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Oxidative Stress and Liver Inflammation

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Studies on Hepatic Disorders

Abstract

The inflammatory response is of prime importance in liver disease, irrespective of inciting cause, and is inextricably linked to oxidative stress and the generation of reactive oxygen species (ROS). During the inflammatory response, ROS in Kupffer cells, neutrophils, and monocytes is predominantly produced by nicotinamide adenine dinucleotide phosphate oxidase (Nox) 2 and myeloperoxidase (MPO). Inflammatory cell-derived oxidative stress can result in activation of nuclear factor (NF)-κB and activator protein (AP)-1, pro-inflammatory cytokine up-regulation, and local effects on neighboring parenchymal cells. Oxidative stress as part of the inflammatory response to liver disease has been demonstrated in a variety of human conditions and experimental animal models, including ischemia-reperfusion injury (IRI), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, endotoxin-induced liver disease, viral hepatitis, fibrosis, hepatocellular carcinoma (HCC), toxin-mediated liver injury, and cholestatic disease. Evidence for the role of inflammation and oxidative stress in these conditions and models is presented and discussed, as is the potential for low levels of oxidative stress to promote a protective inflammatory response and attenuate further injury.

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References

  1. Rosen GM, Pou S, Ramos CL, Cohen MS, Britigan BE (1995) Free radicals and phagocytic cells. FASEB J 9(2):200–209

    CAS  PubMed  Google Scholar 

  2. Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11(11):723–737. doi:10.1038/nri3073

    PubMed Central  CAS  PubMed  Google Scholar 

  3. Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82(1):47–95

    PubMed  Google Scholar 

  4. Jaeschke H (2011) Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol 26(Suppl 1):173–179. doi:10.1111/j.1440-1746.2010.06592.x

    CAS  PubMed  Google Scholar 

  5. D’Autréaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8(10):813–824

    PubMed  Google Scholar 

  6. Novo E, Parola M (2008) Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 1(1):5. doi:10.1186/1755-1536-1-5

    PubMed Central  PubMed  Google Scholar 

  7. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418(6894):191–195

    CAS  PubMed  Google Scholar 

  8. Rock KL, Latz E, Ontiveros F, Kono H (2010) The sterile inflammatory response. Annu Rev Immunol 28:321–342. doi:10.1146/annurev-immunol-030409-101311

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Bianchi ME (2009) HMGB1 loves company. J Leukoc Biol 86(3):573–576. doi:10.1189/jlb.1008585

    CAS  PubMed  Google Scholar 

  10. Schwabe RF, Seki E, Brenner DA (2006) Toll-like receptor signaling in the liver. Gastroenterology 130(6):1886–1900

    CAS  PubMed  Google Scholar 

  11. Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, Li J, Tracey KJ, Geller DA, Billiar TR (2005) The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med 201(7):1135–1143

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Fan J, Li Y, Levy RM, Fan JJ, Hackam DJ, Vodovotz Y, Yang H, Tracey KJ, Billiar TR, Wilson MA (2007) Hemorrhagic shock induces NAD(P)H oxidase activation in neutrophils: role of HMGB1-TLR4 signaling. J Immunol 178(10):6573–6580

    CAS  PubMed  Google Scholar 

  13. Bae YS, Lee JH, Choi SH, Kim S, Almazan F, Witztum JL, Miller YI (2009) Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circ Res 104(2):210–8. doi:10.1161/CIRCRESAHA.108.181040

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Bamboat ZM, Balachandran VP, Ocuin LM, Obaid H, Plitas G, DeMatteo RP (2010) Toll-like receptor 9 inhibition confers protection from liver ischemia-reperfusion injury. Hepatology 51(2):621–632. doi:10.1002/hep.23365

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Klebanoff SJ (2005) Myeloperoxidase: friend and foe. J Leukoc Biol 77(5):598–625

    CAS  PubMed  Google Scholar 

  16. Gujral JS, Farhood A, Bajt ML, Jaeschke H (2003) Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice. Hepatology 38(2):355–363

    PubMed  Google Scholar 

  17. Brown KE, Brunt EM, Heinecke JW (2001) Immunohistochemical detection of myeloperoxidase and its oxidation products in Kupffer cells of human liver. Am J Pathol 159(6):2081–2088

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, Libby P (2001) Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol 158(3):879–891

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Jaeschke H, Farhood A, Bautista AP, Spolarics Z, Spitzer JJ (1993) Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am J Physiol 264(4 Pt 1):G801–G809

    CAS  PubMed  Google Scholar 

  20. Bajt ML, Farhood A, Jaeschke H (2001) Effects of CXC chemokines on neutrophil activation and sequestration in hepatic vasculature. Am J Physiol Gastrointest Liver Physiol 281(5):G1188–G1195

    CAS  PubMed  Google Scholar 

  21. Kubes P, Mehal WZ (2012) Sterile inflammation in the liver. Gastroenterology 143(5):1158–1172. doi:10.1053/j.gastro.2012.09.008

