Oxidative Stress and Liver Injury

Part of the Molecular Pathology Library book series (MPLB, volume 5)


Oxidative stress and liver injury are strongly associated. Oxidative stress in the liver can be triggered during different conditions and by specific etiologies, including hepatotoxins (acetaminophen [1]), viruses (e.g., hepatitis C virus [2]), nonalcoholic steatohepatitis (NASH) [3], hepatocellular carcinoma [4], alcoholic liver disease (ALD) [5], ischemia-­reperfusion, and liver fibrosis [6]. Oxidative stress is a state of imbalance between the production of reactive oxygen species (ROS) and the cellular antioxidant defense neutralizing the reactive intermediates and triggering damage.


Reactive Oxygen Species Liver Injury Kupffer Cell Alcoholic Liver Disease Nonalcoholic Fatty Liver Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Kostopanagiotou GG, Grypioti AD, Matsota P, et al. Acetaminophen-induced liver injury and oxidative stress: protective effect of propofol. Eur J Anaesthesiol. 2009;26:548–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Choi J, Ou JH. Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. Am J Physiol Gastrointest Liver Physiol. 2006;290:G847–51.PubMedCrossRefGoogle Scholar
  3. 3.
    Koruk M, Taysi S, Savas MC, et al. Oxidative stress and enzymatic antioxidant status in patients with nonalcoholic steatohepatitis. Ann Clin Lab Sci. 2004;34:57–62.PubMedGoogle Scholar
  4. 4.
    Sasaki Y. Does oxidative stress participate in the development of hepatocellular carcinoma? J Gastroenterol. 2006;41:1135–48.PubMedCrossRefGoogle Scholar
  5. 5.
    Cubero FJ, Urtasun R, Nieto N. Alcohol and liver fibrosis. Semin Liver Dis. 2009;29:211–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med. 2000;21:49–98.PubMedCrossRefGoogle Scholar
  7. 7.
    Fernandez-Checa JC, Kaplowitz N. Hepatic mitochondrial glutathione: transport and role in disease and toxicity. Toxicol Appl Pharmacol. 2005;204:263–73.PubMedCrossRefGoogle Scholar
  8. 8.
    Kaplowitz N. Liver biology and pathobiology. Hepatology. 2006;43:S235–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Han D, Matsumaru K, Rettori D, Kaplowitz N. Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of mitochondrial function and oxidative stress. Biochem Pharmacol. 2004;67:439–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Kaplowitz N. Biochemical and cellular mechanisms of toxic liver injury. Semin Liver Dis. 2002;22:137–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Fernandez-Checa JC. Alcohol-induced liver disease: when fat and oxidative stress meet. Ann Hepatol. 2003;2:69–75.PubMedGoogle Scholar
  12. 12.
    Cubero FJ, Nieto N. Kupffer cells and alcoholic liver disease. Rev Esp Enferm Dig. 2006;98:460–72.PubMedCrossRefGoogle Scholar
  13. 13.
    Czaja MJ. Induction and regulation of hepatocyte apoptosis by oxidative stress. Antioxid Redox Signal. 2002;4:759–67.PubMedCrossRefGoogle Scholar
  14. 14.
    Czaja MJ. Cell signaling in oxidative stress-induced liver injury. Semin Liver Dis. 2007;27:378–89.PubMedCrossRefGoogle Scholar
  15. 15.
    Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103:239–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Czaja MJ, Liu H, Wang Y. Oxidant-induced hepatocyte injury from menadione is regulated by ERK and AP-1 signaling. Hepatology. 2003;37:1405–13.PubMedCrossRefGoogle Scholar
  17. 17.
    Rosseland CM, Wierod L, Oksvold MP, Werner H, Ostvold AC, Thoresen GH, et al. Cytoplasmic retention of peroxide-activated ERK provides survival in primary cultures of rat hepatocytes. Hepatology. 2005;42:200–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Crews CM, Alessandrini A, Erikson RL. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science. 1992;258:478–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Crews CM, Erikson RL. Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product. Proc Natl Acad Sci U S A. 1992;89:8205–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Crews CM, Erikson RL. Extracellular signals and reversible protein phosphorylation: what to Mek of it all. Cell. 1993;74:215–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Conde de la Rosa L, Schoemaker MH, Vrenken TE, Buist-Homan M, Havinga R, Jansen PL, Moshage H. Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: involvement of JNK and ERK MAP kinases. J Hepatol. 2006;44:918–29.Google Scholar
  22. 22.
