Oxidative stress-related molecules and liver fibrosis
2001; Elsevier BV; Volume: 35; Issue: 2 Linguagem: Inglês
10.1016/s0168-8278(01)00142-8
ISSN1600-0641
Autores Tópico(s)Genomics, phytochemicals, and oxidative stress
Resumo1. IntroductionLiver fibrosis can be considered as a dynamic and highly integrated cellular response to chronic liver injury [[1]Friedman S.L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.J Biol Chem. 2000; 275: 2247-2250Crossref PubMed Scopus (1877) Google Scholar]. 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 [1Friedman S.L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.J Biol Chem. 2000; 275: 2247-2250Crossref PubMed Scopus (1877) Google Scholar, 2Friedman S.L. Maher J.J. Bissell D.M. Mechanisms and therapy of hepatic fibrosis: report of the AASLD single topic basic research conference.Hepatology. 2000; 32: 1403-1408Crossref PubMed Scopus (113) Google Scholar, 3Pinzani M. Gentilini P. Biology of hepatic stellate cells and their possible relevance in the pathogenesis of portal hypertension in cirrhosis.Semin Liver Dis. 1999; 19: 397-410Crossref PubMed Scopus (149) Google Scholar]. 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 [1Friedman S.L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.J Biol Chem. 2000; 275: 2247-2250Crossref PubMed Scopus (1877) Google Scholar, 2Friedman S.L. Maher J.J. Bissell D.M. Mechanisms and therapy of hepatic fibrosis: report of the AASLD single topic basic research conference.Hepatology. 2000; 32: 1403-1408Crossref PubMed Scopus (113) Google Scholar, 3Pinzani M. Gentilini P. Biology of hepatic stellate cells and their possible relevance in the pathogenesis of portal hypertension in cirrhosis.Semin Liver Dis. 1999; 19: 397-410Crossref PubMed Scopus (149) Google Scholar]. 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. [4Pietrangelo A. Iron, oxidative stress and liver fibrogenesis.J Hepatol. 1998; 28: 8-13Abstract Full Text PDF PubMed Google Scholar, 5Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar, 6Parola M. Bellomo G. Robino G. Barrera G. Dianzani M.U. 4-Hydroxynonenal as a biological signal: molecular bases and pathophysiological implications.Antioxidant Redox Signaling. 1999; 1: 255-284Crossref PubMed Scopus (245) Google Scholar]), often in association with decreased antioxidant defenses. As already proposed for atherosclerosis [[7]Kunsch C. Medford R.M. Oxidative stress as a regulator of gene expression in the vasculature.Circ Res. 1999; 85: 753-766Crossref PubMed Scopus (731) Google Scholar] and chronic degenerative diseases of CNS [[8]Keller J.N. Mattson M.P. Role of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction and death in the nervous system.Rev Neurosci. 1998; 9: 105-116Crossref PubMed Scopus (217) Google Scholar], oxidative stress-related molecules may act as mediators able to modulate tissue and cellular events responsible for the progression of liver fibrosis [1Friedman S.L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.J Biol Chem. 2000; 275: 2247-2250Crossref PubMed Scopus (1877) Google Scholar, 3Pinzani M. Gentilini P. Biology of hepatic stellate cells and their possible relevance in the pathogenesis of portal hypertension in cirrhosis.Semin Liver Dis. 1999; 19: 397-410Crossref PubMed Scopus (149) Google Scholar, 4Pietrangelo A. Iron, oxidative stress and liver fibrogenesis.J Hepatol. 1998; 28: 8-13Abstract Full Text PDF PubMed Google Scholar, 5Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar, 6Parola M. Bellomo G. Robino G. Barrera G. Dianzani M.U. 4-Hydroxynonenal as a biological signal: molecular bases and pathophysiological implications.Antioxidant Redox Signaling. 1999; 1: 255-284Crossref PubMed Scopus (245) Google Scholar]. 