    CAS  PubMed  Google Scholar 

  22. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396):2085–2088

    CAS  PubMed  Google Scholar 

  23. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408(6813):740–745

    CAS  PubMed  Google Scholar 

  24. Bilzer M, Jaeschke H, Vollmar AM, Paumgartner G, Gerbes AL (1999) Prevention of Kupffer cell-induced oxidant injury in rat liver by atrial natriuretic peptide. Am J Physiol 276(5 Pt 1):G1137–G1144

    CAS  PubMed  Google Scholar 

  25. Bilzer M, Baron A, Schauer R, Steib C, Ebensberger S, Gerbes AL (2002) Glutathione treatment protects the rat liver against injury after warm ischemia and Kupffer cell activation. Digestion 66(1):49–57

    CAS  PubMed  Google Scholar 

  26. Jaeschke H, Bautista AP, Spolarics Z, Spitzer JJ (1992) Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats. J Leukoc Biol 52(4):377–382

    CAS  PubMed  Google Scholar 

  27. Liu P, McGuire GM, Fisher MA, Farhood A, Smith CW, Jaeschke H (1995) Activation of Kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin-enhanced liver injury after hepatic ischemia. Shock 3(1):56–62

    CAS  PubMed  Google Scholar 

  28. Jaeschke H, Farhood A (1991) Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am J Physiol 260(3 Pt 1):G355–G362

    CAS  PubMed  Google Scholar 

  29. Hirsch J, Hansen KC, Choi S, Noh J, Hirose R, Roberts JP, Matthay MA, Burlingame AL, Maher JJ, Niemann CU (2006) Warm ischemia-induced alterations in oxidative and inflammatory proteins in hepatic Kupffer cells in rats. Mol Cell Proteomics 5(6):979–986

    CAS  PubMed  Google Scholar 

  30. Jaeschke H, Smith CW (1997) Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol 61(6):647–653

    CAS  PubMed  Google Scholar 

  31. Hasegawa T, Malle E, Farhood A, Jaeschke H (2005) Generation of hypochlorite-modified proteins by neutrophils during ischemia-reperfusion injury in rat liver: attenuation by ischemic preconditioning. Am J Physiol Gastrointest Liver Physiol 289(4):G760–G767

    CAS  PubMed  Google Scholar 

  32. Komatsu H, Koo A, Ghadishah E, Zeng H, Kuhlenkamp JF, Inoue M, Guth PH, Kaplowitz N (1992) Neutrophil accumulation in ischemic reperfused rat liver: evidence for a role for superoxide free radicals. Am J Physiol 262(4 Pt 1):G669–G676

    CAS  PubMed  Google Scholar 

  33. Horie Y, Wolf R, Russell J, Shanley TP, Granger DN (1997) Role of Kupffer cells in gut ischemia/reperfusion-induced hepatic microvascular dysfunction in mice. Hepatology 26(6):1499–1505

    CAS  PubMed  Google Scholar 

  34. Schauer RJ, Bilzer M, Kalmuk S, Gerbes AL, Leiderer R, Schildberg FW, Messmer K (2001) Microcirculatory failure after rat liver transplantation is related to Kupffer cell-derived oxidant stress but not involved in early graft dysfunction. Transplantation 72(10):1692–1699

    CAS  PubMed  Google Scholar 

  35. Horie Y, Wolf R, Anderson DC, Granger DN (1997) Hepatic leukostasis and hypoxic stress in adhesion molecule-deficient mice after gut ischemia/reperfusion. J Clin Invest 99(4):781–788

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Shappell SB, Toman C, Anderson DC, Taylor AA, Entman ML, Smith CW (1990) Mac-1(CD11b/CD18) mediates adherence-dependent hydrogen peroxide production by human and canine neutrophils. J Immunol 144(7):2702–2711

    CAS  PubMed  Google Scholar 

  37. Jaeschke H, Farhood A, Bautista AP, Spolarics Z, Spitzer JJ, Smith CW (1993) Functional inactivation of neutrophils with a Mac-1 (CD11b/CD18) monoclonal antibody protects against ischemia-reperfusion injury in rat liver. Hepatology 17(5):915–923

    CAS  PubMed  Google Scholar 

  38. Shibuya H, Ohkohchi N, Seya K, Satomi S (1997) Kupffer cells generate superoxide anions and modulate reperfusion injury in rat livers after cold preservation. Hepatology 25(2):356–360

    CAS  PubMed  Google Scholar 

  39. Cutrín JC, Llesuy S, Boveris A (1998) Primary role of Kupffer cell-hepatocyte communication in the expression of oxidative stress in the post-ischaemic liver. Cell Biochem Funct 16(1):65–72

    PubMed  Google Scholar 

  40. Vega VL, Mardones L, Maldonado M, Nicovani S, Manríquez V, Roa J, Ward PH (2000) Xanthine oxidase released from reperfused hind limbs mediate kupffer cell activation, neutrophil sequestration, and hepatic oxidative stress in rats subjected to tourniquet shock. Shock 14(5):565–571

