Skip to main content
SpringerLink
Log in

Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity

  • Drug-induced Liver Injury (X Ma, Section Editor)
  • Published:
Current Pharmacology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This article provides a brief overview of mechanisms of inflammatory liver injury and how this applies to drug hepatotoxicity with a particular emphasis on the role of inflammation in acetaminophen-induced liver injury.

Recent Findings

Significant progress has been made in the last decade in our understanding of the initiation of sterile inflammation after necrotic cell death by the release of damage-associated molecular patterns and their recognition by toll-like receptors and others on macrophages. These events trigger the formation of cytokines and chemokines directly or with assistance of inflammasome activation thereby activating and recruiting leukocytes including neutrophils and monocyte-derived macrophages into the necrotic areas. Although this sterile inflammatory response is mainly geared towards the removal of necrotic cell debris and preparation of regeneration, there are conditions where these innate immune cells can aggravate the initial injury. The mechanisms and controversial findings of the innate immunity are being discussed in detail. In contrast, drug metabolism and formation of a reactive metabolite that binds to proteins in the absence of extensive cell death can induce an adaptive immune response, which eventually also results in severe liver injury. However, the initiating event appears to be the formation of protein adducts, which act as haptens to activate an adaptive immune response. Overall, these mechanisms are less well understood.

Summary

The past decade has revolutionized our understanding of the mechanisms that control the interplay between cell death and innate or adaptive immune responses. This report provides an update on these mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. Woolbright BL, Jaeschke H. The impact of sterile inflammation in acute liver injury. J Clin Transl Res. 2017;3(Suppl 1):170–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Jaeschke H, Woolbright BL. Current strategies to minimize hepatic ischemia–reperfusion injury by targeting reactive oxygen species. Transplant Rev (Orlando). 2012;26(2):103–14.

    Article  Google Scholar 

  3. McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res. 2013;30(9):2174–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. •• Mak A, Kato R, Weston K, Hayes A, Uetrecht J. Editor’s highlight: an impaired immune tolerance animal model distinguishes the potential of troglitazone/pioglitazone and tolcapone/entacapone to cause IDILI. Toxicol Sci. 2018;161(2):412–20. First demonstration that immune tolerance impairment might mediate differences in DILI in similar drug types.

    Article  PubMed  Google Scholar 

  5. Jaeschke H. Acetaminophen: dose-dependent drug hepatotoxicity and acute liver failure in patients. Dig Dis. 2015;33(4):464–71.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jaeschke H, Naisbitt DJ. Immune mechanisms in drug-induced liver injury. In: Drug-induced liver toxicity, Chen, M. and Will, Y. (eds.), 1st edn. Humana Press, New York, pp. 511–531, 2018.

    Google Scholar 

  7. Kim SH, Naisbitt DJ. Update on advances in research on idiosyncratic drug-induced liver injury. Allergy Asthma Immunol Res. 2016;8(1):3–11.

    Article  CAS  PubMed  Google Scholar 

  8. Tschopp J, Martinon F, Burns K. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol. 2003;4(2):95–104.

    Article  CAS  PubMed  Google Scholar 

  9. Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR, et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev. 2007;220:60–81.

    Article  CAS  PubMed  Google Scholar 

  10. Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012 Nov;143(5):1158–72.

    Article  CAS  PubMed  Google Scholar 

  11. Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P, et al. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology. 2014;3(9):e955691.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20.

    Article  CAS  PubMed  Google Scholar 

  13. • Woolbright BL, Jaeschke H. Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J Hepatol. 2017;66(4):836–48. Recent review fully examining conflicts in the role of the inflammasome in APAP induced liver injury.

    Article  CAS  PubMed  Google Scholar 

  14. • Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407–20. Landmark review on the inflammasome from leading authors.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Vince JE, Silke J. The intersection of cell death and inflammasome activation. Cell Mol Life Sci. 2016;73(11–12):2349–67.

    Article  CAS  PubMed  Google Scholar 

  17. Jaeschke H, Farhood A, Bautista AP, Spolarics Z, Spitzer JJ. Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am J Phys. 1993;264(4 Pt 1):G801–9.

