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Inflammation and Liver Injury

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

Abstract

Inflammation is a common component of almost all types of liver diseases and it is often a cause of liver injury. Liver inflammation is a reaction of the immune system, mostly innate immunity, to danger signals derived from injured host cells such as drug-affected hepatocytes or from invading pathogens such as viruses or bacteria. Liver inflammation is characterized by recruitment of various inflammatory and immune cells to the liver, including but not limited to monocytes, macrophages, neutrophil leukocytes, NK, NKT cells, Th17, and regulatory T cells. Cells in the liver express various pattern recognition receptors (PRR) that sense endogenous or pathogen-derived molecular sequences and induce cell- or pathogen-specific intracellular signal transduction pathways to produce inflammatory mediators and interferons. Immune cells as well as parenchymal cells in the liver produce various chemokines and cytokines that through cross-talk between these cell populations affect the outcome and prognosis of the liver inflammation. Inflammatory mediators produced in the local environment and recruited immune cells can cause injury to parenchymal cells, including hepatocytes and biliary epithelial cells. In addition, prolonged inflammation and/or direct danger signals trigger stellate cell activation and fibrosis leading to progressive liver injury. The cellular sources, PRR, and molecular pathways that lead to inflammation are discussed in this chapter.

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References

  1. Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009;27:147–63.

    PubMed  CAS  Google Scholar 

  2. Szabo G, Mandrekar P, Dolganiuc A. Innate immune response and hepatic inflammation. Semin Liver Dis. 2007;27(4):339–50.

    PubMed  CAS  Google Scholar 

  3. Mandrekar P, Szabo G. Signalling pathways in alcohol-induced liver inflammation. J Hepatol. 2009;50(6):1258–66.

    PubMed  CAS  Google Scholar 

  4. Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors­: a contemporary view on liver diseases. Hepatology. 2006;44(2):287–98.

    PubMed  CAS  Google Scholar 

  5. Parker GA, Picut CA. Liver immunobiology. Toxicol Pathol. 2005;33(1):52–62.

    PubMed  CAS  Google Scholar 

  6. Zarember KA, Godowski PJ. Tissue expression of human toll-like receptors and differential regulation of toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol. 2002;168(2):554–61.

    PubMed  CAS  Google Scholar 

  7. Jiang W, Sun R, Wei H, Tian Z. Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. Proc Natl Acad Sci U S A. 2005;102(47):17077–82.

    PubMed  CAS  Google Scholar 

  8. Ojaniemi M, Liljeroos M, Harju K, Sormunen R, Vuolteenaho R, Hallman M. TLR-2 is upregulated and mobilized to the hepatocyte plasma membrane in the space of disse and to the kupffer cells TLR-4 dependently during acute endotoxemia in mice. Immunol Lett. 2006;102(2):158–68.

    PubMed  CAS  Google Scholar 

  9. Thobe BM, Frink M, Hildebrand F, et al. The role of MAPK in kupffer cell toll-like receptor (TLR) 2-, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage. J Cell Physiol. 2007;210(3):667–75.

    PubMed  CAS  Google Scholar 

  10. Tacke F, Luedde T, Trautwein C. Inflammatory pathways in liver homeostasis and liver injury. Clin Rev Allergy Immunol. 2009;36(1):4–12.

    PubMed  CAS  Google Scholar 

  11. Nath B, Szabo G. Alcohol-induced modulation of signaling ­pathways in liver parenchymal and nonparenchymal cells: Implications for immunity. Semin Liver Dis. 2009;29(2):166–77.

    PubMed  CAS  Google Scholar 

  12. Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47(4):571–9.

    PubMed  CAS  Google Scholar 

  13. Wu L, Dakic A. Development of dendritic cell system. Cell Mol Immunol. 2004;1(2):112–8.

    PubMed  Google Scholar 

  14. Steinman RM, Hemmi H. Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol. 2006;311:17–58.

    PubMed  CAS  Google Scholar 

  15. Yoneyama H, Ichida T. Recruitment of dendritic cells to pathological­ niches in inflamed liver. Med Mol Morphol. 2005;38(3):136–41.

    PubMed  Google Scholar 

  16. Matsuno K, Nomiyama H, Yoneyama H, Uwatoku R. Kupffer cell-mediated recruitment of dendritic cells to the liver crucial for a host defense. Dev Immunol. 2002;9(3):143–9.

    PubMed  CAS  Google Scholar 

  17. Kudo S, Matsuno K, Ezaki T, Ogawa M. A novel migration pathway for rat dendritic cells from the blood: Hepatic sinusoids-lymph translocation. J Exp Med. 1997;185(4):777–84.

    PubMed  CAS  Google Scholar 

  18. Thomson AW, Drakes ML, Zahorchak AF, et al. Hepatic dendritic cells: Immunobiology and role in liver transplantation. J Leukoc Biol. 1999;66(2):322–30.

    PubMed  CAS  Google Scholar 

  19. Bosma BM, Metselaar HJ, Mancham S, et al. Characterization of human liver dendritic cells in liver grafts and perfusates. Liver Transpl. 2006;12(3):384–93.