    CAS  PubMed  Google Scholar 

  41. Matsumura F, Yamaguchi Y, Goto M, Ichiguchi O, Akizuki E, Matsuda T, Okabe K, Liang J, Ohshiro H, Iwamoto T, Yamada S, Mori K, Ogawa M (1998) Xanthine oxidase inhibition attenuates kupffer cell production of neutrophil chemoattractant following ischemia-reperfusion in rat liver. Hepatology 28(6):1578–1587

    CAS  PubMed  Google Scholar 

  42. Blackwell TS, Holden EP, Blackwell TR, DeLarco JE, Christman JW (1994) Cytokine-induced neutrophil chemoattractant mediates neutrophilic alveolitis in rats: association with nuclear factor kappa B activation. Am J Respir Cell Mol Biol 11(4):464–472

    CAS  PubMed  Google Scholar 

  43. Satriano J, Schlondorff D (1994) Activation and attenuation of transcription factor NF-kB in mouse glomerular mesangial cells in response to tumor necrosis factor-alpha, immunoglobulin G, and adenosine 3′:5′-cyclic monophosphate. Evidence for involvement of reactive oxygen species. J Clin Invest 94(4):1629–1636

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Jaeschke H, Woolbright BL (2012) Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. Transplant Rev (Orlando) 26(2):103–114. doi:10.1016/j.trre.2011.10.006

    Google Scholar 

  45. Lehnert M, Arteel GE, Smutney OM, Conzelmann LO, Zhong Z, Thurman RG, Lemasters JJ (2003) Dependence of liver injury after hemorrhage/resuscitation in mice on NADPH oxidase-derived superoxide. Shock 19(4):345–351

    CAS  PubMed  Google Scholar 

  46. Fan C, Li Q, Ross D, Engelhardt JF (2003) Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation. J Biol Chem 278(3):2072–2080

    CAS  PubMed  Google Scholar 

  47. Llacuna L, Marí M, Lluis JM, García-Ruiz C, Fernández-Checa JC, Morales A (2009) Reactive oxygen species mediate liver injury through parenchymal nuclear factor-kappaB inactivation in prolonged ischemia/reperfusion. Am J Pathol 174(5):1776–1785. doi:10.2353/ajpath.2009.080857

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Ikura Y, Ohsawa M, Suekane T, Fukushima H, Itabe H, Jomura H, Nishiguchi S, Inoue T, Naruko T, Ehara S, Kawada N, Arakawa T, Ueda M (2006) Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: impact on disease progression. Hepatology 43(3):506–514

    CAS  PubMed  Google Scholar 

  49. Guyton JR, Lenz ML, Mathews B, Hughes H, Karsan D, Selinger E, Smith CV (1995) Toxicity of oxidized low density lipoproteins for vascular smooth muscle cells and partial protection by antioxidants. Atherosclerosis 118(2):237–249

    CAS  PubMed  Google Scholar 

  50. Wang GP, Deng ZD, Ni J, Qu ZL (1997) Oxidized low density lipoprotein and very low density lipoprotein enhance expression of monocyte chemoattractant protein-1 in rabbit peritoneal exudate macrophages. Atherosclerosis 133(1):31–36

    CAS  PubMed  Google Scholar 

  51. Rensen SS, Slaats Y, Nijhuis J, Jans A, Bieghs V, Driessen A, Malle E, Greve JW, Buurman WA (2009) Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol 175(4):1473–1482. doi:10.2353/ajpath.2009.080999

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Baumgardner JN, Shankar K, Hennings L, Albano E, Badger TM, Ronis MJ (2008) N-acetylcysteine attenuates progression of liver pathology in a rat model of nonalcoholic steatohepatitis. J Nutr 138(10):1872–1879

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J (2004) Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40(1):46–54

    CAS  PubMed  Google Scholar 

  54. Fukushima J, Kamada Y, Matsumoto H, Yoshida Y, Ezaki H, Takemura T, Saji Y, Igura T, Tsutsui S, Kihara S, Funahashi T, Shimomura I, Tamura S, Kiso S, Hayashi N (2009) Adiponectin prevents progression of steatohepatitis in mice by regulating oxidative stress and Kupffer cell phenotype polarization. Hepatol Res 39(7):724–738. doi:10.1111/j.1872-034X.2009.00509.x

    CAS  PubMed  Google Scholar 

  55. Friedman JM (2002) The function of leptin in nutrition, weight, and physiology. Nutr Rev 60(10 Pt 2):S1–S14; discussion S68–S84, 85–87

    PubMed  Google Scholar 

  56. Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, Liddle C, Samarasinghe D, George J (2002) Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 36(2):403–409

    CAS  PubMed  Google Scholar 

  57. Chatterjee S, Ganini D, Tokar EJ, Kumar A, Das S, Corbett J, Kadiiska MB, Waalkes MP, Diehl AM, Mason RP (2013) Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J Hepatol 58(4):778–784. doi:10.1016/j.jhep.2012.11.035