    Lee JS, Kim SY, Kwon CH, Kim YK. EGFR-dependent ERK activation triggers hydrogen peroxide-induced apoptosis in OK renal epithelial cells. Arch Toxicol. 2006;80:337–46.PubMedCrossRefGoogle Scholar
  23. 23.
    Lee WC, Choi CH, Cha SH, Oh HL, Kim YK. Role of ERK in hydrogen peroxide-induced cell death of human glioma cells. Neurochem Res. 2005;30:263–70.PubMedCrossRefGoogle Scholar
  24. 24.
    Davis RJ. Signal transduction by the c-Jun N-terminal kinase. Biochem Soc Symp. 1999;64:1–12.PubMedGoogle Scholar
  25. 25.
    Gerwins P, Blank JL, Johnson GL. Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J Biol Chem. 1997;272:8288–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Gross EA, Callow MG, Waldbaum L, Thomas S, Ruggieri R. MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. J Biol Chem. 2002;277:13873–82.PubMedCrossRefGoogle Scholar
  27. 27.
    Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997;275:90–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Matsuzawa A, Nishitoh H, Tobiume K, Takeda K, Ichijo H. Physiological roles of ASK1-mediated signal transduction in oxidative stress- and endoplasmic reticulum stress-induced apoptosis: advanced findings from ASK1 knockout mice. Antioxid Redox Signal. 2002;4:415–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Karmann K, Min W, Fanslow WC, Pober JS. Activation and homologous desensitization of human endothelial cells by CD40 ligand, tumor necrosis factor, and interleukin 1. J Exp Med. 1996;184:173–82.PubMedCrossRefGoogle Scholar
  30. 30.
    Su JL, Lin MT, Hong CC, Chang CC, Shiah SG, Wu CW, et al. Resveratrol induces FasL-related apoptosis through Cdc42 activation of ASK1/JNK-dependent signaling pathway in human leukemia HL-60 cells. Carcinogenesis. 2005;26:1–10.PubMedCrossRefGoogle Scholar
  31. 31.
    Yu K, Chen YN, Ravera CP, Bayona W, Nalin CM, Mallon R. Ras-dependent apoptosis correlates with persistent activation of stress-activated protein kinases and induction of isoform(s) of Bcl-x. Cell Death Differ. 1997;4:745–55.PubMedCrossRefGoogle Scholar
  32. 32.
    Owuor ED, Kong AN. Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol. 2002;64:765–70.PubMedCrossRefGoogle Scholar
  33. 33.
    Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben-Levy R, Ashworth A, et al. Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circ Res. 1996;79:162–73.PubMedCrossRefGoogle Scholar
  34. 34.
    Birkenkamp KU, Dokter WH, Esselink MT, Jonk LJ, Kruijer W, Vellenga E. A dual function for p38 MAP kinase in hematopoietic cells: involvement in apoptosis and cell activation. Leukemia. 1999;13:1037–45.PubMedCrossRefGoogle Scholar
  35. 35.
    Cheng A, Chan SL, Milhavet O, Wang S, Mattson MP. p38 MAP kinase mediates nitric oxide-induced apoptosis of neural progenitor cells. J Biol Chem. 2001;276:43320–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Kawakami Y, Miura T, Bissonnette R, Hata D, Khan WN, Kitamura T, et al. Bruton’s tyrosine kinase regulates apoptosis and JNK/SAPK kinase activity. Proc Natl Acad Sci U S A. 1997;94:3938–42.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhuang S, Demirs JT, Kochevar IE. p38 mitogen-activated protein kinase mediates bid cleavage, mitochondrial dysfunction, and caspase-3 activation during apoptosis induced by singlet oxygen but not by hydrogen peroxide. J Biol Chem. 2000;275:25939–48.PubMedCrossRefGoogle Scholar
  38. 38.
    Guyton KZ, Liu Y, Gorospe M, Xu Q, Holbrook NJ. Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J Biol Chem. 1996;271:4138–42.PubMedCrossRefGoogle Scholar
  39. 39.
    Lander HM, Jacovina AT, Davis RJ, Tauras JM. Differential activation of mitogen-activated protein kinases by nitric oxide-related species. J Biol Chem. 1996;271:19705–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Schieke SM, Briviba K, Klotz LO, Sies H. Activation pattern of mitogen-activated protein kinases elicited by peroxynitrite: attenuation by selenite supplementation. FEBS Lett. 1999;448:301–3.PubMedCrossRefGoogle Scholar
  41. 41.