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.Table 1Major clinical and experimental conditions of chronic liver injury in which involvement of oxidative stress (mainly lipid peroxidation) has been detected in vivoaIn most of these conditions also a decrease in either hepatic or plasma antioxidant defenses has been reported to occur (see Refs. [4–6,19,20,29] and references therein).Clinical conditionsExperimental animal modelsChronic HCV infectionBile duct ligationAlcoholic liver diseaseChronic CCl4 administrationGenetic hemochromatosisChronic ethanol administrationWilson's diseaseModels of iron overloadPrimary biliary cirrhosisModels for copper overloadVarious cholestatic diseasesMixed models of hepatotoxins (ethanol+iron, CCl4+ethanol)a In most of these conditions also a decrease in either hepatic or plasma antioxidant defenses has been reported to occur (see Refs. 4Pietrangelo A. Iron, oxidative stress and liver fibrogenesis.J Hepatol. 1998; 28: 8-13Abstract Full Text PDF PubMed Google Scholar, 5Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar, 6Parola M. Bellomo G. Robino G. Barrera G. Dianzani M.U. 4-Hydroxynonenal as a biological signal: molecular bases and pathophysiological implications.Antioxidant Redox Signaling. 1999; 1: 255-284Crossref PubMed Scopus (245) Google Scholar, 19Albano E. French S.W. Ingelman-Sundberg M. Hydroxyethyl radicals in ethanol hepatotoxicity.Front Biosci. 1999; 4: 533-540Crossref Google Scholar, 20Lieber C.S. Alcoholic liver disease: new insights in pathogenesis lead to new treatments.J Hepatol. 2000; 32: 113-128Abstract Full Text PDF PubMed Scopus (212) Google Scholar, 29Parola M. Leonarduzzi G. Robino G. Albano E. Poli G. Dianzani M.U. On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis.Free Radic Biol Med. 1996; 20: 351-359Crossref PubMed Scopus (159) Google Scholar and references therein). Open table in a new tab 2. Oxidative stress in CLD: basic and clinically relevant conceptsThe 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]Cadenas E. Biochemistry of oxygen toxicity.Annu Rev Biochem. 1989; 58: 79-110Crossref PubMed Scopus (861) Google Scholar]. 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 been implemented by recent data indicating that major ROI, such as hydrogen peroxide (H2O2) and superoxide anion (O2·−), as well as 4-hydroxy-2,3-nonenal (HNE) and related 4-hydroxy-2,3-alkenals (HAKs), major aldehydic end-products of lipid peroxidation, can act as potential mediators able to affect signal transduction pathways as well as the proliferative and functional response of target cells [6Parola M. Bellomo G. Robino G. Barrera G. Dianzani M.U. 4-Hydroxynonenal as a biological signal: molecular bases and pathophysiological implications.Antioxidant Redox Signaling. 1999; 1: 255-284Crossref PubMed Scopus (245) Google Scholar, 8Keller J.N. Mattson M.P. Role of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction and death in the nervous system.Rev Neurosci. 1998; 9: 105-116Crossref PubMed Scopus (217) Google Scholar, 10Lander H.M. An essential role for free radicals and derived species in signal transduction.FASEB J. 1997; 11: 118-124Crossref PubMed Scopus (819) Google Scholar]. H2O2 and O2·− may be also generated as molecular messengers within the cell as part of the cellular response to defined growth factors, cytokines and other mediators [8Keller J.N. Mattson M.P. Role of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction and death in the nervous system.Rev Neurosci. 1998; 9: 105-116Crossref PubMed Scopus (217) Google Scholar, 10Lander H.M. An essential role for free radicals and derived species in signal transduction.FASEB J. 1997; 11: 118-124Crossref PubMed Scopus (819) Google Scholar]. As it will be emphasized later in this review, the final consequence at tissue, cellular and molecular level (overt cytotoxicity, apoptotic cell death or modulation of cell response and fibrosis progression) is primarily affected by the steady state concentration of oxidative stress-related molecules. This parameter, in turn, may be modulated by conditions that can have a relevant impact on both basic mechanisms and clinical manifestations [5Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar, 6Parola M. Bellomo G. Robino G. Barrera G. Dianzani M.U. 4-Hydroxynonenal as a biological signal: molecular bases and pathophysiological implications.Antioxidant Redox Signaling. 