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Yang YY, Huang YT, Tsai TH, Hou MC, Lee FY, Lee SD, Lin HC (2012) Kupffer cell depletion attenuates leptin-mediated methoxamine-stimulated portal perfusion pressure and thromboxane A2 release in a rodent model of NASH-cirrhosis. Clin Sci (Lond) 123(12):669–680. doi:10.1042/CS20110572

    CAS  Google Scholar 

  59. Hewinson J, Moore SF, Glover C, Watts AG, MacKenzie AB (2008) A key role for redox signaling in rapid P2X7 receptor-induced IL-1 beta processing in human monocytes. J Immunol 180(12):8410–8420

    CAS  PubMed  Google Scholar 

  60. Chatterjee S, Rana R, Corbett J, Kadiiska MB, Goldstein J, Mason RP (2012) P2X7 receptor-NADPH oxidase axis mediates protein radical formation and Kupffer cell activation in carbon tetrachloride-mediated steatohepatitis in obese mice. Free Radic Biol Med 52(9):1666–1679. doi:10.1016/j.freeradbiomed.2012.02.010

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Malle E, Furtmüller PG, Sattler W, Obinger C (2007) Myeloperoxidase: a target for new drug development? Br J Pharmacol 152(6):838–854

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Rensen SS, Bieghs V, Xanthoulea S, Arfianti E, Bakker JA, Shiri-Sverdlov R, Hofker MH, Greve JW, Buurman WA (2012) Neutrophil-derived myeloperoxidase aggravates non-alcoholic steatohepatitis in low-density lipoprotein receptor-deficient mice. PLoS One 7(12):e52411. doi:10.1371/journal.pone.0052411

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Albano E, Mottaran E, Vidali M, Reale E, Saksena S, Occhino G, Burt AD, Day CP (2005) Immune response towards lipid peroxidation products as a predictor of progression of non-alcoholic fatty liver disease to advanced fibrosis. Gut 54(7):987–993

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Nobili V, Parola M, Alisi A, Marra F, Piemonte F, Mombello C, Sutti S, Povero D, Maina V, Novo E, Albano E (2010) Oxidative stress parameters in paediatric non-alcoholic fatty liver disease. Int J Mol Med 26(4):471–476

    CAS  PubMed  Google Scholar 

  65. Sutti S, Jindal A, Locatelli I, Vacchiano M, Gigliotti L, Bozzola C, Albano E (2014) Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 59(3):886–897. doi:10.1002/hep.26749

    CAS  PubMed  Google Scholar 

  66. Ferreyra Solari NE, Inzaugarat ME, Baz P, De Matteo E, Lezama C, Galoppo M, Galoppo C, Cherñavsky AC (2012) The role of innate cells is coupled to a Th1-polarized immune response in pediatric nonalcoholic steatohepatitis. J Clin Immunol 32(3):611–621. doi:10.1007/s10875-011-9635-2

    CAS  PubMed  Google Scholar 

  67. Purohit V, Gao B, Song BJ (2009) Molecular mechanisms of alcoholic fatty liver. Alcohol Clin Exp Res 33(2):191–205. doi:10.1111/j.1530-0277.2008.00827.x

    PubMed Central  CAS  PubMed  Google Scholar 

  68. Kono H, Bradford BU, Yin M, Sulik KK, Koop DR, Peters JM, Gonzalez FJ, McDonald T, Dikalova A, Kadiiska MB, Mason RP, Thurman RG (1999) CYP2E1 is not involved in early alcohol-induced liver injury. Am J Physiol 277(6 Pt 1):G1259–G1267

    CAS  PubMed  Google Scholar 

  69. Knecht KT, Adachi Y, Bradford BU, Iimuro Y, Kadiiska M, Xuang QH, Thurman RG (1995) Free radical adducts in the bile of rats treated chronically with intragastric alcohol: inhibition by destruction of Kupffer cells. Mol Pharmacol 47(5):1028–1034

    CAS  PubMed  Google Scholar 

  70. Hasegawa T, Kikuyama M, Sakurai K, Kambayashi Y, Adachi M, Saniabadi AR, Kuwano H, Nakano M (2002) Mechanism of superoxide anion production by hepatic sinusoidal endothelial cells and Kupffer cells during short-term ethanol perfusion in the rat. Liver 22(4):321–329

    CAS  PubMed  Google Scholar 

  71. Bautista AP, Spitzer JJ (1999) Role of Kupffer cells in the ethanol-induced oxidative stress in the liver. Front Biosci 4:D589–D595

    CAS  PubMed  Google Scholar 

  72. Cubero FJ, Nieto N (2008) 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 48(6):2027–2039. doi:10.1002/hep.22592

    CAS  PubMed  Google Scholar 

  73. Zhou Z, Wang L, Song Z, Lambert JC, McClain CJ, Kang YJ (2003) A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-alpha production. Am J Pathol 163(3):1137–1146

    PubMed Central  CAS  PubMed  Google Scholar 

  74. Ronis MJ, Butura A, Sampey BP, Shankar K, Prior RL, Korourian S, Albano E, Ingelman-Sundberg M, Petersen DR, Badger TM (2005) Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition. Free Radic Biol Med 39(5):619–630

