ReviewOxidative stress-related molecules and liver fibrosis
Introduction
Liver fibrosis can be considered as a dynamic and highly integrated cellular response to chronic liver injury [1]. Whatever the etiology, the evolution of chronic liver disease (CLD) is characterized by perpetuation of parenchymal necrosis, chronic hepatitis and qualitative as well as quantitative alterations in extracellular matrix (ECM) composition, whereas activation of hepatic stellate cells (HSC) and involvement of macrophages and Kupffer cells predominate at cellular level [1], [2], [3]. At the molecular level, growth factors, cytokines and chemokines, changes in ECM organization and composition as well as reactive molecules originated by oxidative stress have been suggested to play a pathogenetic role [1], [2], [3]. Evidence of oxidative stress has been detected in almost all the clinical and experimental conditions of CLD with different etiology and fibrosis progression rate (Table 1 and Refs. [4], [5], [6]), often in association with decreased antioxidant defenses. As already proposed for atherosclerosis [7] and chronic degenerative diseases of CNS [8], oxidative stress-related molecules may act as mediators able to modulate tissue and cellular events responsible for the progression of liver fibrosis [1], [3], [4], [5], [6]. This review will highlight major concepts and recent insights in the field, and the definition ‘oxidative stress-related molecules’ will be used to indicate reactive oxygen intermediates (ROI, i.e. oxygen-centered free radicals or intermediates) as well as aldehydes from lipid peroxidation (i.e. a major feature of hepatic oxidative stress). Major concepts and findings related to the role of nitric oxide (NO) and reactive nitrogen oxide intermediates (RNOI) in chronic liver injury, with special reference to NO interactions with ROI and potential antifibrogenic action of NO, will be also presented.
Section snippets
Oxidative stress in CLD: basic and clinically relevant concepts
The term oxidative stress has been often employed to indicate the outcome of oxidative damage to biologically relevant macromolecules such as nucleic acids, proteins, lipids and carbohydrates [9]. This occurs when oxidative stress-related molecules, generated in the extracellular environment or within the cell, exceed cellular antioxidant defenses and, in the past, this aspect has been mainly related to the potential cytotoxic consequences of oxidative stress. At present this definition has
ROI and HAKs as cytotoxic agents: necrosis versus apoptosis, a matter of concentration?
Parenchymal liver necrosis and its perpetuation is a common condition in the natural history and progression of CLD [1], [2], [3]. Severe oxidative stress, considered a major cause of liver necrosis (i.e. acute liver injury), can be elicited by several pro-oxidants and hepatotoxic agents or drugs, leading to steady state concentrations of approx. 0.15 μM for H2O2 and 0.25 μM for total ROI [13] as well as 10−5 M for HNE and HAKs [12]. In addition, oxidative stress constitutes a key feature of
ROI and HAKs as pro-fibrogenic biological signals in the liver: the present and the future
The progression of fibrosis in CLD of different etiology is, at least in part, sustained by the activation and phenotypical modulation of HSC towards the so-called myofibroblast-like phenotype [1], [2], [3]. This process follows a relatively well defined and programmed temporal sequence that recognizes early (initiation or pre-inflammatory stage) and late events (perpetuation of HSC activation) in which the activated phenotype is fully expressed [1]. Phenotypic responses of activated HSC
NO and RNOI: cytoprotective, cytotoxic and signal intermediates in liver injury
Nitric oxide (NO) is a short-lived gaseous free radical known to exert many actions in the liver as well as in other tissues and organs [15]. In this review only major concepts, potentially relevant in conditions of CLD, with special reference to interactions with ROI at molecular level and effects at cellular level (particularly those on activated HSC), will be summarized [60], [61].
Antioxidants as potential therapeutics?
Several experimental reports have stated that antioxidant treatment in vivo is effective in preventing or reducing liver fibrosis. Liver fibrosis induced by chronic ethanol consumption is prevented by polyenylphosphatidylcholine (PPC), CYP2E1 inhibitors such as diallylsulfide (DAS) or phenylethylisothiocyanate (PIC) as well as by S-adenosyl-methionine (SAMe, used to replenish GSH levels) (reviewed in Refs. [19], [20]). SAMe is effective also in animal models [71] and positive results have been
Conclusions
Current literature indicate that ROI, HAKs and NO (including RNOI) are likely to be involved in the progression of liver fibrosis during CLD of different etiology. They may contribute to such progression by eliciting cytotoxicity or, more likely, by modulating tissue events and the functional response of potential target cells, particularly HSC phenotypic responses, but several possible aspects of their intervention, known to operate in other diseases [7], [8], still remain to be explored.