    CAS  Google Scholar 

  18. Ju C, Reilly TP, Bourdi M, Radonovich MF, Brady JN, George JW, et al. Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol. 2002;15(12):1504–13.

    Article  CAS  PubMed  Google Scholar 

  19. Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG. Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology. 1994;20(2):453–60.

    Article  CAS  PubMed  Google Scholar 

  20. Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am J Phys. 1991;260(3 Pt 1):G355–62.

    CAS  Google Scholar 

  21. Jaeschke H, Bautista AP, Spolarics Z, Spitzer JJ. Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia. Free Radic Res Commun. 1991;15(5):277–84.

    Article  CAS  PubMed  Google Scholar 

  22. Witthaut R, Farhood A, Smith CW, Jaeschke H. Complement and tumor necrosis factor-alpha contribute to Mac-1 (CD11b/CD18) up-regulation and systemic neutrophil activation during endotoxemia in vivo. J Leukoc Biol. 1994;55(1):105–11.

    Article  CAS  PubMed  Google Scholar 

  23. Pfeffer K, Matsuyama T, Kündig TM, Wakeham A, Kishihara K, Shahinian A, et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993;73(3):457–67.

    Article  CAS  PubMed  Google Scholar 

  24. Colletti LM, Remick DG, Burtch GD, Kunkel SL, Strieter RM, Campbell DA Jr. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest. 1990;85(6):1936–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol. 2011;26(Suppl 1):173–9.

    Article  CAS  PubMed  Google Scholar 

  27. Taïeb J, Mathurin P, Elbim C, Cluzel P, Arce-Vicioso M, Bernard B, et al. Blood neutrophil functions and cytokine release in severe alcoholic hepatitis: effect of corticosteroids. J Hepatol. 2000;32(4):579–86.

    Article  PubMed  Google Scholar 

  28. Antoniades CG, Quaglia A, Taams LS, Mitry RR, Hussain M, Abeles R, et al. Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans. Hepatology. 2012;56(2):735–46.

    Article  CAS  PubMed  Google Scholar 

  29. Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T, et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology. 2016;64(5):1667–82.

    Article  CAS  PubMed  Google Scholar 

  30. Hasegawa T, Malle E, Farhood A, Jaeschke H. Generation of hypochlorite-modified proteins by neutrophils during ischemia–reperfusion injury in rat liver: attenuation by ischemic preconditioning. Am J Physiol Gastrointest Liver Physiol. 2005;289(4):G760–7.

    Article  CAS  PubMed  Google Scholar 

  31. Jaeschke H, Williams CD, Ramachandran A, Bajt ML. Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int. 2012;32(1):8–20.

    Article  CAS  PubMed  Google Scholar 

  32. Lee WM. Drug-induced acute liver failure. Clin Liver Dis. 2013;17(4):575–86.

    Article  PubMed  Google Scholar 

  33. Corcoran GB, Mitchell JR, Vaishnav YN, Horning EC. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinoneimine. Mol Pharmacol. 1980;18(3):536–42.

    CAS  PubMed  Google Scholar 

  34. Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther. 1973;187(1):211–7.

    CAS  PubMed  Google Scholar 

  35. McGill MR, Lebofsky M, Norris HR, Slawson MH, Bajt ML, Xie Y, et al. Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose–response, mechanisms, and clinical implications. Toxicol Appl Pharmacol. 2013;269(3):240–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xie Y, McGill MR, Dorko K, Kumer SC, Schmitt TM, Forster J, et al. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. Toxicol Appl Pharmacol. 2014;279(3):266–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Xie Y, McGill MR, Cook SF, Sharpe MR, Winefield RD, Wilkins DG, et al. Time course of acetaminophen-protein adducts and acetaminophen metabolites in circulation of overdose patients and in HepaRG cells. Xenobiotica. 2015;45(10):921–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xie Y, McGill MR, Du K, Dorko K, Kumer SC, Schmitt TM, et al. Mitochondrial protein adducts formation and mitochondrial dysfunction during N-acetyl-m-aminophenol (AMAP)-induced hepatotoxicity in primary human hepatocytes. Toxicol Appl Pharmacol. 2015;289(2):213–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Akakpo JY, Ramachandran A, Kandel SE, Ni HM, Kumer SC, Rumack BH, et al. 4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes. Human Exp Toxicol. 2018; in press

  40. • Kaplowitz N, Win S, Than TA, Liu ZX, Dara L. Targeting signal transduction pathways which regulate necrosis in acetaminophen hepatotoxicity. J Hepatol. 2015;63(1):5–7. Signature review on mechanisms of regulated necrosis in APAP induced liver injury.