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Lv X, Chen Z, Li J, Zhang L, Liu H, Huang C, Zhu P (2010) Caffeine protects against alcoholic liver injury by attenuating inflammatory response and oxidative stress. Inflamm Res 59(8):635–645. doi:10.1007/s00011-010-0176-6

    CAS  PubMed  Google Scholar 

  76. Nanji AA, Jokelainen K, Rahemtulla A, Miao L, Fogt F, Matsumoto H, Tahan SR, Su GL (1999) Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. Hepatology 30(4):934–943

    CAS  PubMed  Google Scholar 

  77. Mandrekar P, Ambade A, Lim A, Szabo G, Catalano D (2011) An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology 54(6):2185–2197. doi:10.1002/hep.24599

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Iimuro Y, Bradford BU, Yamashina S, Rusyn I, Nakagami M, Enomoto N, Kono H, Frey W, Forman D, Brenner D, Thurman RG (2000) The glutathione precursor L-2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat. Hepatology 31(2):391–398

    CAS  PubMed  Google Scholar 

  79. Ahn SG, Thiele DJ (2003) Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev 17(4):516–528

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Mandrekar P, Catalano D, Jeliazkova V, Kodys K (2008) Alcohol exposure regulates heat shock transcription factor binding and heat shock proteins 70 and 90 in monocytes and macrophages: implication for TNF-alpha regulation. J Leukoc Biol 84(5):1335–1345. doi:10.1189/jlb.0407256

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Yin M, Gäbele E, Wheeler MD, Connor H, Bradford BU, Dikalova A, Rusyn I, Mason R, Thurman RG (2001) Alcohol-induced free radicals in mice: direct toxicants or signaling molecules? Hepatology 34(5):935–942

    CAS  PubMed  Google Scholar 

  82. Kono H, Rusyn I, Yin M, Gäbele E, Yamashina S, Dikalova A, Kadiiska MB, Connor HD, Mason RP, Segal BH, Bradford BU, Holland SM, Thurman RG (2000) NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest 106(7):867–872

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Kono H, Rusyn I, Bradford BU, Connor HD, Mason RP, Thurman RG (2000) Allopurinol prevents early alcohol-induced liver injury in rats. J Pharmacol Exp Ther 293(1):296–303

    CAS  PubMed  Google Scholar 

  84. Kono H, Rusyn I, Uesugi T, Yamashina S, Connor HD, Dikalova A, Mason RP, Thurman RG (2001) Diphenyleneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol-induced liver injury in the rat. Am J Physiol Gastrointest Liver Physiol 280(5):G1005–G1012

    CAS  PubMed  Google Scholar 

  85. Wheeler MD, Kono H, Yin M, Rusyn I, Froh M, Connor HD, Mason RP, Samulski RJ, Thurman RG (2001) Delivery of the Cu/Zn-superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats. Gastroenterology 120(5):1241–1250

    CAS  PubMed  Google Scholar 

  86. Wheeler MD, Thurman RG (2003) Up-regulation of CD14 in liver caused by acute ethanol involves oxidant-dependent AP-1 pathway. J Biol Chem 278(10):8435–8441

    CAS  PubMed  Google Scholar 

  87. Wheeler MD, Nakagami M, Bradford BU, Uesugi T, Mason RP, Connor HD, Dikalova A, Kadiiska M, Thurman RG (2001) Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J Biol Chem 276(39):36664–36672

    CAS  PubMed  Google Scholar 

  88. Bode C, Kugler V, Bode JC (1987) Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol 4(1):8–14

    CAS  PubMed  Google Scholar 

  89. Nanji AA, Khettry U, Sadrzadeh SM, Yamanaka T (1993) Severity of liver injury in experimental alcoholic liver disease. Correlation with plasma endotoxin, prostaglandin E2, leukotriene B4, and thromboxane B2. Am J Pathol 142(2):367–373

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG (1995) Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108(1):218–224

    CAS  PubMed  Google Scholar 

  91. Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C (2000) Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol 32(5):742–747

    CAS  PubMed  Google Scholar 

  92. Landmann R, Scherer F, Schumann R, Link S, Sansano S, Zimmerli W (1995) LPS directly induces oxygen radical production in human monocytes via LPS binding protein and CD14. J Leukoc Biol 57(3):440–449

    CAS  PubMed  Google Scholar 

  93. Bellezzo JM, Leingang KA, Bulla GA, Britton RS, Bacon BR, Fox ES (1998) Modulation of lipopolysaccharide-mediated activation in rat Kupffer cells by antioxidants. J Lab Clin Med 131(1):36–44

    CAS  PubMed  Google Scholar 

  94. Wheeler MD, Yamashina S, Froh M, Rusyn I, Thurman RG (2001) Adenoviral gene delivery can inactivate Kupffer cells: role of oxidants in NF-kappaB activation and cytokine production. J Leukoc Biol 69(4):622–630

