paracrine stimulation by damaged hepatocytes. A medium containing products released from cells undergoing oxidative stress was obtained after incubation of hepatocytes with (HCM/Fe) or without (HCM) 0.1 mmol/L ferric nitrilotriacetate complex (FeNTA). Exposure of HSC to HCM/Fe for 24 hours significantly increased the number of proliferating HSC compared with HCM and to controls at all dilutions tested. The simultaneous coincubation of HSC with HCM/Fe and desferrioxamine (50 micromol/L) did not reduce the observed increase in cell proliferation, thus excluding a role for eventually contaminating iron in HCM/Fe. HCM/Fe induced also a significant increase in collagen type I accumulation in HSC culture media. To study the cellular mechanism underlying HCM/Fe effects, we evaluated the activity of the Na+/H+ exchanger, which plays a role in regulating HSC proliferation. The incubation of HSC for 24 hours with HCM/Fe significantly increased baseline intracellular pH (pHi) and Na+/H+ exchanger activity, indicating a plausible role of this antiport in mediating cell response. In conclusion, hepatocytes undergoing oxidative stress release factors which are fibrogenic for HSC, thereby, confirming what has been only hypothesized in vivo. In addition, HSC proliferation is associated with changes in the Na+/H+ exchanger activity, thus providing a useful target for the evaluation of inhibitors of this pathway for the treatment of hepatic fibrosis.