1999; 1: 255-284Crossref PubMed Scopus (245) Google Scholar, 8Keller J.N. Mattson M.P. Role of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction and death in the nervous system.Rev Neurosci. 1998; 9: 105-116Crossref PubMed Scopus (217) Google Scholar, 9Cadenas E. Biochemistry of oxygen toxicity.Annu Rev Biochem. 1989; 58: 79-110Crossref PubMed Scopus (861) Google Scholar, 10Lander H.M. An essential role for free radicals and derived species in signal transduction.FASEB J. 1997; 11: 118-124Crossref PubMed Scopus (819) Google Scholar, 11Kaplowitz N. Mechanisms of liver cell injury.J Hepatol. 2000; 32: 39-47Abstract Full Text PDF PubMed Google Scholar, 12Esterbauer H. Schaur R.J. Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes.Free Radic Biol Med. 1991; : 81-128Crossref PubMed Scopus (5849) Google Scholar, 13Arnaiz S.L. Llesuy S. Cutrin J.C. Boveris A. Oxidative stress by acute acetaminophen administration in mouse liver.Free Radic Biol Med. 1995; 19: 303-310Crossref PubMed Scopus (160) Google Scholar]. These include the following.2.1 Antioxidant defensesThe normal liver is a well equipped organ in terms of either enzymic or non enzymic antioxidants (see Fig. 1) although most of the hepatic antioxidant defenses are essentially confined to parenchymal cells [[14]Inoue M. Protective mechanisms against reactive oxygen species.in: Arias I.M. Fausto N. Jakoby W.B. Schachter D. Shafritz D.A. The liver: biology and pathobiology. Raven, New York1994: 443-459Google Scholar]. Kupffer cells, HSC or endothelial cells are potentially more exposed or sensitive to oxidative stress-related molecules (see later in this review). Published experimental evidence clearly indicates that hepatic as well as plasma antioxidant defenses (in particular, GSH and α-tocopherol) are often significantly decreased in several CLD [4Pietrangelo A. Iron, oxidative stress and liver fibrogenesis.J Hepatol. 1998; 28: 8-13Abstract Full Text PDF PubMed Google Scholar, 5Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar, 14Inoue M. Protective mechanisms against reactive oxygen species.in: Arias I.M. Fausto N. Jakoby W.B. Schachter D. Shafritz D.A. The liver: biology and pathobiology. Raven, New York1994: 443-459Google Scholar].2.2 The nature, the specificity of the reactions and the site of production of the different reactive moleculesOrigin of ROI and other oxidative stress-related molecules as well as their reactions relevant to this review are summarized in Fig. 1 and Table 2. Different ROI have highly variable half life and reactivity: as a general rule, the more unstable intermediate has the highest reactivity and the lowest half life time and vice versa. Hydroxyl radical (·OH), probably the most reactive and cytotoxic oxygen centered radical, has a mean half life of 10−9 seconds, it can diffuse less than 2 nm from the site in which is generated and, as a main consequence, it will essentially react non-specifically with any biological molecules available at the site of production. H2O2 and O2·−, that exert manifold effects, are less reactive, and may have a longer half life; however, only H2O2 can easily diffuse across plasma membrane and throughout the cell, whereas O2·− diffuses poorly across cell membranes [[9]Cadenas E. Biochemistry of oxygen toxicity.Annu Rev Biochem. 