Acknowledgements
This work has been supported by Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST, Rome, Italy), National Project on Molecular and Cellular Biology of Hepatic Fibrosis. The authors are sincerely indebted to Professor Mario Umberto Dianzani for his continuous support and encouragement throughout the years.
References (89)
Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury
J Biol Chem
(2000)- et al.
Mechanisms and therapy of hepatic fibrosis: report of the AASLD single topic basic research conference
Hepatology
(2000) Iron, oxidative stress and liver fibrogenesis
J Hepatol
(1998)- et al.
Oxidative damage and fibrogenesis
Free Radic Biol Med
(1997) Mechanisms of liver cell injury
J Hepatol
(2000)- et al.
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Free Radic Biol Med
(1991) - et al.
Oxidative stress by acute acetaminophen administration in mouse liver
Free Radic Biol Med
(1995) - et al.
Antioxidant activity of sylibin in vivo during chronic iron overload in rats
Gastroenterology
(1995) Alcoholic liver disease: new insights in pathogenesis lead to new treatments
J Hepatol
(2000)- et al.
Pathogenesis, diagnosis and management of hepatitis C
J Hepatol
(2000)
Detection of cytochrome P4503A (CYP3A) in human hepatic stellate cells
Biochem Biophys Res Commun
Plasma membrane hydroxyethyl radical adducts cause antibody-dependent cytotoxicity in rat hepatocytes exposed to alcohol
Gastroenterology
Molecular biology of aging
Cell
Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance
J Hepatol
On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis
Free Radic Biol Med
Interaction between 4-hydroxy-2,3-alkenals and the platelet-derived growth factor-β receptor. Reduced tyrosine phosphorylation and downstream signaling in hepatic stellate cells
J Biol Chem
Glutathione levels discriminate between oxidative stress and transforming growth factor-β signaling in activated rat hepatic stellate cells
J Biol Chem
Glutathione regulation in rat hepatic stellate cells. Comparative studies in primary culture and in liver injury in vivo
Biochem Pharmacol
Manipulation of glutathione stores in rat hepatic stellate cells does not alter collagen synthesis
Hepatology
Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen α1(I) gene expression in human liver fat-storing cells
Biochem Biophys Res Commun
Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide
Hepatology
The Na+/H+ exchanger modulates the fibrogenic effect of oxidative stress in rat hepatic stellate cells
J Hepatol
Induction of procollagen type I gene expression and synthesis in human hepatic stellate cells by 4-hydroxy-2,3-nonenal and other 4-hydroxy-2,3-alkenalks is related to their molecular structure
Biochem Biophys Res Commun
Ethanol and arachidonic acid increase α2(I) collagen expression in rat hepatic stellate cells overexpressing cytochrome P450 2E1
J Biol Chem
UV irradiation activates JNK and increases alpha(I) collagen gene expression in rat hepatic stellate cells
J Biol Chem
Inhibition of the Na+/H+ exchanger reduces rat hepatic stellate cell activity and liver fibrosis: an in vitro and in vivo study
Gastroenterology
Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture
J Hepatol
Regulation of monocyte chemoattractant protein 1 by cytokines and oxygen free radicals in rat hepatic fat-storing cells
Gastroenterology
Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms
J Biol Chem
Nitric oxide prevents tumor necrosis factor α-induced rat hepatocyte apoptosis by the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase 8
Hepatology
Nitric oxide protection of rat liver from lipid peroxidation, collagen accumulation, and liver damage induced by carbon tetrachloride
Biochem Pharmacol
Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells
Gastroenterology
Angiotensin II induces contraction and proliferation of hepatic stellate cells
Gastroenterology
Effects of S-adenosylmethionine on lipid peroxidation and liver fibrogenesis in carbon tetrachloride-induced cirrhosis
J Hepatol
Silymarin retard collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats
Hepatology
The flavonoid quercetin ameliorates liver damage in rats with biliary obstruction
J Hepatol
Strong antiproliferative effects of bacalein in cultured rat hepatic stellate cells
Eur J Pharmacol
A pilot study of the effects of d-α-tocopherol on hepatic stellate cells activation in chronic hepatitis C
Gastroenterology
Vitamin E reduces monocyte tissue factor expression in cirrhotic patients
Blood
Interferon/antioxidant combination therapy for chronic hepatitis C: a controlled pilot trial
Antiviral Res
Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver
J Hepatol
Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol
Biology of hepatic stellate cells and their possible relevance in the pathogenesis of portal hypertension in cirrhosis
Semin Liver Dis
4-Hydroxynonenal as a biological signal: molecular bases and pathophysiological implications
Antioxidant Redox Signaling
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