Cell Signaling in Oxidative Stress-Induced Liver Injury

 

 Buy Article Permissions and Reprints

ABSTRACT

Oxidative stress is a common mechanism of liver injury. Recent investigations have demonstrated that oxidant-induced liver injury is mediated by the direct effects of reactive oxygen species on signal transduction pathways. Although the function of cell signaling in this form of injury is complex and likely variable depending on the type and duration of oxidative stress, common regulatory pathways of hepatocyte oxidant injury have been identified that include the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 (ERK1/2) c-Jun N-terminal kinase (JNK), and the nuclear factor κB (NF-κB) pathway. Studies in cultured hepatocyte and rodent models of oxidative stress have demonstrated that ERK1/2 typically induces resistance to oxidant stress, whereas JNK promotes cell death. The effects of NF-κB activation are more complex and cell-type specific. A further understanding of the signaling pathways that regulate oxidant-induced liver injury may suggest new therapies for hepatic diseases resulting from oxidative stress.

REFERENCES

• 1 Albano E, Clot P, Morimoto M et al.. Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol.  Hepatology. 1996;  23 155-163
  PubMedGoogle Scholar
• 2 Ferret P J, Hammoud R, Tulliez M et al.. Detoxification of reactive oxygen species by a nonpeptidyl mimic of superoxide dismutase cures acetaminophen-induced acute liver failure in the mouse.  Hepatology. 2001;  33 1173-1180
  CrossrefPubMedGoogle Scholar
• 3 Osawa Y, Nagaki M, Banno Y et al.. Possible involvement of reactive oxygen species in D-galactosamine-induced sensitization against tumor necrosis factor-α-induced hepatocyte apoptosis.  J Cell Physiol. 2001;  187 374-385
  CrossrefPubMedGoogle Scholar
• 4 Lesage G, Glaser S, Ueno Y et al.. Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis.  Am J Physiol Gastrointest Liver Physiol. 2001;  281 G182-G190
  PubMedGoogle Scholar
• 5 Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver.  Am J Physiol. 1991;  260 G355-G362
  PubMedGoogle Scholar
• 6 Zhou W, Zhang Y, Hosch M S et al.. Subcellular site of superoxide dismutase expression differentially controls AP-1 activity and injury in mouse liver following ischemia/reperfusion.  Hepatology. 2001;  33 902-914
  CrossrefPubMedGoogle Scholar
• 7 Xu Y, Jones B E, Neufeld D S, Czaja M J. Glutathione modulates rat and mouse hepatocyte sensitivity to tumor necrosis factor toxicity.  Gastroenterology. 1998;  115 1229-1237
  PubMedGoogle Scholar
• 8 Mitchell J R, Jollow D J, Potter W Z, Gillette J R, Brodie B B. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione.  J Pharmacol Exp Ther. 1973;  187 211-217
  PubMedGoogle Scholar
• 9 Czaja M J. Induction and regulation of hepatocyte apoptosis by oxidative stress.  Antioxid Redox Signal. 2002;  4 759-767
  CrossrefPubMedGoogle Scholar
• 10 Han D, Hanawa N, Saberi B, Kaplowitz N. Mechanisms of liver injury. III. Role of glutathione redox status in liver injury.  Am J Physiol Gastrointest Liver Physiol. 2006;  291 G1-G7
  CrossrefPubMedGoogle Scholar
• 11 Chang L, Karin M. Mammalian MAP kinase signalling cascades.  Nature. 2001;  410 37-40
  CrossrefPubMedGoogle Scholar
• 12 Davis R J. Signal transduction by the JNK group of MAP kinases.  Cell. 2000;  103 239-252