    CAS  PubMed  Google Scholar 

  95. Zhou Z, Wang L, Song Z, Saari JT, McClain CJ, Kang YJ (2004) Abrogation of nuclear factor-kappaB activation is involved in zinc inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production and liver injury. Am J Pathol 164(5):1547–1556

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Gujral JS, Hinson JA, Farhood A, Jaeschke H (2004) NADPH oxidase-derived oxidant stress is critical for neutrophil cytotoxicity during endotoxemia. Am J Physiol Gastrointest Liver Physiol 287(1):G243–G252

    CAS  PubMed  Google Scholar 

  97. Thakur V, Pritchard MT, McMullen MR, Wang Q, Nagy LE (2006) Chronic ethanol feeding increases activation of NADPH oxidase by lipopolysaccharide in rat Kupffer cells: role of increased reactive oxygen in LPS-stimulated ERK1/2 activation and TNF-alpha production. J Leukoc Biol 79(6):1348–1356

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Liu S, Shapiro RA, Nie S, Zhu D, Vodovotz Y, Billiar TR (2000) Characterization of rat CD14 promoter and its regulation by transcription factors AP1 and Sp family proteins in hepatocytes. Gene 250(1–2):137–147

    CAS  PubMed  Google Scholar 

  99. Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG (2001) Reduced early alcohol-induced liver injury in CD14-deficient mice. J Immunol 166(7):4737–4742

    CAS  PubMed  Google Scholar 

  100. Jaeschke H, Ho YS, Fisher MA, Lawson JA, Farhood A (1999) Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: importance of an intracellular oxidant stress. Hepatology 29(2):443–450

    CAS  PubMed  Google Scholar 

  101. Jaeschke H, Farhood A, Smith CW (1991) Neutrophil-induced liver cell injury in endotoxin shock is a CD11b/CD18-dependent mechanism. Am J Physiol 261(6 Pt 1):G1051–G1056

    CAS  PubMed  Google Scholar 

  102. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST (2013) Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 57(4):1333–1342. doi:10.1002/hep.26141

    PubMed  Google Scholar 

  103. WHO (2013) Global policy report on the prevention and control of viral hepatitis in WHO member states. WHO, Geneva. ISBN 978 92 4 156463 2

    Google Scholar 

  104. Choi J (2012) Oxidative stress, endogenous antioxidants, alcohol, and hepatitis C: pathogenic interactions and therapeutic considerations. Free Radic Biol Med 52(7):1135–1150. doi:10.1016/j.freeradbiomed.2012.01.008

    CAS  PubMed  Google Scholar 

  105. Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, Lecis E, Burra P, Floreani A, Cecchetto A, Naccarato R (1995) Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol 22(4):449–456

    CAS  PubMed  Google Scholar 

  106. De Maria N, Colantoni A, Fagiuoli S, Liu GJ, Rogers BK, Farinati F, Van Thiel DH, Floyd RA (1996) Association between reactive oxygen species and disease activity in chronic hepatitis C. Free Radic Biol Med 21(3):291–295

    PubMed  Google Scholar 

  107. Boya P, de la Peña A, Beloqui O, Larrea E, Conchillo M, Castelruiz Y, Civeira MP, Prieto J (1999) Antioxidant status and glutathione metabolism in peripheral blood mononuclear cells from patients with chronic hepatitis C. J Hepatol 31(5):808–814

    CAS  PubMed  Google Scholar 

  108. Larrea E, Beloqui O, Muñoz-Navas MA, Civeira MP, Prieto J (1998) Superoxide dismutase in patients with chronic hepatitis C virus infection. Free Radic Biol Med 24(7–8):1235–1241

    CAS  PubMed  Google Scholar 

  109. Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, Weinman SA (2002) Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122(2):366–375

    CAS  PubMed  Google Scholar 

  110. Abdalla MY, Ahmad IM, Spitz DR, Schmidt WN, Britigan BE (2005) Hepatitis C virus-core and non structural proteins lead to different effects on cellular antioxidant defenses. J Med Virol 76(4):489–497

    CAS  PubMed  Google Scholar 

  111. Farinati F, Cardin R, Degan P, De Maria N, Floyd RA, Van Thiel DH, Naccarato R (1999) Oxidative DNA damage in circulating leukocytes occurs as an early event in chronic HCV infection. Free Radic Biol Med 27(11–12):1284–1291

    CAS  PubMed  Google Scholar 

  112. Reynolds WF, Patel K, Pianko S, Blatt LM, Nicholas JJ, McHutchison JG (2002) A genotypic association implicates myeloperoxidase in the progression of hepatic fibrosis in chronic hepatitis C virus infection. Genes Immun 3(6):345–349

    CAS  PubMed  Google Scholar 

  113. Bureau C, Bernad J, Chaouche N, Orfila C, Béraud M, Gonindard C, Alric L, Vinel JP, Pipy B (2001) Nonstructural 3 protein of hepatitis C virus triggers an oxidative burst in human monocytes via activation of NADPH oxidase. J Biol Chem 276(25):23077–23083

