Ethanol and HCV-Induced cytotoxicity: The perfect storm
2005; Elsevier BV; Volume: 128; Issue: 1 Linguagem: Inglês
10.1053/j.gastro.2004.11.044
ISSN1528-0012
Autores Tópico(s)Liver Disease and Transplantation
ResumoMost liver diseases caused either by genetic or environmental factors such as chronic ethanol consumption, viral infection, or toxicant exposure follow similar stages of progression. Hepatitis is a relatively early phase characterized by inflammation, hepatomegaly, and decrease in liver function, which under most circumstances is reversible. Hepatitis progresses, however, to an irreversible tissue scarring (fibrosis), cirrhosis, hepatocellular carcinoma, and chronic liver failure. Although the progression of liver disease seems to be a rather linear series of pathologies, the mechanisms involved in the progression continue to elude researchers. The fact that the combination of factors causing liver disease rapidly accelerates the progression of disease suggests some common themes. One very strong and relatively consistent theme that becomes apparent is the role of oxidative stress in liver disease.The mechanism of oxidative stress seems to have a widening role in pathogenesis of a number of liver diseases and seems to represent a common pathway for liver injury. It has been clear for a long while that oxidative stress was a critical component of the progression of alcoholic liver disease. Early work by DiLuzio and Shaw clearly indicated that "oxidative stress" was an effect of ethanol metabolism in liver.1DiLuzio N.R. Kalish G.H. Enhanced peoxidation of lipid in the pathogenesis of acute ethanol-induced liver injury.Gastroenterology. 1966; 50: 392-396Google Scholar, 2Shaw S. Heller E.A. Friedman H.S. Lieber C.S. Increased hepatic oxygenation following ethanol administration in the baboon.Proc Soc Exp Biol Med. 1977; 156: 509-513Google Scholar It was later shown by a number of groups that oxidants were indeed generated both as a direct result of ethanol metabolism and through other means such as uncoupling of electron transport in mitochondria, and "respiratory burst" of activated macrophages and neutrophils. The association between hepatitis C infection and liver oxidative stress is a more recent finding. Swietek et al reported that chronic infection with HCV caused a depletion of glutathione,3Swietek K. Juszczyk J. Reduced glutathione concentration in erythrocytes of patients with acute and chronic viral hepatitis.J Viral Hepat. 1997; 4: 139-141Google Scholar and Larrea et al almost simultaneously suggested that HCV pathology could be related to oxidative stress because patients with viral persistence showed significantly lower Mn-SOD in liver than infected patients who responded to treatment.4Larrea E. Beloqui O. Munoz-Navas M.A. Civeira M.P. Prieto J. Superoxide dismutase in patients with chronic hepatitis C virus infection.Free Radic Biol Med. 1998; 24: 1235-1241Google ScholarEarly studies found that alcoholic patients were more likely to show evidence of HCV infection than control patients, as well as have persistent viral infections despite treatment,5Rosman A.S. Paronetto F. Galvin K. Williams R.J. Lieber C.S. Hepatitis C virus antibody in alcoholic patients. Association with the presence of portal and/or lobular hepatitis.Arch Intern Med. 1993; 153: 965-969Google Scholar suggesting a strong interaction between ethanol consumption and HCV infection. More important than its effects on HCV persistence, alcohol subsequently was shown to accelerate and enhance two major processes of viral liver disease, namely inflammation and fibrosis. Thus the question arises, does alcohol increase HCV susceptibility or vice versa? Or is the increased injury simply the coming together of two major insults?—the perfect storm, so to speak.While some data supports the idea that chronic ethanol consumption indeed results in a impaired immune function, which may affect the ability of the virus to persist rather than be eliminated,6Encke J. Wands J.R. Ethanol inhibition the humoral and cellular immune response to hepatitis C virus NS5 protein after genetic immunization.Alcohol Clin Exp Res. 2000; 24: 1063-1069Google Scholar recent data suggest that cellular injury, at least, may simply be the added effects of two similar mechanisms, specifically, oxidative stress. Given that ethanol exposure and HCV infection cause hepatic oxidative stress— likely through different mechanisms—it seems rather plausible that the combination of these mechanisms cause elevated pathology. In an article in this issue of Gastroenterology, Steven Weinman's group7Otani K.. Korenaga M.. Beard M.R.. Li K.. Qian T.. Showalter L.A.. Singh A.K.. Wang T.. Weinman S.A.. Hepatitis C virus core protein, cytochrome P4502E1 and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells.Gastroenterology. 