    PubMed  Google Scholar 

  20. Lau AH, de Creus A, Lu L, Thomson AW. Liver tolerance ­mediated by antigen presenting cells: fact or fiction? Gut. 2003;52(8):1075–8.

    PubMed  CAS  Google Scholar 

  21. Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: Which signals induce tolerance or immunity? Trends Immunol. 2002;23(9):445–9.

    PubMed  CAS  Google Scholar 

  22. Jomantaite I, Dikopoulos N, Kroger A, et al. Hepatic dendritic cell subsets in the mouse. Eur J Immunol. 2004;34(2):355–65.

    PubMed  CAS  Google Scholar 

  23. Wu L, Li CL, Shortman K. Thymic dendritic cell precursors: Relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny. J Exp Med. 1996;184(3):903–11.

    PubMed  CAS  Google Scholar 

  24. Bjorck P. Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-­stimulating factor-treated mice. Blood. 2001;98(13):3520–6.

    PubMed  CAS  Google Scholar 

  25. Hemmi H, Akira S. TLR signalling and the function of dendritic cells. Chem Immunol Allergy. 2005;86:120–35.

    PubMed  CAS  Google Scholar 

  26. Seeds RE, Gordon S, Miller JL. Receptors and ligands involved in viral induction of type I interferon production by plasmacytoid dendritic cells. Immunobiology. 2006;211(6–8):525–35.

    PubMed  CAS  Google Scholar 

  27. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 2007;315(5817):1398–401.

    PubMed  CAS  Google Scholar 

  28. Dolganiuc A, Chang S, Kodys K, et al. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol. 2006;177(10):6758–68.

    PubMed  CAS  Google Scholar 

  29. Loseke S, Grage-Griebenow E, Heine H, et al. In vitro-generated viral double-stranded RNA in contrast to polyinosinic: polycytidylic acid induces interferon-alpha in human plasmacytoid dendritic cells. Scand J Immunol. 2006;63(4):264–74.

    PubMed  CAS  Google Scholar 

  30. Dolganiuc A, Garcia C, Kodys K, Szabo G. Distinct toll-like receptor expression in monocytes and T cells in chronic HCV infection. World J Gastroenterol. 2006;12(8):1198–204.

    PubMed  CAS  Google Scholar 

  31. Bain C, Fatmi A, Zoulim F, Zarski JP, Trepo C, Inchauspe G. Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastroenterology. 2001;120(2):512–24.

    PubMed  CAS  Google Scholar 

  32. Aloman C, Gehring S, Wintermeyer P, Kuzushita N, Wands JR. Chronic ethanol consumption impairs cellular immune responses against HCV NS5 protein due to dendritic cell dysfunction. Gastroenterology. 2007;132(2):698–708.

    PubMed  CAS  Google Scholar 

  33. Mandrekar P, Catalano D, Dolganiuc A, Kodys K, Szabo G. Inhibition of myeloid dendritic cell accessory cell function and induction of T cell anergy by alcohol correlates with decreased IL-12 production. J Immunol. 2004;173(5):3398–407.

    PubMed  CAS  Google Scholar 

  34. Lau AH, Abe M, Thomson AW. Ethanol affects the generation, cosignaling molecule expression, and function of plasmacytoid and myeloid dendritic cell subsets in vitro and in vivo. J Leukoc Biol. 2006;79(5):941–53.

    PubMed  CAS  Google Scholar 

  35. Vega VL, Maldonado M, Mardones L, et al. Role of kupffer cells and PMN leukocytes in hepatic and systemic oxidative stress in rats subjected to tourniquet shock. Shock. 1999;11(6):403–10.

    PubMed  CAS  Google Scholar 

  36. Yamashiro S, Kamohara H, Wang JM, Yang D, Gong WH, Yoshimura T. Phenotypic and functional change of cytokine-­activated neutrophils: Inflammatory neutrophils are heterogeneous and enhance adaptive immune responses. J Leukoc Biol. 2001;69(5):698–704.

    PubMed  CAS  Google Scholar 

  37. Wagner JG, Roth RA. Neutrophil migration during endotoxemia. J Leukoc Biol. 1999;66(1):10–24.

    PubMed  CAS  Google Scholar 

  38. Schlayer HJ, Laaff H, Peters T, et al. Involvement of tumor necrosis factor in endotoxin-triggered neutrophil adherence to sinusoidal endothelial cells of mouse liver and its modulation in acute phase. J Hepatol. 1988;7(2):239–49.

    PubMed  CAS  Google Scholar 

  39. Bajt ML, Farhood A, Jaeschke H. Effects of CXC chemokines on neutrophil activation and sequestration in hepatic vasculature. Am J Physiol Gastrointest Liver Physiol. 2001;281(5):G1188–95.

    PubMed  CAS  Google Scholar 

  40. Simonet WS, Hughes TM, Nguyen HQ, Trebasky LD, Danilenko DM, Medlock ES. Long-term impaired neutrophil migration in mice overexpressing human interleukin-8. J Clin Invest. 1994;94(3):1310–9.

    PubMed  CAS  Google Scholar 

  41. Dorman RB, Gujral JS, Bajt ML, Farhood A, Jaeschke H. Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia. Am J Physiol Gastrointest Liver Physiol. 2005;288(5):G880–6.