    CAS  PubMed  Google Scholar 

  114. Thorén F, Romero A, Lindh M, Dahlgren C, Hellstrand K (2004) A hepatitis C virus-encoded, nonstructural protein (NS3) triggers dysfunction and apoptosis in lymphocytes: role of NADPH oxidase-derived oxygen radicals. J Leukoc Biol 76(6):1180–1186

    PubMed  Google Scholar 

  115. Kuwano Y, Kawahara T, Yamamoto H, Teshima-Kondo S, Tominaga K, Masuda K, Kishi K, Morita K, Rokutan K (2006) Interferon-gamma activates transcription of NADPH oxidase 1 gene and upregulates production of superoxide anion by human large intestinal epithelial cells. Am J Physiol Cell Physiol 290(2):C433–C443

    CAS  PubMed  Google Scholar 

  116. de Mochel NS, Seronello S, Wang SH, Ito C, Zheng JX, Liang TJ, Lambeth JD, Choi J (2010) Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis C virus infection. Hepatology 52(1):47–59. doi:10.1002/hep.23671

    PubMed Central  PubMed  Google Scholar 

  117. Casini A, Ceni E, Salzano R, Biondi P, Parola M, Galli A, Foschi M, Caligiuri A, Pinzani M, Surrenti C (1997) Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide. Hepatology 25(2):361–367

    CAS  PubMed  Google Scholar 

  118. Nieto N (2006) Oxidative-stress and IL-6 mediate the fibrogenic effects of Kupffer cells on stellate cells. Hepatology 44(6):1487–1501

    CAS  PubMed  Google Scholar 

  119. Leonarduzzi G, Scavazza A, Biasi F, Chiarpotto E, Camandola S, Vogel S, Dargel R, Poli G (1997) The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis. FASEB J 11(11):851–857

    CAS  PubMed  Google Scholar 

  120. Camandola S, Aragno M, Cutrin JC, Tamagno E, Danni O, Chiarpotto E, Parola M, Leonarduzzi G, Biasi F, Poli G (1999) Liver AP-1 activation due to carbon tetrachloride is potentiated by 1,2-dibromoethane but is inhibited by alpha-tocopherol or gadolinium chloride. Free Radic Biol Med 26(9–10):1108–1116

    CAS  PubMed  Google Scholar 

  121. Marra F, DeFranco R, Grappone C, Parola M, Milani S, Leonarduzzi G, Pastacaldi S, Wenzel UO, Pinzani M, Dianzani MU, Laffi G, Gentilini P (1999) Expression of monocyte chemotactic protein-1 precedes monocyte recruitment in a rat model of acute liver injury, and is modulated by vitamin E. J Investig Med 47(1):66–75

    CAS  PubMed  Google Scholar 

  122. Zamara E, Galastri S, Aleffi S, Petrai I, Aragno M, Mastrocola R, Novo E, Bertolani C, Milani S, Vizzutti F, Vercelli A, Pinzani M, Laffi G, LaVilla G, Parola M, Marra F (2007) Prevention of severe toxic liver injury and oxidative stress in MCP-1-deficient mice. J Hepatol 46(2):230–238

    CAS  PubMed  Google Scholar 

  123. Luckey SW, Petersen DR (2001) Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol 71(3):226–240

    CAS  PubMed  Google Scholar 

  124. Wang H, Wei W, Wang NP, Gui SY, Wu L, Sun WY, Xu SY (2005) Melatonin ameliorates carbon tetrachloride-induced hepatic fibrogenesis in rats via inhibition of oxidative stress. Life Sci 77(15):1902–1915

    CAS  PubMed  Google Scholar 

  125. Paik YH, Iwaisako K, Seki E, Inokuchi S, Schnabl B, Osterreicher CH, Kisseleva T, Brenner DA (2011) The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology 53(5):1730–1741. doi:10.1002/hep.24281

    PubMed Central  CAS  PubMed  Google Scholar 

  126. De Minicis S, Seki E, Paik YH, Osterreicher CH, Kodama Y, Kluwe J, Torozzi L, Miyai K, Benedetti A, Schwabe RF, Brenner DA (2010) Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis. Hepatology 52(4):1420–1430. doi:10.1002/hep.23804

    PubMed Central  PubMed  Google Scholar 

  127. Wang ZL, Deng CY, Zheng H, Xie CF, Wang XH, Luo YF, Chen ZZ, Cheng P, Chen LJ (2012) (Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid protects rats from CCl(4) -induced liver injury. J Gastroenterol Hepatol 27(5):966–973. doi:10.1111/j.1440-1746.2011.06913.x

    CAS  PubMed  Google Scholar 

  128. Simonetti RG, Cammà C, Fiorello F, Politi F, D’Amico G, Pagliaro L (1991) Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci 36(7):962–972

    CAS  PubMed  Google Scholar 

  129. Teufelhofer O, Parzefall W, Kainzbauer E, Ferk F, Freiler C, Knasmüller S, Elbling L, Thurman R, Schulte-Hermann R (2005) Superoxide generation from Kupffer cells contributes to hepatocarcinogenesis: studies on NADPH oxidase knockout mice. Carcinogenesis 26(2):319–329