2004; 128: 96-107Abstract Full Text Full Text PDF Scopus (122) Google Scholar addresses the combined effects of ethanol metabolism and HCV core protein overexpression in the Huh-7 hepatoma cell line. This work built on previously published findings that overexpression of the HCV core protein leads to increases in reactive oxygen species in a number of cell lines,8Okuda M. Li K. Beard M.R. Showalter L.A. Scholle F. Lemon S.M. Weinman S.A. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.Gastroenterology. 2002; 122: 366-375Abstract Full Text Full Text PDF Scopus (799) Google Scholar as well as an increase in metallothionein (MT) family of antioxidant proteins,9Li K. Prow T. Lemon S.M. Beard M.R. Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells.Hepatology. 2002; 35: 1237-1246Google Scholar both suggesting that HCV is capable of inducing oxidative stress in isolated cells. Moreover, Cederbaum's group has demonstrated in a similar hepatoma cell line overexpressing CYP2E1, that ethanol causes a rapid depletion of glutathione and increase in lipid peroxidation, which were prevented in the presence of the antioxidants vitamin E and vitamin C.10Wu D. Cederbaum A.I. Ethanol-induced apoptosis to stable HepG2 cell lines expressing human cytochrome P-4502E1.Alcohol Clin Exp Res. 1999; 23: 67-76Google Scholar, 11Chen Q. Cederbaum A.I. Menadione cytotoxicity to Hep G2 cells and protection by activation of nuclear factor-κB.Mol Pharmacol. 1997; 52: 648-657Crossref Scopus (33) Google Scholar, 12Bai J. Rodriguez A.M. Melendez J.A. Cederbaum A.I. Overexpression of catalase in cytosolic or mitochondrial compartment protects HepG2 cells against oxidative injury.J Biol Chem. 1999; 274: 26217-26224Google Scholar It has been subsequently demonstrated that ethanol induces mitochondrial permeability transition and apoptosis in CYP2E1-overexpressing hepatoma cells.The combined effects of HCV core protein expression and ethanol challenge in CYP2E1-overexpressing cells revealed no real surprises. Specifically, Otani et al showed that ethanol caused a significant increase in oxidant production and mitochondrial permeability transition (MPT) in cells expressing both HCV core and CYP2E1, compared with the cells expressing either HCV core protein or CYP2E1 alone. These findings suggest that the combined effects of HCV core protein and ethanol metabolism were through the common mechanism of oxidative stress. To more clearly demonstrate the overall importance of oxidative stress, the group added a more potent oxidant tBOOH to the mix. Now, not only was there an increase in oxidant production and MPT, cytotoxicity (presumably apoptosis since cell death was inhibited by cyclosporine A) was observed. Quite surprising, however, was the fact that cytotoxicity was completely inhibited in the presence of antioxidant N-acetylcysteine (NAC). To further support this notion, mitochondrial glutathione was depleted to a greater extent in ethanol/tBOOH treated CY2E1 and HCV core expressing cells. This too was prevented by antioxidants.In the real life drama The Perfect Storm, several hurricanes merged on one another in the Atlantic ocean, overtaking a small fishing crew, who had experienced and survived many single storms. Of people infected with HCV, only a minority develop severe, life-threatening liver disease. A small percentage (about 20%) recovers spontaneously, and some infected people exhibit stable, nonprogressive hepatitis. A study of HCV-infected patients reveals a two- to three-fold greater risk of cirrhosis and decompensated liver disease in those that also were heavy drinkers.13Byard R.W. Harrison R. Wells R. Gilbert J.D. Glycine toxicity and unexpected intra-operative death.J Forensic Sci. 2001; 46: 1244-1246Google Scholar There is a clear relationship between higher self-reported alcohol consumption score (SRAC) and liver fibrosis in HCV-infected patients.14Pessione F. Degos F. Marcellin P. Duchatelle V. Njapoum C. Martinot-Peignoux M. Degott C. Valla D. Erlinger S. Rueff B. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C.Hepatology. 1998; 27: 1717-1722Google Scholar So, do these data suggest that the exacerbation of HCV-induced liver disease by chronic ethanol consumption is merely the combined "oxidative stress?" Otani and Weinman7Otani K.. Korenaga M.. Beard M.R.. Li K.. Qian T.. Showalter L.A.. Singh A.K.. Wang T.. Weinman S.A.. Hepatitis C virus core protein, cytochrome P4502E1 and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells.Gastroenterology. 2004; 128: 96-107Abstract Full Text Full Text PDF Scopus (122) Google Scholar would suggest so. Rigamonti et al, who reported that alcohol consumption increases oxidative stress markers 4-hydroxy-nonenal and malondialdehyde in HCV-infected patients, may also agree.15Rigamonti C. Mottaran E. Reale E. Rolla R. Cipriani V. Capelli F. Boldorini R. Vidali M. Sartori M. Albano E. Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C.Hepatology. 2003; 38: 42-49Google ScholarWhat then are the implications?The report by Otani et al clearly suggest that ethanol-induced oxidative stress and HCV-associated oxidative stress combine to give a deleterious punch. However, the report fails to address other potent sources of oxidants that certainly play a role in alcoholic liver disease. Thus, a weakness and limitation of the cell culture model is that other factors may play a critical role in oxidative stress. Specifically, macrophage-derived oxidants through NADPH oxidase are necessary for the development of ethanol-induced liver injury.16Kono H. Rusyn I. Yin M. Gabele E. Yamashina S. Dikalova A. Kadiiska M.B. Connor H.D. Mason R.P. Segal B.H. Bradford B.U. Holland S.M. Thurman R.G. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease.J Clin Invest. 2000; 106: 867-872Google Scholar Moreover, a recent study followed oxidative stress markers before and after the treatment of HCV-infected patients with interferon. The study demonstrated that interferon suppresses malondialdehyde and oxidized plasma thoils along with an improvement of liver function and decrease in fibrosis.17Mahmood S. Kawanaka M. Kamei A. Izumi A. Nakata K. Niiyama G. Ikeda H. Hanano S. Suehiro M. Togawa K. Yamada G. Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C.Antioxid Redox Signal. 2004; 6: 19-24Google Scholar It would be suggested by these studies that oxidants involved in the immune response are important for the progression of liver disease. On the other hand, the simplicity of the model also highlights the seemingly straightforward conclusion that oxidants, regardless of the source, are important for cytotoxicity. This suggests, however, that the most logical approach for therapy of either early alcoholic liver disease, hepatitis C infection, or both, would be antioxidants. Another difficulty with this logical conclusion is that there is little evidence that the mechanism of oxidative stress is important for the progression of severe liver disease. The report by Otani et al and other in vitro approaches focus only a narrow window, an early one at that. Another difficulty with the conclusions from this approach, specifically, the approach of using hepatoma cell lines, is the suggestion that hepatocyte cytotoxicity is a critical initiator or mediator of the fibrotic response. While it is likely that hepatocellular injury plays an important role, there is still a disconnect between hepatocellular injury and apoptosis as described in Otani et al and hepatic macrophage cell, cytokine production, T cell influx and activation, hepatic stellate cell activation, and ultimately, collagen production.The next important question is whether the "combined" oxidative stress from ethanol metabolism and HCV core protein is the key to the progression of liver fibrosis, and ultimately cirrhosis. The next reasonable step would be to determine whether transgenic mice overexpressing HCV core protein develop fibrosis when challenged with chronic ethanol. More importantly, would that injury be inhibited by antioxidants? Since these transgenic mice already exhibit hepatic steatosis and mild changes in lipid peroxidation in response to liquid ethanol diet,18Lerat H. Honda M. Beard M.R. Loesch K. Sun J. Yang Y. Okuda M. Gosert R. Xiao S.Y. Weinman S.A. Lemon S.M. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus.Gastroenterology. 2002; 122: 352-365Abstract Full Text Full Text PDF Scopus (406) Google Scholar, 19Perlemuter G. Letteron P. Carnot F. Zavala F. Pessayre D. Nalpas B. Brechot C. Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model.J Hepatol. 2003; 39: 1020-1027Google Scholar the answer to whether fibrosis ensues in these mice is presumably forthcoming. Most liver diseases caused either by genetic or environmental factors such as chronic ethanol consumption, viral infection, or toxicant exposure follow similar stages of progression. Hepatitis is a relatively early phase characterized by inflammation, hepatomegaly, and decrease in liver function, which under most circumstances is reversible. Hepatitis progresses, however, to an irreversible tissue scarring (fibrosis), cirrhosis, hepatocellular carcinoma, and chronic liver failure. Although the progression of liver disease seems to be a rather linear series of pathologies, the mechanisms involved in the progression continue to elude researchers. The fact that the combination of factors causing liver disease rapidly accelerates the progression of disease suggests some common themes. One very strong and relatively consistent theme that becomes apparent is the role of oxidative stress in liver disease. The mechanism of oxidative stress seems to have a widening role in pathogenesis of a number of liver diseases and seems to represent a common pathway for liver injury. It has been clear for a long while that oxidative stress was a critical component of the progression of alcoholic liver disease. Early work by DiLuzio and Shaw clearly indicated that "oxidative stress" was an effect of ethanol metabolism in liver.1DiLuzio N.R. Kalish G.H. Enhanced peoxidation of lipid in the pathogenesis of acute ethanol-induced liver injury.Gastroenterology. 1966; 50: 392-396Google Scholar, 2Shaw S. Heller E.A. Friedman H.S. Lieber C.S. Increased hepatic oxygenation following ethanol administration in the baboon.Proc Soc Exp Biol Med. 1977; 156: 509-513Google Scholar It was later shown by a number of groups that oxidants were indeed generated both as a direct result of ethanol metabolism and through other means such as uncoupling of electron transport in mitochondria, and "respiratory burst" of activated macrophages and neutrophils. The association between hepatitis C infection and liver oxidative stress is a more recent finding. Swietek et al reported that chronic infection with HCV caused a depletion of glutathione,3Swietek K. Juszczyk J. Reduced glutathione concentration in erythrocytes of patients with acute and chronic viral hepatitis.J Viral Hepat. 1997; 4: 139-141Google Scholar and Larrea et al almost simultaneously suggested that HCV pathology could be related to oxidative stress because patients with viral persistence showed significantly lower Mn-SOD in liver than infected patients who responded to treatment.4Larrea E. Beloqui O. Munoz-Navas M.A. Civeira M.P. Prieto J. Superoxide dismutase in patients with chronic hepatitis C virus infection.Free Radic Biol Med. 1998; 24: 1235-1241Google Scholar Early studies found that alcoholic patients were more likely to show evidence of HCV infection than control patients, as well as have persistent viral infections despite treatment,5Rosman A.S. Paronetto F. Galvin K. Williams R.J. Lieber C.S. Hepatitis C virus antibody in alcoholic patients. Association with the presence of portal and/or lobular hepatitis.Arch Intern Med. 1993; 153: 965-969Google Scholar suggesting a strong interaction between ethanol consumption and HCV infection. More important than its effects on HCV persistence, alcohol subsequently was shown to accelerate and enhance two major processes of viral liver disease, namely inflammation and fibrosis. Thus the question arises, does alcohol increase HCV susceptibility or vice versa? Or is the increased injury simply the coming together of two major insults?