  CrossrefPubMedGoogle Scholar
• 13 Conze D, Krahl T, Kennedy N et al.. c-Jun NH₂-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8 ⁺ T cell activation.  J Exp Med. 2002;  195 811-823
  CrossrefPubMedGoogle Scholar
• 14 Qiao L, Han S I, Fang Y et al.. Bile acid regulation of C/EBPβ, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH₂-terminal kinase pathways, modulates the apoptotic response of hepatocytes.  Mol Cell Biol. 2003;  23 3052-3066
  CrossrefPubMedGoogle Scholar
• 15 Sabapathy K, Hochedlinger K, Nam S Y et al.. Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation.  Mol Cell. 2004;  15 713-725
  CrossrefPubMedGoogle Scholar
• 16 Schattenberg J M, Singh R, Wang Y et al.. JNK1 but not JNK2 promotes the development of steatohepatitis in mice.  Hepatology. 2006;  43 163-172
  CrossrefPubMedGoogle Scholar
• 17 Wang Y, Singh R, Lefkowitch J H, Rigoli R M, Czaja M J. Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway.  J Biol Chem. 2006;  281 15258-15267
  CrossrefPubMedGoogle Scholar
• 18 Czaja M J, Liu H, Wang Y. Oxidant-induced hepatocyte injury from menadione is regulated by ERK and AP-1 signaling.  Hepatology. 2003;  37 1405-1413
  CrossrefPubMedGoogle Scholar
• 19 Rosseland C M, Wierod L, Oksvold M P et al.. Cytoplasmic retention of peroxide-activated ERK provides survival in primary cultures of rat hepatocytes.  Hepatology. 2005;  42 200-207
  CrossrefPubMedGoogle Scholar
• 20 Czaja M J. The future of GI and liver research: editorial perspectives. III. JNK/AP-1 regulation of hepatocyte death.  Am J Physiol Gastrointest Liver Physiol. 2003;  284 G875-G879
  PubMedGoogle Scholar
• 21 Higuchi H, Grambihler A, Canbay A, Bronk S F, Gores G J. Bile acids up-regulate death receptor 5/TRAIL-receptor 2 expression via a c-Jun N-terminal kinase-dependent pathway involving Sp1.  J Biol Chem. 2004;  279 51-60
  CrossrefPubMedGoogle Scholar
• 22 Whitfield J, Neame S J, Paquet L, Bernard O, Ham J. Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release.  Neuron. 2001;  29 629-643
  CrossrefPubMedGoogle Scholar
• 23 Lei K, Davis R J. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis.  Proc Natl Acad Sci U S A. 2003;  100 2432-2437
  CrossrefPubMedGoogle Scholar
• 24 Putcha G V, Le S, Frank S et al.. JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis.  Neuron. 2003;  38 899-914
  CrossrefPubMedGoogle Scholar
• 25 Chang L, Kamata H, Solinas G et al.. The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIP_L turnover.  Cell. 2006;  124 601-613
  CrossrefPubMedGoogle Scholar
• 26 Karin M, Lin A. NF-κB at the crossroads of life and death.  Nat Immunol. 2002;  3 221-227
  CrossrefPubMedGoogle Scholar
• 27 Fan C, Li Q, Zhang Y et al.. IκBα and IκBβ possess injury context-specific functions that uniquely influence hepatic NF-κB induction and inflammation.  J Clin Invest. 2004;  113 746-755
  CrossrefPubMedGoogle Scholar
• 28 Hatano E, Bennett B L, Manning A M et al.. NF-κB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF-α- and Fas-mediated apoptosis.  Gastroenterology. 2001;  120 1251-1262
  CrossrefPubMedGoogle Scholar
• 29 Kreuz S, Siegmund D, Scheurich P, Wajant H. NF-κB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling.  Mol Cell Biol. 2001;  21 3964-3973
  CrossrefPubMedGoogle Scholar