    PubMed  CAS  Google Scholar 

  42. Maher JJ, Scott MK, Saito JM, Burton MC. Adenovirus-mediated expression of cytokine-induced neutrophil chemoattractant in rat liver induces a neutrophilic hepatitis. Hepatology. 1997;25(3):624–30.

    PubMed  CAS  Google Scholar 

  43. Zhang P, Xie M, Zagorski J, Spitzer JA. Attenuation of hepatic neutrophil sequestration by anti-CINC antibody in endotoxic rats. Shock. 1995;4(4):262–8.

    PubMed  CAS  Google Scholar 

  44. Sweet MJ, Hume DA. Endotoxin signal transduction in ­macrophages. J Leukoc Biol. 1996;60(1):8–26.

    PubMed  CAS  Google Scholar 

  45. Chosay JG, Essani NA, Dunn CJ, Jaeschke H. Neutrophil margination­ and extravasation in sinusoids and venules of liver during endotoxin­-induced injury. Am J Physiol. 1997;272(5 Pt 1):G1195–200.

    PubMed  CAS  Google Scholar 

  46. Ajuebor MN, Wondimu Z, Hogaboam CM, Le T, Proudfoot AE, Swain MG. CCR5 deficiency drives enhanced natural killer cell trafficking to and activation within the liver in murine T cell-mediated hepatitis. Am J Pathol. 2007;170(6):1975–88.

    PubMed  CAS  Google Scholar 

  47. Swain MG. Hepatic NKT cells: friend or foe? Clin Sci (Lond). 2008;114(7):457–66.

    CAS  Google Scholar 

  48. Ahmad A, Alvarez F. Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis. J Leukoc Biol. 2004;76(4):743–59.

    PubMed  CAS  Google Scholar 

  49. Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: Immunobiology and emerging roles in liver diseases. J Leukoc Biol. 2009;86(3):513–28.

    PubMed  CAS  Google Scholar 

  50. Shen K, Zheng SS, Park O, Wang H, Sun Z, Gao B. Activation of innate immunity (NK/IFN-gamma) in rat allogeneic liver transplantation: Contribution to liver injury and suppression of hepatocyte proliferation. Am J Physiol Gastrointest Liver Physiol. 2008;294(4):G1070–7.

    PubMed  CAS  Google Scholar 

  51. Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G. Activated natural killer T cells induce liver injury by fas and tumor necrosis factor-alpha during alcohol consumption. Gastroenterology. 2004;126(5):1387–99.

    PubMed  CAS  Google Scholar 

  52. Doherty DG, O’Farrelly C. Innate and adaptive lymphoid cells in the human liver. Immunol Rev. 2000;174:5–20.

    PubMed  CAS  Google Scholar 

  53. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11(1):7–13.

    PubMed  CAS  Google Scholar 

  54. Fu J, Xu D, Liu Z, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132(7):2328–39.

    PubMed  Google Scholar 

  55. Ebinuma H, Nakamoto N, Li Y, et al. Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection. J Virol. 2008;82(10):5043–53.

    PubMed  CAS  Google Scholar 

  56. Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T. Regulatory T cells: How do they suppress immune responses? Int Immunol. 2009;21(10):1105–11.

    PubMed  CAS  Google Scholar 

  57. Kido M, Watanabe N, Okazaki T, et al. Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling. Gastroenterology. 2008;135(4):1333–43.

    PubMed  CAS  Google Scholar 

  58. Tiegs G, Lohse AW. Immune tolerance: what is unique about the liver. J Autoimmun. 2010;34(1):1–6.

    Google Scholar 

  59. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.

    PubMed  CAS  Google Scholar 

  60. Li W, Kuhr CS, Zheng XX, et al. New insights into mechanisms of spontaneous liver transplant tolerance: The role of Foxp3-expressing CD25+CD4+ regulatory T cells. Am J Transplant. 2008;8(8):1639–51.

    PubMed  CAS  Google Scholar 

  61. Tokita D, Mazariegos GV, Zahorchak AF, et al. High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance. Transplantation. 2008;85(3):369–77.

    PubMed  Google Scholar 

  62. Awasthi A, Kuchroo VK. Th17 cells: from precursors to players in inflammation and infection. Int Immunol. 2009;21(5):489–98.

    PubMed  CAS  Google Scholar 

  63. Spolski R, Leonard WJ. Cytokine mediators of Th17 function. Eur J Immunol. 2009;39(3):658–61.

    PubMed  CAS  Google Scholar 

  64. Crispe IN, Giannandrea M, Klein I, John B, Sampson B, Wuensch S. Cellular and molecular mechanisms of liver tolerance. Immunol Rev. 2006;213:101–18.

    PubMed  Google Scholar 

  65. Lan RY, Salunga TL, Tsuneyama K, et al. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun. 2009;32(1):43–51.

    PubMed  CAS  Google Scholar 

  66. Rong G, Zhou Y, Xiong Y, et al. Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary ­cirrhosis: the serum cytokine profile and peripheral cell population­. Clin Exp Immunol. 2009;156(2):217–25.

    PubMed  CAS  Google Scholar 

  67. Fabrega E, Lopez-Hoyos M. San Segundo D, Casafont F, Pons-Romero F. Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl. 2009;15(6):629–33.