    Article  CAS  PubMed  Google Scholar 

  41. • Du K, Ramachandran A, Jaeschke H. Oxidative stress during acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential. Redox Biol. 2016;10:148–56. Authoritative review on the role of oxidative stress in APAP overdose.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Du K, Farhood A, Jaeschke H. Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity. Arch Toxicol. 2017;91(2):761–73.

    Article  CAS  PubMed  Google Scholar 

  43. Bajt ML, Farhood A, Lemasters JJ, Jaeschke H. Mitochondrial bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther. 2008;324(1):8–14.

    Article  CAS  PubMed  Google Scholar 

  44. Bajt ML, Cover C, Lemasters JJ, Jaeschke H. Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Toxicol Sci. 2006;94(1):217–25.

    Article  CAS  PubMed  Google Scholar 

  45. Kon K, Kim JS, Jaeschke H, Lemasters JJ. Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology. 2004;40(5):1170–9.

    Article  CAS  PubMed  Google Scholar 

  46. Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H. Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol Sci. 2002;67(2):322–8.

    Article  CAS  PubMed  Google Scholar 

  47. Chao X, Wang H, Jaeschke H, Ding WX. Role and mechanisms of autophagy in acetaminophen-induced liver injury. Liver Int. 2018 Apr 23; https://doi.org/10.1111/liv.13866.

    Article  CAS  PubMed  Google Scholar 

  48. • Du K, Ramachandran A, MR MG, Mansouri A, Asselah T, Farhood A, et al. Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food Chem Toxicol. 2017 Oct;108(Pt A):339–50. First demonstration of the role of mitochondrial biogenesis in APAP overdose.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 2012;122(4):1574–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Antoine DJ, Jenkins RE, Dear JW, Williams DP, McGill MR, Sharpe MR, et al. Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J Hepatol. 2012;56(5):1070–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Laskin DL, Gardner CR, Price VF, Jollow DJ. Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology. 1995;21(4):1045–50.

    Article  CAS  PubMed  Google Scholar 

  52. Holt MP, Cheng L, Ju C. Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury. J Leukoc Biol. 2008;84(6):1410–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zigmond E, Samia-Grinberg S, Pasmanik-Chor M, Brazowski E, Shibolet O, Halpern Z, et al. Infiltrating monocyte-derived macrophages and resident Kupffer cells display different ontogeny and functions in acute liver injury. J Immunol. 2014;193(1):344–53.

    Article  CAS  PubMed  Google Scholar 

  54. James LP, McCullough SS, Knight TR, Jaeschke H, Hinson JA. Acetaminophen toxicity in mice lacking NADPH oxidase activity: role of peroxynitrite formation and mitochondrial oxidant stress. Free Radic Res. 2003;37(12):1289–97.

    Article  CAS  PubMed  Google Scholar 

  55. Williams CD, Bajt ML, Sharpe MR, McGill MR, Farhood A, Jaeschke H. Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans. Toxicol Appl Pharmacol. 2014;275(2):122–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dambach DM, Watson LM, Gray KR, Durham SK, Laskin DL. Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse. Hepatology. 2002;35(5):1093–103.

    Article  CAS  PubMed  Google Scholar 

  57. •• Zhang C, Feng J, Du J, Zhuo Z, Yang S, Zhang W, et al. Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity. Cell Mol Immunol. 2017; https://doi.org/10.1038/cmi.2017.22. Important paper discussing the implications of inflammatory cell death and alarmin release.

  58. • Perugorria MJ, Esparza-Baquer A, Oakley F, Labiano I, Korosec A, Jais A, Mann J, Tiniakos D, Santos-Laso A, Arbelaiz A, Gawish R, Sampedro A, Fontanellas A, Hijona E, Jimenez-Agüero R, Esterbauer H, Stoiber D, Bujanda L, Banales JM, Knapp S, Sharif O, Mann DA. Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage. Gut 2018. Recent publication on a potential role for TREM2 in the control macrophages of macrophage-mediated liver injury.