    Matsukawa J, Matsuzawa A, Takeda K, Ichijo H. The ASK1-MAP kinase cascades in mammalian stress response. J Biochem. 2004;136:261–5.PubMedCrossRefGoogle Scholar
  42. 42.
    McCubrey JA, Lahair MM, Franklin RA. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal. 2006;8:1775–89.PubMedCrossRefGoogle Scholar
  43. 43.
    Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee JD. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature. 1998;395:713–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Cavanaugh JE, Ham J, Hetman M, Poser S, Yan C, Xia Z. Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J Neurosci. 2001;21:434–43.PubMedGoogle Scholar
  45. 45.
    Kamakura S, Moriguchi T, Nishida E. Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J Biol Chem. 1999;274:26563–71.PubMedCrossRefGoogle Scholar
  46. 46.
    Storz P, Toker A. Protein kinase D mediates a stress-induced NF-kappaB activation and survival pathway. EMBO J. 2003;22:109–20.PubMedCrossRefGoogle Scholar
  47. 47.
    Waldron RT, 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;275:17114–21.PubMedCrossRefGoogle Scholar
  48. 48.
    Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene. 1999;18:6910–24.PubMedCrossRefGoogle Scholar
  49. 49.
    Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol. 2002;3:221–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Luo JL, Kamata H, Karin M. The anti-death machinery in IKK/NF-kappaB signaling. J Clin Immunol. 2005;25:541–50.PubMedCrossRefGoogle Scholar
  51. 51.
    Luedde T, Beraza N, Trautwein C. Evaluation of the role of nuclear factor-kappaB signaling in liver injury using genetic animal models. J Gastroenterol Hepatol. 2006;21 Suppl 3:S43–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science. 1999;284:316–20.PubMedCrossRefGoogle Scholar
  53. 53.
    Takeda K, Takeuchi O, Tsujimura T, Itami S, Adachi O, Kawai T, et al. Limb and skin abnormalities in mice lacking IKKalpha. Science. 1999;284:313–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Tanaka M, Fuentes ME, Yamaguchi K, Durnin MH, Dalrymple SA, Hardy KL, et al. Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice. Immunity. 1999;10:421–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Li Q, Van Antwerp D, Mercurio F, Lee KF, Verma IM. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science. 1999;284:321–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Rudolph D, Yeh WC, Wakeham A, Rudolph B, Nallainathan D, Potter J, et al. Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. Genes Dev. 2000;14:854–62.PubMedGoogle Scholar
  57. 57.
    Luedde T, Assmus U, Wustefeld T, Meyer zu Vilsendorf A, Roskams T, Schmidt-Supprian M, Rajewsky K, Brenner DA, Manns MP, Pasparakis M, Trautwein C. Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. J Clin Invest. 2005;115:849–59.Google Scholar
  58. 58.
    Funaki H, Shimizu K, Harada S, Tsuyama H, Fushida S, Tani T, et al. Essential role for nuclear factor kappaB in ischemic preconditioning for ischemia-reperfusion injury of the mouse liver. Transplantation. 2002;74:551–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Hur GM, Ryu YS, Yun HY, Jeon BH, Kim YM, Seok JH, et al. Hepatic ischemia/reperfusion in rats induces iNOS gene transcription by activation of NF-kappaB. Biochem Biophys Res Commun. 1999;261:917–22.PubMedCrossRefGoogle Scholar
  60. 60.
    Meyer M, Schreck R, Baeuerle PA. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J. 1993;12:2005–15.PubMedGoogle Scholar
  61. 61.
    Wang X, Martindale JL, Liu Y, Holbrook NJ. The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J. 1998;333 (Pt 2):291–300.PubMedGoogle Scholar
  62. 62.
    Sen CK, Packer L. Antioxidant and redox regulation of gene transcription. FASEB J. 1996;10:709–20.PubMedGoogle Scholar
  63. 63.
    Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991;10:2247–58.PubMedGoogle Scholar
  64. 64.
    Manna SK, Zhang HJ, Yan T, Oberley LW, Aggarwal BB. Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappaB and activated protein-1. J Biol Chem. 1998;273:13245–54.PubMedCrossRefGoogle Scholar
  65. 65.
    Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6:593–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Meister A. Selective modification of glutathione metabolism. Science. 1983;220:472–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Tai DI, Tsai SL, Chang YH, Huang SN, Chen TC, Chang KS, et al. Constitutive activation of nuclear factor kappaB in hepatocellular carcinoma. Cancer. 2000;89:2274–81.PubMedCrossRefGoogle Scholar
  68. 68.
    Bender K, Gottlicher M, Whiteside S, Rahmsdorf HJ, Herrlich P. Sequential DNA damage-independent and -dependent activation of NF-kappaB by UV. EMBO J. 1998;17:5170–81.PubMedCrossRefGoogle Scholar
  69. 69.
    Kretz-Remy C, Bates EE, Arrigo AP. Amino acid analogs activate NF-kappaB through redox-dependent IkappaB-alpha degradation by the proteasome without apparent IkappaB-alpha phosphorylation. Consequence on HIV-1 long terminal repeat activation. J Biol Chem. 1998;273:3180–91.PubMedCrossRefGoogle Scholar
  70. 70.
    Li N, Karin M. Is NF-kappaB the sensor of oxidative stress? FASEB J. 1999;13:1137–43.PubMedGoogle Scholar
  71. 71.
    Lee WM. Acute liver failure in the United States. Semin Liver Dis. 2003;23:217–26.PubMedCrossRefGoogle Scholar
  72. 72.
    Bessems JG, Vermeulen NP. Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol. 2001;31:55–138.PubMedCrossRefGoogle Scholar
  73. 73.
    James LP, Mayeux PR, Hinson JA. Acetaminophen-induced hepatotoxicity. Drug Metab Dispos. 2003;31:1499–506.PubMedCrossRefGoogle Scholar
  74. 74.
    Lee SS, Buters JT, Pineau T, Fernandez-Salguero P, Gonzalez FJ. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem. 1996;271:12063–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Cohen SD, Pumford NR, Khairallah EA, Boekelheide K, Pohl LR, Amouzadeh HR, et al. Selective protein covalent binding and target organ toxicity. Toxicol Appl Pharmacol. 1997;143:1–12.PubMedCrossRefGoogle Scholar
  76. 76.
    Reid AB, Kurten RC, McCullough SS, Brock RW, Hinson JA. Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. J Pharmacol Exp Ther. 2005;312:509–16.PubMedCrossRefGoogle Scholar
  77. 77.
    Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D, Kaplowitz N. Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem. 2008;283:13565–77.PubMedCrossRefGoogle Scholar
  78. 78.
    Latchoumycandane C, Goh CW, Ong MM, Boelsterli UA. Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury. Hepatology. 2007;45:412–21.PubMedCrossRefGoogle Scholar
  79. 79.
    Henderson NC, Pollock KJ, Frew J, Mackinnon AC, Flavell RA, Davis RJ, et al. Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure. Gut. 2007;56:982–90.PubMedCrossRefGoogle Scholar
  80. 80.
    Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov. 2005;4:489–99.PubMedCrossRefGoogle Scholar
  81. 81.
    Wang Y, Singh R, Lefkowitch JH, Rigoli RM, Czaja MJ. Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. J Biol Chem. 2006;281:15258–67.PubMedCrossRefGoogle Scholar
  82. 82.
    Qureshi K, Abrams GA. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2007;13:3540–53.PubMedGoogle Scholar
  83. 83.
    Angulo P. NAFLD, obesity, and bariatric surgery. Gastroenterology. 2006;130:1848–52.PubMedCrossRefGoogle Scholar
  84. 84.
    Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440:944–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Araya J, Rodrigo R, Videla LA, Thielemann L, Orellana M, Pettinelli P, et al. Increase in long-chain polyunsaturated fatty acid n–6/n–3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond). 2004;106:635–43.CrossRefGoogle Scholar
  86. 86.
    Videla LA, Rodrigo R, Araya J, Poniachik J. Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trends Mol Med. 2006;12:555–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Dela Pena A, Leclercq I, Field J, George J, Jones B, Farrell G. NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis. Gastroenterology. 2005;129:1663–74.CrossRefGoogle Scholar
  88. 88.
    Yu J, Ip E, Dela Pena A, Hou JY, Sesha J, Pera N, et al. COX-2 induction in mice with experimental nutritional steatohepatitis: role as pro-inflammatory mediator. Hepatology. 2006;43:826–36.PubMedCrossRefGoogle Scholar
  89. 89.
    McCullough AJ. Update on nonalcoholic fatty liver disease. J Clin Gastroenterol. 2002;34:255–62.PubMedCrossRefGoogle Scholar
  90. 90.