    PubMed  Google Scholar 

  68. Harada K, Shimoda S, Sato Y, Isse K, Ikeda H, Nakanuma Y. Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in ­primary biliary cirrhosis. Clin Exp Immunol. 2009;157(2):261–70.

    PubMed  CAS  Google Scholar 

  69. Lemmers A, Moreno C, Gustot T, et al. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology. 2009;49(2):646–57.

    PubMed  CAS  Google Scholar 

  70. Zhang JY, Zhang Z, Lin F, et al. Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology. 2010;51(1):81–91.

    PubMed  CAS  Google Scholar 

  71. Popp FC, Piso P, Schlitt HJ, Dahlke MH. Therapeutic potential of bone marrow stem cells for liver diseases. Curr Stem Cell Res Ther. 2006;1(3):411–8.

    PubMed  CAS  Google Scholar 

  72. Alison MR, Islam S, Lim S. Stem cells in liver regeneration, fibrosis and cancer: The good, the bad and the ugly. J Pathol. 2009;217(2):282–98.

    PubMed  CAS  Google Scholar 

  73. Wells RG. Cellular sources of extracellular matrix in hepatic fibrosis. Clin Liver Dis. 2008;12(4):759–68; viii.

    Google Scholar 

  74. Furze RC, Rankin SM. Neutrophil mobilization and clearance in the bone marrow. Immunology. 2008;125(3):281–8.

    PubMed  CAS  Google Scholar 

  75. Witowski J, Pawlaczyk K, Breborowicz A, et al. IL-17 stimulates intraperitoneal neutrophil infiltration through the release of GRO alpha chemokine from mesothelial cells. J Immunol. 2000;165(10):5814–21.

    PubMed  CAS  Google Scholar 

  76. Miyamoto M, Prause O, Sjostrand M, Laan M, Lotvall J, Linden A. Endogenous IL-17 as a mediator of neutrophil recruitment caused by endotoxin exposure in mouse airways. J Immunol. 2003;170(9):4665–72.

    PubMed  CAS  Google Scholar 

  77. Schwabe RF, Seki E, Brenner DA. Toll-like receptor signaling in the liver. Gastroenterology. 2006;130(6):1886–900.

    PubMed  CAS  Google Scholar 

  78. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17(1):1–14.

    PubMed  CAS  Google Scholar 

  79. Vodovotz Y, Liu S, McCloskey C, Shapiro R, Green A, Billiar TR. The hepatocyte as a microbial product-responsive cell. J Endotoxin Res. 2001;7(5):365–73.

    PubMed  CAS  Google Scholar 

  80. Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology. 2003;37(5):1043–55.

    PubMed  CAS  Google Scholar 

  81. Yumoto H, Chou HH, Takahashi Y, Davey M, Gibson 3rd FC, Genco CA. Sensitization of human aortic endothelial cells to lipopolysaccharide via regulation of toll-like receptor 4 by ­bacterial fimbria-dependent invasion. Infect Immun. 2005;73(12):8050–9.

    PubMed  CAS  Google Scholar 

  82. Matsumura T, Ito A, Takii T, Hayashi H, Onozaki K. Endotoxin and cytokine regulation of toll-like receptor (TLR) 2 and TLR4 gene expression in murine liver and hepatocytes. J Interferon Cytokine Res. 2000;20(10):915–21.

    PubMed  CAS  Google Scholar 

  83. Akira S. TLR signaling. Curr Top Microbiol Immunol. 2006;311:1–16.

    PubMed  CAS  Google Scholar 

  84. Seth RB, Sun L, Chen ZJ. Antiviral innate immunity pathways. Cell Res. 2006;16(2):141–7.

    PubMed  CAS  Google Scholar 

  85. Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303(5663):1526–9.

    PubMed  CAS  Google Scholar 

  86. Sen GC, Sarkar SN. Transcriptional signaling by double-stranded RNA: role of TLR3. Cytokine Growth Factor Rev. 2005;16(1):1–14.

    PubMed  CAS  Google Scholar 

  87. Jiang Z, Georgel P, Du X, et al. CD14 is required for MyD88-independent LPS signaling. Nat Immunol. 2005;6(6):565–70.

    PubMed  CAS  Google Scholar 

  88. Kamada N, Davies HS, Roser B. Reversal of transplantation immunity by liver grafting. Nature. 1981;292(5826):840–2.

    PubMed  CAS  Google Scholar 

  89. Lang KS, Georgiev P, Recher M, et al. Immunoprivileged status of the liver is controlled by toll-like receptor 3 signaling. J Clin Invest. 2006;116(9):2456–63.

    PubMed  CAS  Google Scholar 

  90. De Creus A, Abe M, Lau AH, Hackstein H, Raimondi G, Thomson AW. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. J Immunol. 2005;174(4):2037–45.

    PubMed  Google Scholar 

  91. Gustot T, Lemmers A, Moreno C, et al. Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology. 2006;43(5):989–1000.

    PubMed  CAS  Google Scholar 

  92. Unterholzner L, Bowie AG. The interplay between viruses and innate immune signaling: recent insights and therapeutic opportunities. Biochem Pharmacol. 2008;75(3):589–602.