1989; 58: 79-110Crossref PubMed Scopus (861) Google Scholar]. NO and the highly lipophilic aldehyde HNE, that have a relatively high diffusion range and long half-life, may also react in a less unspecific way with biological macromolecules [12Esterbauer H. Schaur R.J. Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes.Free Radic Biol Med. 1991; : 81-128Crossref PubMed Scopus (5849) Google Scholar, 15Grisham M.B. Jourd'Heuil D. Wink D.A. Nitric oxide I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation.Am J Physiol. 1998; 278: G315-G321Google Scholar]. However, this is just a theoretic scenario: for example, NO can react at extremely fast rate constants when produced in the same microenvironment in which superoxide anion (i.e. by activated inflammatory cells) or carbon dioxide are generated. Moreover, any ROI may rapidly change into other radicals or intermediates depending on local chemical and biochemical conditions, including pH value and the presence of metals [9Cadenas E. Biochemistry of oxygen toxicity.Annu Rev Biochem. 1989; 58: 79-110Crossref PubMed Scopus (861) Google Scholar, 15Grisham M.B. Jourd'Heuil D. Wink D.A. Nitric oxide I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation.Am J Physiol. 1998; 278: G315-G321Google Scholar].Table 2Major consequences of reaction of ROI, HAKs and NO with biologically relevant macromolecules that may mediate pathophysiological effects of these compoundsaNote the following: (a) ROI may act primarily as oxidising agents or by eliciting lipid peroxidation; (b) HAKs do not act as oxidising entities but rather as nucleophilic agents; (c) NO exerts reported effects mainly under the form of N2O3 or interacting with superoxide anion to form ONOO−. More details on chemistry and biochemistry of ROI, HAKs as well as NO and RNOI may be found in specialized reviews (see Refs. [9,12,15,89]).ROIDNA: oxidation, strand breaks, genotoxicityProteins: oxidation, fragmentation, formation of carbonylsLipids: lipid peroxidation and degradationHAKsDNA: adducts (low doses), strand breaks, genotoxicity (high doses)Proteins: adducts (Michael type reactions on Lys, Cys and His residues)NODNA: oxidation, strand breaksProteins: oxidation, nitrosation, nitration (nytrosylation of tyrosine)Lipids: lipid peroxidation and degradationa Note the following: (a) ROI may act primarily as oxidising agents or by eliciting lipid peroxidation; (b) HAKs do not act as oxidising entities but rather as nucleophilic agents; (c) NO exerts reported effects mainly under the form of N2O3 or interacting with superoxide anion to form ONOO−. More details on chemistry and biochemistry of ROI, HAKs as well as NO and RNOI may be found in specialized reviews (see Refs. 9Cadenas E. Biochemistry of oxygen toxicity.Annu Rev Biochem. 1989; 58: 79-110Crossref PubMed Scopus (861) Google Scholar, 12Esterbauer H. Schaur R.J. Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes.Free Radic Biol Med. 1991; : 81-128Crossref PubMed Scopus (5849) Google Scholar, 15Grisham M.B. Jourd'Heuil D. Wink D.A. Nitric oxide I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation.Am J Physiol. 1998; 278: G315-G321Google Scholar, 89Berlett S. Stadtman E.R. Protein oxidation in aging, disease and oxidative stress.J Biol Chem. 1997; 272: 20313-20316Crossref PubMed Scopus (2763) Google Scholar). Open table in a new tab 2.3 Hepatic levels of metal catalysts of oxidative stressHepatic iron overload is associated with hepatocellular injury, inflammation, fibrosis, cirrhosis and hepatocellular cancer [[4]Pietrangelo A. Iron, oxidative stress and liver fibrogenesis.J Hepatol. 1998; 28: 8-13Abstract Full Text PDF PubMed Google Scholar]. Iron accumulates in the liver as a consequence of genetic defects in the absorption, as in genetic hemochromatosis associated with either HFE and non-HFE mutations, or following repeated parenteral administration (i.e. transfusions). Excess free iron represents a potent deleterious hepatotoxic as well as pro-fibrogenic cofactor in the presence of chronic alcohol abuse, viral hepatitis or hepatotoxic xenobiotics [4Pietrangelo A. Iron, oxidative stress and liver fibrogenesis.J Hepatol. 