    Combettes-Souverain M, Issad T. Molecular basis of insulin action. Diabetes Metab. 1998;24:477–89.PubMedGoogle Scholar
  91. 91.
    Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology. 2006;43:163–72.PubMedCrossRefGoogle Scholar
  92. 92.
    Hines IN, Wheeler MD. Recent advances in alcoholic liver disease III. Role of the innate immune response in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol. 2004;287:G310–4.PubMedCrossRefGoogle Scholar
  93. 93.
    Wheeler MD, Kono H, Yin M, Nakagami M, Uesugi T, Arteel GE, et al. The role of Kupffer cell oxidant production in early ethanol-induced liver disease. Free Radic Biol Med. 2001;31:1544–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43:S54–62.PubMedCrossRefGoogle Scholar
  95. 95.
    Siegmund SV, Brenner DA. Molecular pathogenesis of alcohol-induced hepatic fibrosis. Alcohol Clin Exp Res. 2005;29:102S–9S.PubMedCrossRefGoogle Scholar
  96. 96.
    Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG. Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology. 1994;20:453–60.PubMedCrossRefGoogle Scholar
  97. 97.
    Thurman RG, Bradford BU, Iimuro Y, Knecht KT, Connor HD, Adachi Y, et al. Role of Kupffer cells, endotoxin and free radicals in hepatotoxicity due to prolonged alcohol consumption: studies in female and male rats. J Nutr. 1997;127:903S–6S.PubMedGoogle Scholar
  98. 98.
    Arendt E, Ueberham U, Bittner R, Gebhardt R, Ueberham E. Enhanced matrix degradation after withdrawal of TGF-beta1 triggers hepatocytes from apoptosis to proliferation and regeneration. Cell Prolif. 2005;38:287–99.PubMedCrossRefGoogle Scholar
  99. 99.
    DeLeve LD, Wang X, Kanel GC, Atkinson RD, McCuskey RS. Prevention of hepatic fibrosis in a murine model of metabolic syndrome with nonalcoholic steatohepatitis. Am J Pathol. 2008;173:993–1001.PubMedCrossRefGoogle Scholar
  100. 100.
    Cubero FJ, Nieto N. Ethanol and arachidonic acid synergize to activate Kupffer cells and modulate the fibrogenic response via tumor necrosis factor alpha, reduced glutathione, and transforming growth factor beta-dependent mechanisms. Hepatology. 2008;48:2027–39.PubMedCrossRefGoogle Scholar
  101. 101.
    Thurman RG. II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol. 1998;275:G605–11.PubMedGoogle Scholar
  102. 102.
    Osna NA, White RL, Todero S, et al. Ethanol-induced oxidative stress suppresses generation of peptides for antigen presentation by hepatoma cells. Hepatology. 2007;45:53–61.PubMedCrossRefGoogle Scholar
  103. 103.
    Nieto N. Oxidative-stress and IL-6 mediate the fibrogenic effects of [corrected] Kupffer cells on stellate cells. Hepatology. 2006;44:1487–501.PubMedCrossRefGoogle Scholar
  104. 104.
    Kohno M, Pouyssegur J. Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. Prog Cell Cycle Res. 2003;5:219–24.PubMedGoogle Scholar
  105. 105.
    Ohori M, Takeuchi M, Maruki R, Nakajima H, Miyake H. FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice. Naunyn Schmiedebergs Arch Pharmacol. 2007;374:311–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Resnick L, Fennell M. Targeting JNK3 for the treatment of neurodegenerative disorders. Drug Discov Today. 2004;9:932–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Kunkel EJ, Plavec I, Nguyen D, Melrose J, Rosler ES, Kao LT, et al. Rapid structure-activity and selectivity analysis of kinase inhibitors by BioMAP analysis in complex human primary cell-based models. Assay Drug Dev Technol. 2004;2:431–41.PubMedCrossRefGoogle Scholar
  108. 108.
    Dombroski MA, Letavic MA, McClure KF, et al. Benzimidazolone p38 inhibitors. Bioorg Med Chem Lett. 2004;14:919–23.PubMedCrossRefGoogle Scholar
  109. 109.
    Yun TH, Cott JE, Tapping RI, et al. Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins. Blood. 2009;113:1139–48.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Internal Medicine IIIUniversity Hospital Aachen (RTWH)AachenGermany

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