    PubMed  CAS  Google Scholar 

  93. Johnson CL, Owen DM, Gale Jr M. Functional and therapeutic analysis of hepatitis C virus NS3.4A protease control of antiviral immune defense. J Biol Chem. 2007;282(14):10792–803.

    PubMed  CAS  Google Scholar 

  94. Abe T, Kaname Y, Hamamoto I, et al. Hepatitis C virus nonstructural protein 5A modulates the toll-like receptor-MyD88-dependent signaling pathway in macrophage cell lines. J Virol. 2007;81(17):8953–66.

    PubMed  CAS  Google Scholar 

  95. Takeuchi O, Akira S. MDA5/RIG-I and virus recognition. Curr Opin Immunol. 2008;20(1):17–22.

    PubMed  CAS  Google Scholar 

  96. Li K, Chen Z, Kato N, Gale Jr M, Lemon SM. Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes. J Biol Chem. 2005;280(17):16739–47.

    PubMed  CAS  Google Scholar 

  97. Franchi L, Warner N, Viani K, Nunez G. Function of nod-like receptors in microbial recognition and host defense. Immunol Rev. 2009;227(1):106–28.

    PubMed  CAS  Google Scholar 

  98. Pedra JH, Cassel SL, Sutterwala FS. Sensing pathogens and danger­ signals by the inflammasome. Curr Opin Immunol. 2009;21(1):10–6.

    PubMed  CAS  Google Scholar 

  99. Bryant C, Fitzgerald KA. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol. 2009;19(9):455–64.

    PubMed  CAS  Google Scholar 

  100. Imaeda AB, Watanabe A, Sohail MA, et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest. 2009;119(2):305–14.

    PubMed  CAS  Google Scholar 

  101. Ishibe T, Kimura A, Ishida Y, et al. Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist. Lab Invest. 2009;89(1):68–79.

    PubMed  CAS  Google Scholar 

  102. Watanabe A, Sohail MA, Gomes DA, et al. Inflammasome-mediated regulation of hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2009;296(6):G1248–57.

    PubMed  CAS  Google Scholar 

  103. Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell Signal. 2001;13(2):85–94.

    PubMed  CAS  Google Scholar 

  104. Shi L, Kishore R, McMullen MR, Nagy LE. Lipopolysaccharide stimulation of ERK1/2 increases TNF-alpha production via egr-1. Am J Physiol Cell Physiol. 2002;282(6):C1205–11.

    PubMed  CAS  Google Scholar 

  105. Kishore R, McMullen MR, Nagy LE. Stabilization of tumor necrosis factor alpha mRNA by chronic ethanol: Role of A + U-rich elements and p38 mitogen-activated protein kinase signaling pathway. J Biol Chem. 2001;276(45):41930–7.

    PubMed  CAS  Google Scholar 

  106. Schattenberg JM, Singh R, Wang Y, et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology. 2006;43(1):163–72.

    PubMed  CAS  Google Scholar 

  107. Kodama Y, Kisseleva T, Iwaisako K, et al. c-jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis­ to steatohepatitis and fibrosis in mice. Gastroenterology. 2009;137(4):1467–77.e5.

    Google Scholar 

  108. Ghosh S. Regulation of inducible gene expression by the ­transcription factor NF-kappaB. Immunol Res. 1999;19(2–3):183–9.

    PubMed  CAS  Google Scholar 

  109. Zima T, Kalousova M. Oxidative stress and signal transduction pathways in alcoholic liver disease. Alcohol Clin Exp Res. 2005;29(11 Suppl):110S–5S.

    PubMed  CAS  Google Scholar 

  110. Schwabe RF, Brenner DA. Mechanisms of liver injury. I. ­TNF-alpha-induced liver injury: Role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G583–9.

    PubMed  CAS  Google Scholar 

  111. De Minicis S, Bataller R, Brenner DA. NADPH oxidase in the liver: Defensive, offensive, or fibrogenic? Gastroenterology. 2006;131(1):272–5.

    PubMed  Google Scholar 

  112. 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(5):1663–74.

    Google Scholar 

  113. Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology. 2008;134(6):1641–54.

    PubMed  CAS  Google Scholar 

  114. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305(5684):626–9.

    PubMed  CAS  Google Scholar 

  115. Guicciardi ME, Deussing J, Miyoshi H, et al. Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest. 2000;106(9):1127–37.

    PubMed  CAS  Google Scholar 

  116. Pastorino JG, Hoek JB. Ethanol potentiates tumor necrosis factor-alpha cytotoxicity in hepatoma cells and primary rat hepatocytes by promoting induction of the mitochondrial permeability transition. Hepatology. 2000;31(5):1141–52.

    PubMed  CAS  Google Scholar 

  117. Pianko S, Patella S, Ostapowicz G, Desmond P, Sievert W. Fas-mediated hepatocyte apoptosis is increased by hepatitis C virus infection and alcohol consumption, and may be associated with hepatic fibrosis: mechanisms of liver cell injury in chronic hepatitis C virus infection. J Viral Hepat. 2001;8(6):406–13.

    PubMed  CAS  Google Scholar 

  118. Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125(2):437–43.

    PubMed  Google Scholar 

  119. Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to fas ­mediated liver injury in mice. J Hepatol. 2003;39(6):978–83.