  59. Antoniades CG, Khamri W, Abeles RD, Taams LS, Triantafyllou E, Possamai LA, et al. Secretory leukocyte protease inhibitor: a pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure. Hepatology. 2014;59(4):1564–76.

    Article  CAS  PubMed  Google Scholar 

  60. •• Graubardt N, Vugman M, Mouhadeb O, Caliari G, Pasmanik-Chor M, Reuveni D, et al. Ly6Chi monocytes and their macrophage descendants regulate neutrophil function and clearance in acetaminophen-induced liver injury. Front Immunol. 2017;8:626. Recent publication emphasizing a bi-phasic role for macrophages in neutrophil activation and wound healing after APAP overdose.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. •• Triantafyllou E, Pop OT, Possamai LA, Wilhelm A, Liaskou E, Singanayagam A, et al. MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure. Gut. 2018;67(2):333–47. Signature paper on a role for macrophage mediated wound resolution after APAP overdose in patients.

    Article  PubMed  Google Scholar 

  62. Stutchfield BM, Antoine DJ, Mackinnon AC, Gow DJ, Bain CC, Hawley CA, et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology. 2015;149(7):1896–909.e14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Moore JK, MacKinnon AC, Man TY, Manning JR, Forbes SJ, Simpson KJ. Patients with the worst outcomes after paracetamol (acetaminophen)-induced liver failure have an early monocytopenia. Aliment Pharmacol Ther. 2017;45(3):443–54.

    Article  CAS  PubMed  Google Scholar 

  64. Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology. 2004;127(6):1760–74.

    Article  CAS  PubMed  Google Scholar 

  65. Huebener P, Pradere JP, Hernandez C, Gwak GY, Caviglia JM, Mu X, et al. The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis. J Clin Invest. 2015;125(2):539–50.

    Article  PubMed  Google Scholar 

  66. Lawson JA, Farhood A, Hopper RD, Bajt ML, Jaeschke H. The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci. 2000;54(2):509–16.

    Article  CAS  PubMed  Google Scholar 

  67. Cover C, Liu J, Farhood A, Malle E, Waalkes MP, Bajt ML, et al. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol. 2006;216(1):98–107.

    Article  CAS  PubMed  Google Scholar 

  68. Williams CD, Bajt ML, Farhood A, Jaeschke H. Acetaminophen-induced hepatic neutrophil accumulation and inflammatory liver injury in CD18-deficient mice. Liver Int. 2010;30(9):1280–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gujral JS, Hinson JA, Farhood A, Jaeschke H. NADPH oxidase-derived oxidant stress is critical for neutrophil cytotoxicity during endotoxemia. Am J Physiol Gastrointest Liver Physiol. 2004;287(1):G243–52.

    Article  CAS  PubMed  Google Scholar 

  70. Jaeschke H. Molecular mechanisms of hepatic ischemia–reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol. 2003;284(1):G15–26.

    Article  CAS  PubMed  Google Scholar 

  71. Williams CD, Antoine DJ, Shaw PJ, Benson C, Farhood A, Williams DP, et al. Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury. Toxicol Appl Pharmacol. 2011;252(3):289–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Williams CD, Farhood A, Jaeschke H. Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury. Toxicol Appl Pharmacol. 2010;247(3):169–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jaeschke H, Liu J. Neutrophil depletion protects against murine acetaminophen hepatotoxicity: another perspective. Hepatology. 2007;45(6):1588–9.

    Article  PubMed  Google Scholar 

  74. James LP, Simpson PM, Farrar HC, Kearns GL, Wasserman GS, Blumer JL, et al. Cytokines and toxicity in acetaminophen overdose. J Clin Pharmacol. 2005;45(10):1165–71.

    Article  CAS  PubMed  Google Scholar 

  75. Berry PA, Antoniades CG, Hussain MJ, McPhail MJ, Bernal W, Vergani D, et al. Admission levels and early changes in serum interleukin-10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis. Liver Int. 2010;30(5):733–40.