—the perfect storm, so to speak. While some data supports the idea that chronic ethanol consumption indeed results in a impaired immune function, which may affect the ability of the virus to persist rather than be eliminated,6Encke J. Wands J.R. Ethanol inhibition the humoral and cellular immune response to hepatitis C virus NS5 protein after genetic immunization.Alcohol Clin Exp Res. 2000; 24: 1063-1069Google Scholar recent data suggest that cellular injury, at least, may simply be the added effects of two similar mechanisms, specifically, oxidative stress. Given that ethanol exposure and HCV infection cause hepatic oxidative stress— likely through different mechanisms—it seems rather plausible that the combination of these mechanisms cause elevated pathology. In an article in this issue of Gastroenterology, Steven Weinman's group7Otani K.. Korenaga M.. Beard M.R.. Li K.. Qian T.. Showalter L.A.. Singh A.K.. Wang T.. Weinman S.A.. Hepatitis C virus core protein, cytochrome P4502E1 and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells.Gastroenterology. 2004; 128: 96-107Abstract Full Text Full Text PDF Scopus (122) Google Scholar addresses the combined effects of ethanol metabolism and HCV core protein overexpression in the Huh-7 hepatoma cell line. This work built on previously published findings that overexpression of the HCV core protein leads to increases in reactive oxygen species in a number of cell lines,8Okuda M. Li K. Beard M.R. Showalter L.A. Scholle F. Lemon S.M. Weinman S.A. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.Gastroenterology. 2002; 122: 366-375Abstract Full Text Full Text PDF Scopus (799) Google Scholar as well as an increase in metallothionein (MT) family of antioxidant proteins,9Li K. Prow T. Lemon S.M. Beard M.R. Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells.Hepatology. 2002; 35: 1237-1246Google Scholar both suggesting that HCV is capable of inducing oxidative stress in isolated cells. Moreover, Cederbaum's group has demonstrated in a similar hepatoma cell line overexpressing CYP2E1, that ethanol causes a rapid depletion of glutathione and increase in lipid peroxidation, which were prevented in the presence of the antioxidants vitamin E and vitamin C.10Wu D. Cederbaum A.I. Ethanol-induced apoptosis to stable HepG2 cell lines expressing human cytochrome P-4502E1.Alcohol Clin Exp Res. 1999; 23: 67-76Google Scholar, 11Chen Q. Cederbaum A.I. Menadione cytotoxicity to Hep G2 cells and protection by activation of nuclear factor-κB.Mol Pharmacol. 1997; 52: 648-657Crossref Scopus (33) Google Scholar, 12Bai J. Rodriguez A.M. Melendez J.A. Cederbaum A.I. Overexpression of catalase in cytosolic or mitochondrial compartment protects HepG2 cells against oxidative injury.J Biol Chem. 1999; 274: 26217-26224Google Scholar It has been subsequently demonstrated that ethanol induces mitochondrial permeability transition and apoptosis in CYP2E1-overexpressing hepatoma cells. The combined effects of HCV core protein expression and ethanol challenge in CYP2E1-overexpressing cells revealed no real surprises. Specifically, Otani et al showed that ethanol caused a significant increase in oxidant production and mitochondrial permeability transition (MPT) in cells expressing both HCV core and CYP2E1, compared with the cells expressing either HCV core protein or CYP2E1 alone. These findings suggest that the combined effects of HCV core protein and ethanol metabolism were through the common mechanism of oxidative stress. To more clearly demonstrate the overall importance of oxidative stress, the group added a more potent oxidant tBOOH to the mix. Now, not only was there an increase in oxidant production and MPT, cytotoxicity (presumably apoptosis since cell death was inhibited by cyclosporine A) was observed. Quite surprising, however, was the fact that cytotoxicity was completely inhibited in the presence of antioxidant N-acetylcysteine (NAC). To further support this notion, mitochondrial glutathione was depleted to a greater extent in ethanol/tBOOH treated CY2E1 and HCV core expressing cells. This too was prevented by antioxidants. In the real life drama The Perfect Storm, several hurricanes merged on one another in the Atlantic ocean, overtaking a small fishing crew, who had experienced and survived many single storms. Of people infected with HCV, only a minority develop severe, life-threatening liver disease. A small percentage (about 20%) recovers spontaneously, and some infected people exhibit stable, nonprogressive hepatitis. A study of HCV-infected patients reveals a two- to three-fold greater risk of cirrhosis and decompensated liver disease in those that also were heavy drinkers.13Byard R.W. Harrison R. Wells R. Gilbert J.D. Glycine toxicity and unexpected intra-operative death.J Forensic Sci. 2001; 46: 1244-1246Google Scholar There is a clear relationship between higher self-reported alcohol consumption score (SRAC) and liver fibrosis in HCV-infected patients.14Pessione F. Degos F. Marcellin P. Duchatelle V. Njapoum C. Martinot-Peignoux M. Degott C. Valla D. Erlinger S. Rueff B. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C.Hepatology. 1998; 27: 1717-1722Google Scholar So, do these data suggest that the exacerbation of HCV-induced liver disease by chronic ethanol consumption is merely the combined "oxidative stress?" Otani and Weinman7Otani K.. Korenaga M.. Beard M.R.. Li K.. Qian T.. Showalter L.A.. Singh A.K.. Wang T.. Weinman S.A.. Hepatitis C virus core protein, cytochrome P4502E1 and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells.Gastroenterology. 2004; 128: 96-107Abstract Full Text Full Text PDF Scopus (122) Google Scholar would suggest so. Rigamonti et al, who reported that alcohol consumption increases oxidative stress markers 4-hydroxy-nonenal and malondialdehyde in HCV-infected patients, may also agree.15Rigamonti C. Mottaran E. Reale E. Rolla R. Cipriani V. Capelli F. Boldorini R. Vidali M. Sartori M. Albano E. Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C.Hepatology. 2003; 38: 42-49Google Scholar What then are the implications?The report by Otani et al clearly suggest that ethanol-induced oxidative stress and HCV-associated oxidative stress combine to give a deleterious punch. However, the report fails to address other potent sources of oxidants that certainly play a role in alcoholic liver disease. Thus, a weakness and limitation of the cell culture model is that other factors may play a critical role in oxidative stress. Specifically, macrophage-derived oxidants through NADPH oxidase are necessary for the development of ethanol-induced liver injury.16Kono H. Rusyn I. Yin M. Gabele E. Yamashina S. Dikalova A. Kadiiska M.B. Connor H.D. Mason R.P. Segal B.H. Bradford B.U. Holland S.M. Thurman R.G. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease.J Clin Invest. 2000; 106: 867-872Google Scholar Moreover, a recent study followed oxidative stress markers before and after the treatment of HCV-infected patients with interferon. The study demonstrated that interferon suppresses malondialdehyde and oxidized plasma thoils along with an improvement of liver function and decrease in fibrosis.17Mahmood S. Kawanaka M. Kamei A. Izumi A. Nakata K. Niiyama G. Ikeda H. Hanano S. Suehiro M. Togawa K. Yamada G. Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C.Antioxid Redox Signal. 2004; 6: 19-24Google Scholar It would be suggested by these studies that oxidants involved in the immune response are important for the progression of liver disease. On the other hand, the simplicity of the model also highlights the seemingly straightforward conclusion that oxidants, regardless of the source, are important for cytotoxicity. This suggests, however, that the most logical approach for therapy of either early alcoholic liver disease, hepatitis C infection, or both, would be antioxidants. Another difficulty with this logical conclusion is that there is little evidence that the mechanism of oxidative stress is important for the progression of severe liver disease. The report by Otani et al and other in vitro approaches focus only a narrow window, an early one at that. Another difficulty with the conclusions from this approach, specifically, the approach of using hepatoma cell lines, is the suggestion that hepatocyte cytotoxicity is a critical initiator or mediator of the fibrotic response. While it is likely that hepatocellular injury plays an important role, there is still a disconnect between hepatocellular injury and apoptosis as described in Otani et al and hepatic macrophage cell, cytokine production, T cell influx and activation, hepatic stellate cell activation, and ultimately, collagen production.The next important question is whether the "combined" oxidative stress from ethanol metabolism and HCV core protein is the key to the progression of liver fibrosis, and ultimately cirrhosis. The next reasonable step would be to determine whether transgenic mice overexpressing HCV core protein develop fibrosis when challenged with chronic ethanol. More importantly, would that injury be inhibited by antioxidants? Since these transgenic mice already exhibit hepatic steatosis and mild changes in lipid peroxidation in response to liquid ethanol diet,18Lerat H. Honda M. Beard M.R. Loesch K. Sun J. Yang Y. Okuda M. Gosert R. Xiao S.Y. Weinman S.A. Lemon S.M. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus.Gastroenterology. 2002; 122: 352-365Abstract Full Text Full Text PDF Scopus (406) Google Scholar, 19Perlemuter G. Letteron P. Carnot F. Zavala F. Pessayre D. Nalpas B. Brechot C. Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model.J Hepatol. 2003; 39: 1020-1027Google Scholar the answer to whether fibrosis ensues in these mice is presumably forthcoming. The report by Otani et al clearly suggest that ethanol-induced oxidative stress and HCV-associated oxidative stress combine to give a deleterious punch. However, the report fails to address other potent sources of oxidants that certainly play a role in alcoholic liver disease. Thus, a weakness and limitation of the cell culture model is that other factors may play a critical role in oxidative stress. Specifically, macrophage-derived oxidants through NADPH oxidase are necessary for the development of ethanol-induced liver injury.16Kono H. Rusyn I. Yin M. Gabele E. Yamashina S. Dikalova A. Kadiiska M.B. Connor H.D. Mason R.P. Segal B.H. Bradford B.U. Holland S.M. Thurman R.G. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease.J Clin Invest. 2000; 106: 867-872Google Scholar Moreover, a recent study followed oxidative stress markers before and after the treatment of HCV-infected patients with interferon. The study demonstrated that interferon suppresses malondialdehyde and oxidized plasma thoils along with an improvement of liver function and decrease in fibrosis.17Mahmood S. Kawanaka M. Kamei A. Izumi A. Nakata K. Niiyama G. Ikeda H. Hanano S. Suehiro M. Togawa K. Yamada G. Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C.Antioxid Redox Signal. 2004; 6: 19-24Google Scholar It would be suggested by these studies that oxidants involved in the immune response are important for the progression of liver disease. On the other hand, the simplicity of the model also highlights the seemingly straightforward conclusion that oxidants, regardless of the source, are important for cytotoxicity. This suggests, however, that the most logical approach for therapy of either early alcoholic liver disease, hepatitis C infection, or both, would be antioxidants. Another difficulty with this logical conclusion is that there is little evidence that the mechanism of oxidative stress is important for the progression of severe liver disease. The report by Otani et al and other in vitro approaches focus only a narrow window, an early one at that. Another difficulty with the conclusions from this approach, specifically, the approach of using hepatoma cell lines, is the suggestion that hepatocyte cytotoxicity is a critical initiator or mediator of the fibrotic response. While it is likely that hepatocellular injury plays an important role, there is still a disconnect between hepatocellular injury and apoptosis as described in Otani et al and hepatic macrophage cell, cytokine production, T cell influx and activation, hepatic stellate cell activation, and ultimately, collagen production. The next important question is whether the "combined" oxidative stress from ethanol metabolism and HCV core protein is the key to the progression of liver fibrosis, and ultimately cirrhosis. The next reasonable step would be to determine whether transgenic mice overexpressing HCV core protein develop fibrosis when challenged with chronic ethanol. More importantly, would that injury be inhibited by antioxidants? Since these transgenic mice already exhibit hepatic steatosis and mild changes in lipid peroxidation in response to liquid ethanol diet,18Lerat H. Honda M. Beard M.R. Loesch K. Sun J. Yang Y. Okuda M. Gosert R. Xiao S.Y. Weinman S.A. Lemon S.M. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus.Gastroenterology. 2002; 122: 352-365Abstract Full Text Full Text PDF Scopus (406) Google Scholar, 19Perlemuter G. Letteron P. Carnot F. Zavala F. Pessayre D. Nalpas B. Brechot C. Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model.J Hepatol. 2003; 39: 1020-1027Google Scholar the answer to whether fibrosis ensues in these mice is presumably forthcoming.
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