Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: Role of nitric oxide

Abstract

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...

Deferoxamine reduces and nitric oxide synthase inhibition increases neutrophil-mediated myotube injury

“…3) suggests that NO and/or downstream RNS protects skeletal muscle from injury caused by neutrophils. This interpretation is in agreement with several in vitro studies which reported a significant protective role of NO against neutrophil-mediated cellular injury (Casini et al 1997;Hansen and Stawski 1994;Murphy et al 1999;Wink and Mitchell 1998). The mechanism for the protection in the present study may be related to NO's ability to inhibit neutrophil adhesion, reduce neutrophilderived ROS production, interrupt lipid peroxidation chain reactions, and/or scavenge other cytolytic molecules (Clancy et al 1992;Kubes et al 1991;Sethi and Dikshit 2000).…”

Characterization of the protective effects of melatonin and related indoles against ?-naphthylisothiocyanate-induced liver injury in rats

“…These workers believe that hepatic lipid peroxidation associated with ANIT-induced liver injury involves oxygen radicals derived from neutrophils which in®ltrate the liver. Neutrophils are known to mediate lipid peroxidation through the production of superoxide anion via activated NADPH oxidoreductase [Casini et al, 1997]. In the present study histological analyses of liver tissue after ANIT administration showed the in®ltration of neutrophils.…”

Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies

“…Neutrophils are an important source of ROS, which may have a direct stimulatory effect on HSC collagen synthesis via superoxide. 13 Activated neutrophils also produce NO, which may counteract the effect of superoxide on collagen production but not abrogate it. 13 Endothelial cells are also likely to participate in HSC activation, both by production of cellular fi bronectin and via conversion of TGF-β from the latent to the active, profi brogenic form.…”