    Article  CAS  PubMed  Google Scholar 

  76. Bourdi M, Masubuchi Y, Reilly TP, Amouzadeh HR, Martin JL, George JW, et al. Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology. 2002;35(2):289–98.

    Article  CAS  PubMed  Google Scholar 

  77. Kleinschmidt D, Giannou AD, McGee HM, Kempski J, Steglich B, Huber FJ, et al. A protective function of IL-22BP in ischemia reperfusion and acetaminophen-induced liver injury. J Immunol. 2017;199(12):4078–90.

    Article  CAS  PubMed  Google Scholar 

  78. Feng D, Wang Y, Wang H, Weng H, Kong X, Martin-Murphy BV, et al. Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. J Immunol. 2014;193(5):2512–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. James LP, Lamps LW, McCullough S, Hinson JA. Interleukin 6 and hepatocyte regeneration in acetaminophen toxicity in the mouse. Biochem Biophys Res Commun. 2003;309(4):857–63.

    Article  CAS  PubMed  Google Scholar 

  80. Bajt ML, Knight TR, Farhood A, Jaeschke H. Scavenging peroxynitrite with glutathione promotes regeneration and enhances survival during acetaminophen-induced liver injury in mice. J Pharmacol Exp Ther. 2003;307(1):67–73.

    Article  CAS  PubMed  Google Scholar 

  81. Moore JK, Craig DG, Pryde EA, Walker SW, Beckett GJ, Hayes PC, et al. Persistently elevated troponin I in paracetamol hepatotoxicity: association with liver injury, organ failure, and outcome. Clin Toxicol (Phila). 2013;51(7):532–9.

    Article  CAS  Google Scholar 

  82. Bourdi M, Eiras DP, Holt MP, Webster MR, Reilly TP, Welch KD, et al. Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury. Chem Res Toxicol. 2007;20(2):208–16.

    Article  CAS  PubMed  Google Scholar 

  83. Ryan PM, Bourdi M, Korrapati MC, Proctor WR, Vasquez RA, Yee SB, et al. Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice. Chem Res Toxicol. 2012;25(1):83–93.

    Article  CAS  PubMed  Google Scholar 

  84. Lagadic-Gossmann D, Lerche C, Rissel M, Joannard F, Galisteo M, Guillouzo A, et al. The induction of the human hepatic CYP2E1 gene by interleukin 4 is transcriptional and regulated by protein kinase C. Cell Biol Toxicol. 2000;16(4):221–33.

    Article  CAS  PubMed  Google Scholar 

  85. Yee SB, Bourdi M, Masson MJ, Pohl LR. Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease. Chem Res Toxicol. 2007;20(5):734–44.

    Article  CAS  PubMed  Google Scholar 

  86. Lee HC, Liao CC, Day YJ, Liou JT, Li AH, Liu FC. IL-17 deficiency attenuates acetaminophen-induced hepatotoxicity in mice. Toxicol Lett. 2018;292:20–30.

    Article  CAS  PubMed  Google Scholar 

  87. Stutchfield BM, Antoine DJ, Mackinnon AC, Gow DJ, Bain CC, Hawley CA, et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology. 2015;149(7):1896–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Tujios SR, Lee WM. Acute liver failure induced by idiosyncratic reaction to drugs: challenges in diagnosis and therapy. Liver Int. 2018;38(1):6–14.

    Article  PubMed  Google Scholar 

  89. Proctor WR, Chakraborty M, Chea LS, Morrison JC, Berkson JD, Semple K, et al. Eosinophils mediate the pathogenesis of halothane-induced liver injury in mice. Hepatology. 2013;57(5):2026–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yano A, Higuchi S, Tsuneyama K, Fukami T, Nakajima M, Yokoi T. Involvement of immune-related factors in diclofenac-induced acute liver injury in mice. Toxicology. 2012;293(1–3):107–14.

    Article  CAS  PubMed  Google Scholar 

  91. Oker-Blom C, Mäkinen J, Gothoni G. Toxicological studies on tienilic acid in rats. Toxicol Lett. 1980;6(2):93–9.

    Article  CAS  PubMed  Google Scholar 

  92. Pariente EA, Pessayre D, Bernuau J, Degott C, Benhamou JP. Dihydralazine hepatitis: report of a case and review of the literature. Digestion. 1983;27(1):47–52.