1998; 28: 8-13Abstract Full Text PDF PubMed Google Scholar, 16Tsukamoto H. Horne W. Kamimura S. Niemela O. Parkkila S. Yla-Herttuala S. et al.Experimental liver cirrhosis induced by alcohol and iron.J Clin Invest. 1995; 96: 620-630Crossref PubMed Scopus (450) Google Scholar]. Iron is the ideal metal catalyst for generation of ROI and other free radical intermediates as well as for the induction of lipid peroxidation, and oxidative stress is a common finding in all conditions of iron overload [4Pietrangelo A. Iron, oxidative stress and liver fibrogenesis.J Hepatol. 1998; 28: 8-13Abstract Full Text PDF PubMed Google Scholar, 5Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar]. Antioxidant supplementation prevents liver injury and fibrosis progression in animal models of iron overload [17Pietrangelo A. Borella F. Casalgrandi G. Montosi G. Ceccarelli D. Gallesi D. et al.Antioxidant activity of sylibin in vivo during chronic iron overload in rats.Gastroenterology. 1995; 109: 1941-1949Abstract Full Text PDF PubMed Scopus (162) Google Scholar, 18Pietrangelo A. Gualdi R. Casalgrandi G. Montosi G. Ventura E. Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents.J Clin Invest. 1995; 95: 1824-1831Crossref PubMed Scopus (133) Google Scholar] although iron may be also fibrogenic per se [[4]Pietrangelo A. Iron, oxidative stress and liver fibrogenesis.J Hepatol. 1998; 28: 8-13Abstract Full Text PDF PubMed Google Scholar]. Since copper is another excellent catalyst of oxidative stress [[9]Cadenas E. Biochemistry of oxygen toxicity.Annu Rev Biochem. 1989; 58: 79-110Crossref PubMed Scopus (861) Google Scholar], similar considerations should apply also to Wilson's disease and related animal models in which the involvement of oxidative stress has been detected [[5]Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar].2.4 Alcohol consumptionDetection of oxidative stress and reduced antioxidant defenses has been found in either human alcoholics and in experimental animal models [19Albano E. French S.W. Ingelman-Sundberg M. Hydroxyethyl radicals in ethanol hepatotoxicity.Front Biosci. 1999; 4: 533-540Crossref Google Scholar, 20Lieber C.S. Alcoholic liver disease: new insights in pathogenesis lead to new treatments.J Hepatol. 2000; 32: 113-128Abstract Full Text PDF PubMed Scopus (212) Google Scholar]. Relationships between alcohol consumption and CLD are crucial for alcoholics and for patients with iron overload; moreover alcohol consumption is one of the few relevant host-related factor able to accelerate the progression of fibrosis and the development of cirrhosis in patients affected by chronic hepatitis C [[21]Boyer N. Marcellin P. Pathogenesis, diagnosis and management of hepatitis C.J Hepatol. 2000; 32: 98-112Abstract Full Text PDF PubMed Scopus (189) Google Scholar]. A major determinant of oxidative stress during chronic alcohol consumption is represented by the induction of cytochrome P450 isoform CYP2E1 in hepatocytes and in Kupffer cells [19Albano E. French S.W. Ingelman-Sundberg M. Hydroxyethyl radicals in ethanol hepatotoxicity.Front Biosci. 1999; 4: 533-540Crossref Google Scholar, 20Lieber C.S. Alcoholic liver disease: new insights in pathogenesis lead to new treatments.J Hepatol. 2000; 32: 113-128Abstract Full Text PDF PubMed Scopus (212) Google Scholar], but not in hepatic stellate cells (HSC) [[22]Parola M. Robino G. Bordone R. Leonarduzzi G. Casini A. Pinzani M. et al.Detection of cytochrome P4503A (CYP3A) in human hepatic stellate cells.Biochem Biophys Res Commun. 