• 30 Zender L, Hutker S, Mundt B et al.. NFκB-mediated upregulation of bcl-xl restrains TRAIL-mediated apoptosis in murine viral hepatitis.  Hepatology. 2005;  41 280-288
  CrossrefPubMedGoogle Scholar
• 31 Liu H, Lo C R, Czaja M J. NF-κB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun.  Hepatology. 2002;  35 772-778
  CrossrefPubMedGoogle Scholar
• 32 Schwabe R F, Uchinami H, Qian T et al.. Differential requirement for c-Jun NH₂-terminal kinase in TNFα- and Fas-mediated apoptosis in hepatocytes.  FASEB J. 2004;  18 720-722
  PubMedGoogle Scholar
• 33 Tonks N K. Redox redux: revisiting PTPs and the control of cell signaling.  Cell. 2005;  121 667-670
  CrossrefPubMedGoogle Scholar
• 34 Storz P, Toker A. Protein kinase D mediates a stress-induced NF-κB activation and survival pathway.  EMBO J. 2003;  22 109-120
  CrossrefPubMedGoogle Scholar
• 35 Waldron R T, Rozengurt E. Oxidative stress induces protein kinase D activation in intact cells. Involvement of Src and dependence on protein kinase C.  J Biol Chem. 2000;  275 17114-17121
  CrossrefPubMedGoogle Scholar
• 36 Wang Y, Schattenberg J M, Rigoli R M, Storz P, Czaja M J. Hepatocyte resistance to oxidative stress is dependent on protein kinase C-mediated down-regulation of c-Jun/AP-1.  J Biol Chem. 2004;  279 31089-31097
  CrossrefPubMedGoogle Scholar
• 37 Lee W M. Acute liver failure in the United States.  Semin Liver Dis. 2003;  23 217-226
  Article in Thieme ConnectPubMedGoogle Scholar
• 38 David Josephy P. The molecular toxicology of acetaminophen.  Drug Metab Rev. 2005;  37 581-594
  CrossrefPubMedGoogle Scholar
• 39 Gunawan B K, Liu Z X, Han D et al.. c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity.  Gastroenterology. 2006;  131 165-178
  CrossrefPubMedGoogle Scholar
• 40 Higuchi H, Gores G J. Bile acid regulation of hepatic physiology: IV. Bile acids and death receptors.  Am J Physiol Gastrointest Liver Physiol. 2003;  284 G734-G738
  PubMedGoogle Scholar
• 41 Faubion W A, Guicciardi M E, Miyoshi H et al.. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas.  J Clin Invest. 1999;  103 137-145
  CrossrefPubMedGoogle Scholar
• 42 Sodeman T, Bronk S F, Roberts P J, Miyoshi H, Gores G J. Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas.  Am J Physiol Gastrointest Liver Physiol. 2000;  278 G992-G999
  PubMedGoogle Scholar
• 43 Reinehr R, Becker S, Eberle A, Grether-Beck S, Haussinger D. Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis.  J Biol Chem. 2005;  280 27179-27194
  CrossrefPubMedGoogle Scholar
• 44 Lambeth J D. NOX enzymes and the biology of reactive oxygen.  Nat Rev Immunol. 2004;  4 181-189
  CrossrefPubMedGoogle Scholar
• 45 Reinehr R, Becker S, Wettstein M, Haussinger D. Involvement of the Src family kinase yes in bile salt-induced apoptosis.  Gastroenterology. 2004;  127 1540-1557
  CrossrefPubMedGoogle Scholar
• 46 Reinehr R, Becker S, Keitel V et al.. Bile salt-induced apoptosis involves NADPH oxidase isoform activation.  Gastroenterology. 2005;  129 2009-2031
  CrossrefPubMedGoogle Scholar
• 47 Sokol R J, McKim Jr J M, Goff M C et al.. Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat.  Gastroenterology. 1998;  114 164-174
  CrossrefPubMedGoogle Scholar
• 48 Gupta S, Natarajan R, Payne S G et al.. Deoxycholic acid activates the c-Jun N-terminal kinase pathway via FAS receptor activation in primary hepatocytes. Role of acidic sphingomyelinase-mediated ceramide generation in FAS receptor activation.  J Biol Chem. 2004;  279 5821-5828