    Article  CAS  PubMed  Google Scholar 

  93. Li F, Lu J, Cheng J, Wang L, Matsubara T, Csanaky IL, et al. Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy. Nat Med. 2013;19(4):418–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Metushi IG, Hayes MA, Uetrecht J. Treatment of PD-1(−/−) mice with amodiaquine and anti-CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients. Hepatology. 2015;61(4):1332–42.

    Article  CAS  PubMed  Google Scholar 

  95. Wuillemin N, Terracciano L, Beltraminelli H, Schlapbach C, Fontana S, Krähenbühl S, et al. T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury. Am J Pathol. 2014;184(6):1677–82.

    Article  CAS  PubMed  Google Scholar 

  96. •• Cho T, Uetrecht J. How reactive metabolites induce an immune response that sometimes leads to an idiosyncratic drug reaction. Chem Res Toxicol. 2017;30(1):295–314. Recent review on mechanisms of idiosyncratice liver disease initiated by reactive metabolite formation.

    Article  CAS  PubMed  Google Scholar 

  97. Uetrecht J. Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol. 2008;21(1):84–92.

    Article  CAS  PubMed  Google Scholar 

  98. Pohl LR, Kenna JG, Satoh H, Christ D, Martin JL. Neoantigens associated with halothane hepatitis. Drug Metab Rev. 1989;20(2–4):203–17.

    Article  CAS  PubMed  Google Scholar 

  99. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;1:683–93.

    Article  Google Scholar 

  100. Naisbitt DJ, Farrell J, Wong G, Depta JP, Dodd CC, Hopkins JE, et al. Characterization of drug-specific T cells in lamotrigine hypersensitivity. J Allergy Clin Immunol. 2003;1:1393–403.

    Article  CAS  Google Scholar 

  101. Pichler WJ, Adam J, Watkins S, Wuillemin N, Yun J, Yerly D. Drug hypersensitivity: how drugs stimulate T cells via pharmacological interaction with immune receptors. Int Arch Allergy Immunol. 2015;168(1):13–24.

    Article  CAS  PubMed  Google Scholar 

  102. deLemos AS, Foureau DM, Jacobs C, Ahrens W, Russo MW, Bonkovsky HL. Drug-induced liver injury with autoimmune features. Semin Liver Dis. 2014;34(2):194–204.

    Article  CAS  PubMed  Google Scholar 

  103. Hintermann E, Holdener M, Bayer M, Loges S, Pfeilschifter JM, Granier C, et al. Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model. J Autoimmun. 2011;37(3):242–53.

    Article  CAS  PubMed  Google Scholar 

  104. Kitteringham NR, Kenna JG, Park BK. Detection of autoantibodies directed against human hepatic endoplasmic reticulum in sera from patients with halothane-associated hepatitis. Br J Clin Pharmacol. 1995;40(4):379–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. de Boer YS, Kosinski AS, Urban TJ, Zhao Z, Long N, Chalasani N, et al. Features of autoimmune hepatitis in patients with drug-induced liver injury. Clin Gastroenterol Hepatol. 2017;15(1):103–112.e2.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Work in the authors’ laboratory was supported in part by the National Institutes of Health grants R01 DK102142 and R01 AA12916, the Robert Hanlon Trust, and by grants from the National Institute of General Medical Sciences (P20 GM103549 and P30 GM118247) of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Urology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Benjamin L. Woolbright

  2. Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA

    Hartmut Jaeschke

Authors
  1. Benjamin L. Woolbright
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hartmut Jaeschke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hartmut Jaeschke.

Ethics declarations

Conflict of Interest

The authors have no conflict of interest to disclose.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Additional information

This article is part of the Topical Collection on Drug-induced Liver Injury

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Woolbright, B.L., Jaeschke, H. Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity. Curr Pharmacol Rep 4, 346–357 (2018). https://doi.org/10.1007/s40495-018-0147-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40495-018-0147-0

Keywords

Search

Navigation