    PubMed  CAS  Google Scholar 

  120. Volkmann X, Fischer U, Bahr MJ, et al. Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in ­diseased human liver. Hepatology. 2007;46(5):1498–508.

    PubMed  CAS  Google Scholar 

  121. Dunn C, Brunetto M, Reynolds G, et al. Cytokines induced ­during chronic hepatitis B virus infection promote a pathway for NK ­cell-mediated liver damage. J Exp Med. 2007;204(3):667–80.

    PubMed  CAS  Google Scholar 

  122. Chen Y, Wei H, Sun R, Dong Z, Zhang J, Tian Z. Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology. 2007;46(3):706–15.

    PubMed  CAS  Google Scholar 

  123. Pulitano C, Aldrighetti L. The protective role of steroids in ischemia-reperfusion injury of the liver. Curr Pharm Des. 2008;14(5):496–503.

    PubMed  CAS  Google Scholar 

  124. Rongey C, Kaplowitz N. Current concepts and controversies in the treatment of alcoholic hepatitis. World J Gastroenterol. 2006;12(43):6909–21.

    PubMed  CAS  Google Scholar 

  125. Adam-Stitah S, Penna L, Chambon P, Rochette-Egly C. Hyperphosphorylation of the retinoid X receptor alpha by activated c-jun NH2-terminal kinases. J Biol Chem. 1999;274(27):18932–41.

    PubMed  CAS  Google Scholar 

  126. Uchimura K, Nakamuta M, Enjoji M, et al. Activation of retinoic X receptor and peroxisome proliferator-activated receptor-gamma inhibits nitric oxide and tumor necrosis factor-alpha production in rat kupffer cells. Hepatology. 2001;33(1):91–9.

    PubMed  CAS  Google Scholar 

  127. Na SY, Kang BY, Chung SW, et al. Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid­ X receptor and NFkappaB. J Biol Chem. 1999;274(12):7674–80.

    PubMed  CAS  Google Scholar 

  128. Bensinger SJ, Tontonoz P. Integration of metabolism and ­inflammation by lipid-activated nuclear receptors. Nature. 2008;454(7203):470–7.

    PubMed  CAS  Google Scholar 

  129. Rosen ED, Spiegelman BM. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem. 2001;276(41):37731–4.

    PubMed  CAS  Google Scholar 

  130. Tsai YS, Maeda N. PPARgamma: a critical determinant of body fat distribution in humans and mice. Trends Cardiovasc Med. 2005;15(3):81–5.

    PubMed  CAS  Google Scholar 

  131. Gervois P, Torra IP, Fruchart JC, Staels B. Regulation of lipid and lipoprotein metabolism by PPAR activators. Clin Chem Lab Med. 2000;38(1):3–11.

    PubMed  CAS  Google Scholar 

  132. Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem. 2000;275(47):36703–7.

    PubMed  CAS  Google Scholar 

  133. Dubuquoy L, Louvet A, Hollebecque A, Mathurin P, Dharancy S. Peroxisome proliferator-activated receptors in HBV-related infection. PPAR Res. 2009;2009:145124.

    PubMed  Google Scholar 

  134. de Gottardi A, Pazienza V, Pugnale P, et al. Peroxisome proliferator-activated receptor-alpha and -gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection. Aliment Pharmacol Ther. 2006;23(1):107–14.

    PubMed  Google Scholar 

  135. Chang F, Jaber LA, Berlie HD, O’Connell MB. Evolution of peroxisome proliferator-activated receptor agonists. Ann Pharmacother. 2007;41(6):973–83.

    PubMed  CAS  Google Scholar 

  136. Okazaki T, Honjo T. PD-1 and PD-1 ligands: From discovery to clinical application. Int Immunol. 2007;19(7):813–24.

    PubMed  CAS  Google Scholar 

  137. Dolganiuc A, Paek E, Kodys K, Thomas J, Szabo G. Myeloid dendritic cells of patients with chronic HCV infection induce proliferation of regulatory T lymphocytes. Gastroenterology. 2008;135(6):2119–27.

    PubMed  CAS  Google Scholar 

  138. Kassel R, Cruise MW, Iezzoni JC, Taylor NA, Pruett TL, Hahn YS. Chronically inflamed livers up-regulate expression of inhibitory B7 family members. Hepatology. 2009;50(5):1625–37.

    PubMed  Google Scholar 

  139. Muriel P. Role of free radicals in liver diseases. Hepatol Int. 2009;3(4):526–536.

    Google Scholar 

  140. Wu D, Cederbaum AI. Oxidative stress and alcoholic liver disease. Semin Liver Dis. 2009;29(2):141–54.

    PubMed  CAS  Google Scholar 

  141. De Minicis S, Brenner DA. Oxidative stress in alcoholic liver disease: role of NADPH oxidase complex. J Gastroenterol Hepatol. 2008;23 Suppl 1:S98–103.

    PubMed  Google Scholar 

  142. Kono H, Bradford BU, Rusyn I, et al. Development of an intragastric enteral model in the mouse: studies of alcohol-induced liver disease using knockout technology. J Hepatobiliary Pancreat Surg. 2000;7(4):395–400.