1997; 238: 420-424Crossref PubMed Scopus (13) Google Scholar]. Induction of CYP2E1 is responsible for most of ethanol metabolism to acetaldehyde but also for the increased vulnerability of alcoholics to the toxicity of various drugs, industrial solvents and anesthetics [[20]Lieber C.S. Alcoholic liver disease: new insights in pathogenesis lead to new treatments.J Hepatol. 2000; 32: 113-128Abstract Full Text PDF PubMed Scopus (212) Google Scholar]. CYP2E1 has a very high NADPH oxidase activity and extensively produce O2·− and H2O2 as well as hydroxyethyl radicals that are likely to be responsible for ethanol induction of oxidative stress and lipid peroxidation [19Albano E. French S.W. Ingelman-Sundberg M. Hydroxyethyl radicals in ethanol hepatotoxicity.Front Biosci. 1999; 4: 533-540Crossref Google Scholar, 20Lieber C.S. Alcoholic liver disease: new insights in pathogenesis lead to new treatments.J Hepatol. 2000; 32: 113-128Abstract Full Text PDF PubMed Scopus (212) Google Scholar]. Hydroxyethyl radicals have been shown to alkylate proteins and to induce, particularly in human alcoholics, the production of related specific antibodies, in addition to antibodies directed against adducts generated by the interaction of proteins with acetaldehyde [19Albano E. French S.W. Ingelman-Sundberg M. Hydroxyethyl radicals in ethanol hepatotoxicity.Front Biosci. 1999; 4: 533-540Crossref Google Scholar, 20Lieber C.S. Alcoholic liver disease: new insights in pathogenesis lead to new treatments.J Hepatol. 2000; 32: 113-128Abstract Full Text PDF PubMed Scopus (212) Google Scholar]. These antibodies recognize hydroxyethyl radical-derived antigens on the plasma membrane of hepatocytes (one identified as CYP2E1 itself) exposed to ethanol, and are able to elicit antibody-dependent cell-mediated immunological reactions towards parenchymal cells [19Albano E. French S.W. Ingelman-Sundberg M. Hydroxyethyl radicals in ethanol hepatotoxicity.Front Biosci. 1999; 4: 533-540Crossref Google Scholar, 23Clot P. Parola M. Bellomo G. Dianzani U. Carini R. Tabone M. et al.Plasma membrane hydroxyethyl radical adducts cause antibody-dependent cytotoxicity in rat hepatocytes exposed to alcohol.Gastroenterology. 1997; 113: 265-276Abstract Full Text PDF PubMed Scopus (74) Google Scholar]. As a consequence, oxidative stress-related intermediates may contribute to liver injury during alcohol abuse also by means of immunological mechanisms.2.5 Age, obesity and non-alcoholic steatohepatitis (NASH)Aging is usually associated with an increased susceptibility to oxidative stress and a significant reduction of antioxidant defenses [[24]Johnson F.B. Sinclair D.A. Guarente L. Molecular biology of aging.Cell. 1999; 22: 291-302Abstract Full Text Full Text PDF Scopus (398) Google Scholar], and this reduction may sustain, at least in part, the increased rate of fibrosis progression observed in older patients. Age at infection is considered a relevant individual factor able to accelerate fibrosis progression in chronic HCV patients [[21]Boyer N. Marcellin P. Pathogenesis, diagnosis and management of hepatitis C.J Hepatol. 2000; 32: 98-112Abstract Full Text PDF PubMed Scopus (189) Google Scholar] and a significant association between age (>50 years) and septal fibrosis has also been described in overweight patients [[25]Ratziu V. Giral P. Charlotte F. Bruckert E. Thibault V. Theodorou I. et al.Liver fibrosis in overweight patients.Gastroenterology. 2000; 118: 1117-1723Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar]. NASH is a liver disease characterized by histopathological features similar to those observed in alcoholic liver disease, in the absence of significant alcohol consumption [[26]James O.F.W. Day C.P. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance.J Hepatol. 1998; 29: 495-501Abstract Full Text PDF PubMed Scopus (349) Google Scholar]. Oxidative stress and lipid peroxidation have been implicated in the pathogenesis of NASH, possibly as the results of two conditions [[26]James O.F.W. Day C.P. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance.J Hepatol. 1998; 29: 495-501Abstract Full Text PDF PubMed Scopus (349) Google Scholar]: (a) it has been proposed that non-insulin dependent diabetes mellitus (NIDDM) and rapid weight loss in obese patients, two recognized risk factors for NASH, may lead to increased concentration of free fatty acids in mitochondria, saturation of mitochondrial β-oxidation and excess H2O2 generation during peroxisomal β-oxidation; (b) CYP2E1 is induced in either human NASH patients as well as in a related experimental model of NASH [27Weltman M.D. Farrell G.C. Hall P. Ingelman-Sundberg M. Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with non-alcoholic steatohepatitis.Hepatology. 1998; 27: 128-133Crossref PubMed Scopus (557) Google Scholar, 28Leclerq I.A. Farrell G.C. Field J. Bell D.R. Gonzalez F.J. Robertson G.R. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine non-alcoholic steatohepatitis.J Clin Invest. 2000; 105: 1067-1075Crossref PubMed Scopus (660) Google Scholar]; recently, also the CYP4A isoform has been suggested as a catalyst of lipid peroxide generation in experimental NASH [[28]Leclerq I.A. Farrell G.C. Field J. Bell D.R. Gonzalez F.J. Robertson G.R. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine non-alcoholic steatohepatitis.J Clin Invest. 2000; 105: 1067-1075Crossref PubMed Scopus (660) Google Scholar]. Moreover, CYP2E1 is also induced by free fatty acids and ketones and, indeed, diabetes (NIDDM) and obesity are considered risk factors for NASH [[26]James O.F.W. Day C.P. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance.J Hepatol. 1998; 29: 495-501Abstract Full Text PDF PubMed Scopus (349) Google Scholar].2.6 Bile acids and cholestasisIn the last decade, several reports have proposed the involvement of oxidative stress and decreased antioxidant defenses in experimental and clinical cholestatic liver injury, including primary biliary cirrhosis [5Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar, 6Parola M. Bellomo G. Robino G. Barrera G. Dianzani M.U. 4-Hydroxynonenal as a biological signal: molecular bases and pathophysiological implications.Antioxidant Redox Signaling. 1999; 1: 255-284Crossref PubMed Scopus (245) Google Scholar]. Whether oxidative stress, mainly lipid peroxidation, may represent a component of bile acids cytotoxicity, the consequence of activation of inflammatory cells or of decreased antioxidant defenses [5Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar, 29Parola M. Leonarduzzi G. Robino G. Albano E. Poli G. Dianzani M.U. On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis.Free Radic Biol Med. 1996; 20: 351-359Crossref PubMed Scopus (159) Google Scholar] is still unclear. Moreover, the scenario is even more complicated by the fact that bilirubin may act as an antioxidant [5Poli G. Parola M. Oxidative damage and fibrogenesis.Free Radic Biol Med. 1997; 22: 287-305Crossref PubMed Scopus (454) Google Scholar, 7Kunsch C. Medford R.M. Oxidative stress as a regulator of gene expression in the vasculature.Circ Res. 1999; 85: 753-766Crossref PubMed Scopus (731) Google Scholar, 9Cadenas E. Biochemistry of oxygen toxicity.Annu Rev Biochem. 1989; 58: 79-110Crossref PubMed Scopus (861) Google Scholar].3. 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 [1Friedman S.L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.J Biol Chem. 2000; 275: 2247-2250Crossref PubMed Scopus (1877) Google Scholar, 2Friedman S.L. Maher J.J. Bissell D.M. Mechanisms and therapy of hepatic fibrosis: report of the AASLD single topic basic research conference.Hepatology. 2000; 32: 1403-1408Crossref PubMed Scopus (113) Google Scholar, 3Pinzani M. Gentilini P. Biology of hepatic stella
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