    CAS  PubMed  Google Scholar 

  130. Bernal W, Auzinger G, Dhawan A, Wendon J (2010) Acute liver failure. Lancet 376(9736):190–201. doi:10.1016/S0140-6736(10)60274-7

    PubMed  Google Scholar 

  131. Michael SL, Pumford NR, Mayeux PR, Niesman MR, Hinson JA (1999) Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology 30(1):186–195

    CAS  PubMed  Google Scholar 

  132. Andrés D, Sánchez-Reus I, Bautista M, Cascales M (2003) Depletion of Kupffer cell function by gadolinium chloride attenuates thioacetamide-induced hepatotoxicity. Expression of metallothionein and HSP70. Biochem Pharmacol 66(6):917–926

    PubMed  Google Scholar 

  133. Dambach DM, Durham SK, Laskin JD, Laskin DL (2006) Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity. Toxicol Appl Pharmacol 211(2):157–165

    CAS  PubMed  Google Scholar 

  134. Al-Belooshi T, John A, Tariq S, Al-Otaiba A, Raza H (2010) Increased mitochondrial stress and modulation of mitochondrial respiratory enzyme activities in acetaminophen-induced toxicity in mouse macrophage cells. Food Chem Toxicol 48(10):2624–2632. doi:10.1016/j.fct.2010.06.031

    CAS  PubMed  Google Scholar 

  135. Chen Q, Xue Y, Sun J (2013) Kupffer cell-mediated hepatic injury induced by silica nanoparticles in vitro and in vivo. Int J Nanomedicine 8:1129–1140. doi:10.2147/IJN.S42242

    PubMed Central  CAS  PubMed  Google Scholar 

  136. Zhong Z, Froh M, Wheeler MD, Smutney O, Lehmann TG, Thurman RG (2002) Viral gene delivery of superoxide dismutase attenuates experimental cholestasis-induced liver fibrosis in the rat. Gene Ther 9(3):183–191

    CAS  PubMed  Google Scholar 

  137. Gujral JS, Liu J, Farhood A, Hinson JA, Jaeschke H (2004) Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice. Am J Physiol Gastrointest Liver Physiol 286(3):G499–G507

    CAS  PubMed  Google Scholar 

  138. Schauer RJ, Gerbes AL, Vonier D, op den Winkel M, Fraunberger P, Bilzer M (2003) Induction of cellular resistance against Kupffer cell-derived oxidant stress: a novel concept of hepatoprotection by ischemic preconditioning. Hepatology 37(2):286–295

    CAS  PubMed  Google Scholar 

  139. Rüdiger HA, Graf R, Clavien PA (2003) Sub-lethal oxidative stress triggers the protective effects of ischemic preconditioning in the mouse liver. J Hepatol 39(6):972–977

    PubMed  Google Scholar 

  140. Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116

    CAS  PubMed  Google Scholar 

  141. Tsuchihashi S, Fondevila C, Kupiec-Weglinski JW (2004) Heme oxygenase system in ischemia and reperfusion injury. Ann Transplant 9(1):84–87

    CAS  PubMed  Google Scholar 

  142. Kiemer AK, Gerwig T, Gerbes AL, Meissner H, Bilzer M, Vollmar AM (2003) Kupffer-cell specific induction of heme oxygenase 1 (hsp32) by the atrial natriuretic peptide–role of cGMP. J Hepatol 38(4):490–498

    CAS  PubMed  Google Scholar 

  143. Yeligar SM, Machida K, Kalra VK (2010) Ethanol-induced HO-1 and NQO1 are differentially regulated by HIF-1alpha and Nrf2 to attenuate inflammatory cytokine expression. J Biol Chem 285(46):35359–35373. doi:10.1074/jbc.M110.138636

    PubMed Central  CAS  PubMed  Google Scholar 

  144. Bautista AP (2002) Acute ethanol binge followed by withdrawal regulates production of reactive oxygen species and cytokine-induced neutrophil chemoattractant and liver injury during reperfusion after hepatic ischemia. Antioxid Redox Signal 4(5):721–731

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. The University of Edinburgh/Medical Research Council Centre for Inflammation Research, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK

    Stephen N. Greenhalgh, Alexandra I. Thompson, Neil C. Henderson & John P. Iredale

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  1. Stephen N. Greenhalgh
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  2. Alexandra I. Thompson
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  3. Neil C. Henderson
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  4. John P. Iredale
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Correspondence to Stephen N. Greenhalgh .

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  1. Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy

    Emanuele Albano

  2. Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, School of Medicine, University of Torino, Torino, Italy

    Maurizio Parola

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Greenhalgh, S.N., Thompson, A.I., Henderson, N.C., Iredale, J.P. (2015). Oxidative Stress and Liver Inflammation. In: Albano, E., Parola, M. (eds) Studies on Hepatic Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15539-5_6

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