    PubMed  CAS  Google Scholar 

  143. De Minicis S, Brenner DA. NOX in liver fibrosis. Arch Biochem Biophys. 2007;462(2):266–72.

    PubMed  Google Scholar 

  144. Shinohara M, Ybanez MD, Win S, et al. Silencing glycogen synthase kinase-3{beta} inhibits acetaminophen hepatotoxicity and attenuates JNK activation and loss of glutamate cysteine ligase and myeloid cell leukemia sequence 1. J Biol Chem. 2010;285(11):8244–8255.

    Google Scholar 

  145. Mahmood S, Kawanaka M, Kamei A, et al. Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C. Antioxid Redox Signal. 2004;6(1):19–24.

    PubMed  CAS  Google Scholar 

  146. Li Y, Boehning DF, Qian T, Popov VL, Weinman SA. Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. FASEB J. 2007;21(10):2474–85.

    PubMed  CAS  Google Scholar 

  147. Pennington HL, Wilce PA, Worrall S. Chemokine and cell adhesion molecule mRNA expression and neutrophil infiltration in lipopolysaccharide-induced hepatitis in ethanol-fed rats. Alcohol Clin Exp Res. 1998;22(8):1713–8.

    PubMed  CAS  Google Scholar 

  148. Jaeschke H, Farhood A, Fisher MA, Smith CW. Sequestration of neutrophils in the hepatic vasculature during endotoxemia is independent of beta 2 integrins and intercellular adhesion molecule-1. Shock. 1996;6(5):351–6.

    PubMed  CAS  Google Scholar 

  149. Lalor PF, Shields P, Grant A, Adams DH. Recruitment of lymphocytes to the human liver. Immunol Cell Biol. 2002;80(1):52–64.

    PubMed  CAS  Google Scholar 

  150. Oo YH, Adams DH. The role of chemokines in the recruitment of lymphocytes to the liver. J Autoimmun. 2010;34(1):45–54.

    PubMed  CAS  Google Scholar 

  151. Jaeschke H. Mechanisms of liver injury. II. mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions. Am J Physiol Gastrointest Liver Physiol. 2006;290(6):G1083–8.

    PubMed  CAS  Google Scholar 

  152. Karlmark KR, Wasmuth HE, Trautwein C, Tacke F. Chemokine-directed immune cell infiltration in acute and chronic liver disease. Expert Rev Gastroenterol Hepatol. 2008;2(2):233–42.

    PubMed  CAS  Google Scholar 

  153. Seki E, De Minicis S, Gwak GY, et al. CCR1 and CCR5 promote hepatic fibrosis in mice. J Clin Invest. 2009;119(7):1858–70.

    PubMed  CAS  Google Scholar 

  154. Seki E, de Minicis S, Inokuchi S, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50(1):185–97.

    PubMed  CAS  Google Scholar 

  155. Diehl AM. Cytokine regulation of liver injury and repair. Immunol Rev. 2000;174:160–71.

    PubMed  CAS  Google Scholar 

  156. McClain CJ, Hill DB, Song Z, Deaciuc I, Barve S. Monocyte activation in alcoholic liver disease. Alcohol. 2002;27(1):53–61.

    PubMed  CAS  Google Scholar 

  157. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48(2):206–11.

    PubMed  CAS  Google Scholar 

  158. Tomita K, Tamiya G, Ando S, et al. Tumour necrosis factor alpha signalling through activation of kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut. 2006;55(3):415–24.

    PubMed  CAS  Google Scholar 

  159. Menon KV, Stadheim L, Kamath PS, et al. A pilot study of the safety and tolerability of etanercept in patients with alcoholic hepatitis. Am J Gastroenterol. 2004;99(2):255–60.

    PubMed  CAS  Google Scholar 

  160. Luedde T, Trautwein C. Intracellular survival pathways in the liver. Liver Int. 2006;26(10):1163–74.

    PubMed  CAS  Google Scholar 

  161. Trautwein C, Boker K, Manns MP. Hepatocyte and immune system: Acute phase reaction as a contribution to early defence mechanisms. Gut. 1994;35(9):1163–6.

    PubMed  CAS  Google Scholar 

  162. Streetz KL, Tacke F, Leifeld L, et al. Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases. Hepatology. 2003;38(1):218–29.

    PubMed  CAS  Google Scholar 

  163. Klein C, Wustefeld T, Assmus U, et al. The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. J Clin Invest. 2005;115(4):860–9.

    PubMed  CAS  Google Scholar 

  164. Sun Z, Klein AS, Radaeva S, et al. In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats. Gastroenterology. 2003;125(1):202–15.

    PubMed  CAS  Google Scholar 

  165. Aberle JH, Formann E, Steindl-Munda P, et al. Prospective study of viral clearance and CD4(+) T-cell response in acute hepatitis C primary infection and reinfection. J Clin Virol. 2006;36(1):24–31.

    PubMed  CAS  Google Scholar 

  166. Fujimoto T, Tomimatsu M, Iga D, Endo H, Otsuka K. Changes in the Th1/Th2 ratio during a 24-week course of an interferon alpha-2b plus ribavirin combination therapy for patients with chronic hepatitis C. J Gastroenterol Hepatol. 2008;23(8 Pt 2):e432–7.