  PubMedGoogle Scholar
• 49 Frey R S, Rahman A, Kefer J C, Minshall R D, Malik A B. PKCζ regulates TNF-α-induced activation of NADPH oxidase in endothelial cells.  Circ Res. 2002;  90 1012-1019
  CrossrefPubMedGoogle Scholar
• 50 Frey R S, Gao X, Javaid K et al.. Phosphatidylinositol 3-kinase gamma signaling through protein kinase Cζ induces NADPH oxidase-mediated oxidant generation and NF-κB activation in endothelial cells.  J Biol Chem. 2006;  281 16128-16138
  CrossrefPubMedGoogle Scholar
• 51 Higuchi H, Bronk S F, Takikawa Y et al.. The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis.  J Biol Chem. 2001;  276 38610-38618
  CrossrefPubMedGoogle Scholar
• 52 Grattagliano I, Vendemiale G, Lauterburg B H. Reperfusion injury of the liver: role of mitochondria and protection by glutathione ester.  J Surg Res. 1999;  86 2-8
  CrossrefPubMedGoogle Scholar
• 53 Liu P, Fisher M A, Farhood A, Smith C W, Jaeschke H. Beneficial effects of extracellular glutathione against endotoxin-induced liver injury during ischemia and reperfusion.  Circ Shock. 1994;  43 64-70
  PubMedGoogle Scholar
• 54 Zwacka R M, Zhou W, Zhang Y et al.. Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-κB activation.  Nat Med. 1998;  4 698-704
  PubMedGoogle Scholar
• 55 Rymsa B, Wang J F, de Groot H. O₂ ^-. release by activated Kupffer cells upon hypoxia-reoxygenation.  Am J Physiol. 1991;  261 G602-G607
  PubMedGoogle Scholar
• 56 Jaeschke H, Bautista A P, Spolarics Z, Spitzer J J. Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats.  J Leukoc Biol. 1992;  52 377-382
  PubMedGoogle Scholar
• 57 Gonzalez-Flecha B, Cutrin J C, Boveris A. Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion.  J Clin Invest. 1993;  91 456-464
  PubMedGoogle Scholar
• 58 Ozaki M, Deshpande S S, Angkeow P et al.. Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo.  FASEB J. 2000;  14 418-429
  PubMedGoogle Scholar
• 59 Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning.  Am J Physiol Gastrointest Liver Physiol. 2003;  284 G15-G26
  PubMedGoogle Scholar
• 60 Kobayashi M, Takeyoshi I, Yoshinari D, Matsumoto K, Morishita Y. P38 mitogen-activated protein kinase inhibition attenuates ischemia-reperfusion injury of the rat liver.  Surgery. 2002;  131 344-349
  CrossrefPubMedGoogle Scholar
• 61 Onishi I, Tani T, Hashimoto T et al.. Activation of c-Jun N-terminal kinase during ischemia and reperfusion in mouse liver.  FEBS Lett. 1997;  420 201-204
  CrossrefPubMedGoogle Scholar
• 62 Uehara T, Bennett B, Sakata S T et al.. JNK mediates hepatic ischemia reperfusion injury.  J Hepatol. 2005;  42 850-859
  CrossrefPubMedGoogle Scholar
• 63 Lee K H, Kim S E, Lee Y S. SP600125, a selective JNK inhibitor, aggravates hepatic ischemia-reperfusion injury.  Exp Mol Med. 2006;  38 408-416
  PubMedGoogle Scholar
• 64 Luedde T, Assmus U, Wustefeld T et al.. Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury.  J Clin Invest. 2005;  115 849-859
  CrossrefPubMedGoogle Scholar
• 65 Ryo A, Suizu F, Yoshida Y et al.. Regulation of NF-κB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA.  Mol Cell. 2003;  12 1413-1426
  CrossrefPubMedGoogle Scholar
• 66 Kuboki S, Okaya T, Schuster R et al.. Hepatocyte NF-κB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia.  Am J Physiol Gastrointest Liver Physiol. 2007;  292 G201-G207
  PubMedGoogle Scholar
• 67 Bradham C A, Qian T, Streetz K et al.. The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release.  Mol Cell Biol. 1998;  18 6353-6364
  PubMedGoogle Scholar
• 68 Xu Y, Bialik S, Jones B E et al.. NF-κB inactivation converts a hepatocyte cell line TNF-α response from proliferation to apoptosis.  Am J Physiol. 1998;  275 C1058-C1066
  PubMedGoogle Scholar
• 69 Jones B E, Lo C R, Liu H et al.. Role of caspases and NF-κB signaling in hydrogen peroxide- and superoxide-induced hepatocyte apoptosis.  Am J Physiol Gastrointest Liver Physiol. 2000;  278 G693-G699
  PubMedGoogle Scholar
• 70 Tsung A, Hoffman R A, Izuishi K et al.. Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells.  J Immunol. 2005;  175 7661-7668
  PubMedGoogle Scholar
• 71 Lieber C S. CYP2E1: from ASH to NASH.  Hepatol Res. 2004;  28 1-11
  PubMedGoogle Scholar
• 72 Ingelman-Sundberg M, Johansson I. Mechanisms of hydroxyl radical formation and ethanol oxidation by ethanol-inducible and other forms of rabbit liver microsomal cytochromes P-450.  J Biol Chem. 1984;  259 6447-6458
  PubMedGoogle Scholar
• 73 Dai Y, Rashba-Step J, Cederbaum A I. Stable expression of human cytochrome P4502E1 in HepG2 cells: characterization of catalytic activities and production of reactive oxygen intermediates.  Biochemistry. 1993;  32 6928-6937
  CrossrefPubMedGoogle Scholar
• 74 Jones B E, Liu H, Lo C R, Koop D R, Czaja M J. Cytochrome P450 2E1 expression induces hepatocyte resistance to cell death from oxidative stress.  Antioxid Redox Signal. 2002;  4 701-709
  CrossrefPubMedGoogle Scholar
• 75 Mari M, Cederbaum A I. Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress.  Hepatology. 2001;  33 652-661
  CrossrefPubMedGoogle Scholar
• 76 Schattenberg J M, Wang Y, Rigoli R M, Koop D R, Czaja M J. CYP2E1 overexpression alters hepatocyte death from menadione and fatty acids by activation of ERK1/2 signaling.  Hepatology. 2004;  39 444-455
  CrossrefPubMedGoogle Scholar
• 77 Chen Q, Galleano M, Cederbaum A I. Cytotoxicity and apoptosis produced by arachidonic acid in Hep G2 cells overexpressing human cytochrome P4502E1.  J Biol Chem. 1997;  272 14532-14541
  CrossrefPubMedGoogle Scholar
• 78 Wu D, Cederbaum A I. Ethanol and arachidonic acid produce toxicity in hepatocytes from pyrazole-treated rats with high levels of CYP2E1.  Mol Cell Biochem. 2000;  204 157-167
  CrossrefPubMedGoogle Scholar
• 79 Gong P, Cederbaum A I, Nieto N. Increased expression of cytochrome P450 2E1 induces heme oxygenase-1 through ERK MAPK pathway.  J Biol Chem. 2003;  278 29693-29700
  CrossrefPubMedGoogle Scholar
• 80 Wu D, Cederbaum A I. Role of p38 MAPK in CYP2E1-dependent arachidonic acid toxicity.  J Biol Chem. 2003;  278 1115-1124
  CrossrefPubMedGoogle Scholar
• 81 Chen Q, Cederbaum A I. Cytotoxicity and apoptosis produced by cytochrome P450 2E1 in Hep G2 cells.  Mol Pharmacol. 1998;  53 638-648
  PubMedGoogle Scholar
• 82 Gong P, Cederbaum A I. Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1.  Hepatology. 2006;  43 144-153
  CrossrefPubMedGoogle Scholar
• 83 Liu H, Jones B E, Bradham C, Czaja M J. Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α.  Am J Physiol Gastrointest Liver Physiol. 2002;  282 G257-G266
  PubMedGoogle Scholar