    PubMed  CAS  Google Scholar 

  167. de Vries JE. Immunosuppressive and anti-inflammatory properties of interleukin 10. Ann Med. 1995;27(5):537–41.

    PubMed  Google Scholar 

  168. Louis H, Le Moine O, Goldman M, Deviere J. Modulation of liver injury by interleukin-10. Acta Gastroenterol Belg. 2003;66(1):7–14.

    PubMed  CAS  Google Scholar 

  169. Lau AH, Szabo G, Thomson AW. Antigen-presenting cells under the influence of alcohol. Trends Immunol. 2009;30(1):13–22.

    PubMed  CAS  Google Scholar 

  170. Szabo G, Mandrekar P. A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res. 2009;33(2):220–32.

    PubMed  CAS  Google Scholar 

  171. Parsons CJ, Takashima M, Rippe RA. Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol. 2007;22 Suppl 1:S79–84.

    PubMed  CAS  Google Scholar 

  172. Marra F, Bertolani C. Adipokines in liver diseases. Hepatology. 2009;50(3):957–69.

    PubMed  CAS  Google Scholar 

  173. Tomita K, Azuma T, Kitamura N, et al. Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through suppression of metallothionein. Am J Physiol Gastrointest Liver Physiol. 2004;287(5):G1078–85.

    PubMed  CAS  Google Scholar 

  174. Balasubramaniyan V, Murugaiyan G, Shukla R, Bhonde RR, Nalini N. Leptin downregulates ethanol-induced secretion of proinflammatory cytokines and growth factor. Cytokine. 2007;37(1):96–100.

    PubMed  CAS  Google Scholar 

  175. Leclercq IA, Field J, Farrell GC. Leptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury. Gastroenterology. 2003;124(5):1451–64.

    PubMed  CAS  Google Scholar 

  176. Kitade M, Yoshiji H, Kojima H, et al. Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. Hepatology. 2006;44(4):983–91.

    PubMed  CAS  Google Scholar 

  177. Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol. 2006;101(11):2629–40.

    PubMed  CAS  Google Scholar 

  178. Esposito K, Pontillo A, Di Palo C, et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA. 2003;289(14):1799–804.

    PubMed  CAS  Google Scholar 

  179. You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology. 2005;42(3):568–77.

    PubMed  CAS  Google Scholar 

  180. Song Z, Zhou Z, Deaciuc I, Chen T, McClain CJ. Inhibition of adiponectin production by homocysteine: A potential mechanism for alcoholic liver disease. Hepatology. 2008;47(3):867–79.

    PubMed  CAS  Google Scholar 

  181. Masaki T, Chiba S, Tatsukawa H, et al. Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-ay obese mice. Hepatology. 2004;40(1):177–84.

    PubMed  CAS  Google Scholar 

  182. Singhal NS, Patel RT, Qi Y, Lee YS, Ahima RS. Loss of resistin ameliorates hyperlipidemia and hepatic steatosis in leptin-deficient mice. Am J Physiol Endocrinol Metab. 2008;295(2):E331–8.

    PubMed  CAS  Google Scholar 

  183. Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ. Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem Biophys Res Commun. 2005;334(4):1092–101.

    PubMed  CAS  Google Scholar 

  184. Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol. 2005;174(9):5789–95.

    PubMed  CAS  Google Scholar 

  185. Bertolani C, Sancho-Bru P, Failli P, et al. Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am J Pathol. 2006;169(6):2042–53.

    PubMed  CAS  Google Scholar 

  186. Kisseleva T, Brenner DA. Hepatic stellate cells and the reversal of fibrosis. J Gastroenterol Hepatol. 2006;21 Suppl 3:S84–7.

    PubMed  CAS  Google Scholar 

  187. Connolly MK, Bedrosian AS, Mallen-St Clair J, et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J Clin Invest. 2009;119(11):3213–25.

    PubMed  CAS  Google Scholar 

  188. Park O, Jeong WI, Wang L, et al. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology. 2009;49(5):1683–94.

    PubMed  CAS  Google Scholar 

  189. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–6.

    PubMed  CAS  Google Scholar 

  190. Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA. Inflammation and liver cancer: New molecular links. Ann N Y Acad Sci. 2009;1155:206–21.

    PubMed  CAS  Google Scholar 

  191. Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology. 010;51(1):154–64.

    PubMed  CAS  Google Scholar 

  192. Hallam S, Escorcio-Correia M, Soper R, Schultheiss A, Hagemann T. Activated macrophages in the tumour microenvironment-dancing to the tune of TLR and NF-kappaB. J Pathol. 2009;219(2):143–52.

    PubMed  CAS  Google Scholar 

  193. Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121(7):977–90.

    PubMed  CAS  Google Scholar 

  194. Machida K, Tsukamoto H, Mkrtchyan H, et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker nanog. Proc Natl Acad Sci U S A. 2009;106(5):1548–53.

    PubMed  CAS  Google Scholar 

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Mandrekar, P., Szabo, G. (2011). Inflammation and Liver Injury. In: Monga, S. (eds) Molecular Pathology of Liver Diseases. Molecular Pathology Library, vol 5. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7107-4_27

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