• 84 Lu Y, Wang X, Cederbaum A I. Lipopolysaccharide-induced liver injury in rats treated with the CYP2E1 inducer pyrazole.  Am J Physiol Gastrointest Liver Physiol. 2005;  289 G308-G319
  CrossrefPubMedGoogle Scholar
• 85 Wang X, Lu Y, Cederbaum A I. Induction of cytochrome P450 2E1 increases hepatotoxicity caused by Fas agonistic Jo2 antibody in mice.  Hepatology. 2005;  42 400-410
  CrossrefPubMedGoogle Scholar
• 86 Kono H, Bradford B U, Yin M et al.. CYP2E1 is not involved in early alcohol-induced liver injury.  Am J Physiol. 1999;  277 G1259-G1267
  PubMedGoogle Scholar
• 87 Leclercq I A, Farrell G C, Field J et al.. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis.  J Clin Invest. 2000;  105 1067-1075
  PubMedGoogle Scholar
• 88 Jokelainen K, Reinke L A, Nanji A A. NF-κB activation is associated with free radical generation and endotoxemia and precedes pathological liver injury in experimental alcoholic liver disease.  Cytokine. 2001;  16 36-39
  CrossrefPubMedGoogle Scholar
• 89 Nanji A A, Jokelainen K, Rahemtulla A et al.. Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat.  Hepatology. 1999;  30 934-943
  CrossrefPubMedGoogle Scholar
• 90 Kono H, Rusyn I, Yin M et al.. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease.  J Clin Invest. 2000;  106 867-872
  CrossrefPubMedGoogle Scholar
• 91 Kishore R, Hill J R, McMullen M R, Frenkel J, Nagy L E. ERK1/2 and Egr-1 contribute to increased TNF-α production in rat Kupffer cells after chronic ethanol feeding.  Am J Physiol Gastrointest Liver Physiol. 2002;  282 G6-G15
  PubMedGoogle Scholar
• 92 Yin M, Wheeler M D, Kono H et al.. Essential role of tumor necrosis factor α in alcohol-induced liver injury in mice.  Gastroenterology. 1999;  117 942-952
  PubMedGoogle Scholar
• 93 Colell A, Garcia-Ruiz C, Miranda M et al.. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor.  Gastroenterology. 1998;  115 1541-1551
  PubMedGoogle Scholar
• 94 Wang X D, Liu C, Chung J et al.. Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver.  Hepatology. 1998;  28 744-750
  CrossrefPubMedGoogle Scholar
• 95 Koteish A, Yang S, Lin H, Huang X, Diehl A M. Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation.  J Biol Chem. 2002;  277 13037-13044
  CrossrefPubMedGoogle Scholar
• 96 Sampey B P, Stewart B J, Petersen D R. Ethanol-induced modulation of hepatocellular extracellular signal-regulated kinase-1/2 activity via 4-hydroxynonenal.  J Biol Chem. 2007;  282 1925-1937
  PubMedGoogle Scholar
• 97 Dela Pena A, Leclercq I, Field J et al.. NF-κB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis.  Gastroenterology. 2005;  129 1663-1674
  CrossrefPubMedGoogle Scholar
• 98 Yu J, Ip E, Dela Pena A et al.. COX-2 induction in mice with experimental nutritional steatohepatitis: role as pro-inflammatory mediator.  Hepatology. 2006;  43 826-836
  CrossrefPubMedGoogle Scholar
• 99 Demetri G D, von Mehren M, Blanke C D et al.. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.  N Engl J Med. 2002;  347 472-480
  CrossrefPubMedGoogle Scholar
• 100 Ranson M, Mansoor W, Jayson G ZD. 1839 (IRESSA): a selective EGFR-TK inhibitor.  Expert Rev Anticancer Ther. 2002;  2 161-168
  CrossrefPubMedGoogle Scholar

Mark J CzajaM.D. 

Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine

1300 Morris Park Avenue, Bronx, NY 10461

Email: czaja@aecom.yu.edu