Liver Regeneration After Acetaminophen Hepatotoxicity: Mechanisms and Therapeutic Opportunities

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2019 Jan 18

PMID 30653954

Citations 83

Authors

Bharat Bhushan

Udayan Apte

Affiliations

Soon will be listed here.

Abstract

Acetaminophen (N-acetyl-para-aminophenol; APAP) overdose is the most common cause of acute liver failure in the Western world, with limited treatment opportunities. For years, research on APAP overdose has been focused on investigating the mechanisms of hepatotoxicity, with limited success in advancing therapeutic strategies. Acute liver injury after any insult, including APAP overdose, is followed by compensatory liver regeneration, which promotes recovery and is a crucial determinant of the final outcome. Liver regeneration after APAP-induced liver injury is dose dependent and impaired after severe APAP overdose. Although robust regenerative response is associated with spontaneous recovery and survival, impaired regeneration results in faster progression of injury and death after APAP overdose. APAP hepatotoxicity-induced liver regeneration involves a complex time- and dose-dependent interplay of several signaling mediators, including growth factors, cytokines, angiogenic factors, and other mitogenic pathways. Compared with the liver injury, which is established before most patients seek medical attention and has proved difficult to manipulate, liver regeneration can be potentially modulated even in late-stage APAP-induced acute liver failure. Despite recent efforts to study the mechanisms of liver regeneration after APAP-induced liver injury, more comprehensive research in this area is required, especially regarding factors that contribute to impaired regenerative response, to develop novel regenerative therapies for APAP-induced acute liver failure.

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References

McGreal S, Bhushan B, Walesky C, McGill M, Lebofsky M, Kandel S . Modulation of O-GlcNAc Levels in the Liver Impacts Acetaminophen-Induced Liver Injury by Affecting Protein Adduct Formation and Glutathione Synthesis. Toxicol Sci. 2018; 162(2):599-610. PMC: 6012490. DOI: 10.1093/toxsci/kfy002. View

Bird T, Muller M, Boulter L, Vincent D, Ridgway R, Lopez-Guadamillas E . TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med. 2018; 10(454). PMC: 6420144. DOI: 10.1126/scitranslmed.aan1230. View

Bernal W, Wendon J . Acute liver failure. N Engl J Med. 2013; 369(26):2525-34. DOI: 10.1056/NEJMra1208937. View

Borude P, Bhushan B, Apte U . DNA Damage Response Regulates Initiation of Liver Regeneration Following Acetaminophen Overdose. Gene Expr. 2018; 18(2):115-123. PMC: 5954624. DOI: 10.3727/105221618X15205260749346. View

Torbenson M, Yang S, Liu H, Huang J, Gage W, Diehl A . STAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers. Am J Pathol. 2002; 161(1):155-61. PMC: 1850692. DOI: 10.1016/S0002-9440(10)64167-3. View

Jaeschke H, McGill M, Ramachandran A . Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev. 2012; 44(1):88-106. PMC: 5319847. DOI: 10.3109/03602532.2011.602688. View

Michalopoulos G . Liver regeneration. J Cell Physiol. 2007; 213(2):286-300. PMC: 2701258. DOI: 10.1002/jcp.21172. View

Wustefeld T, Rakemann T, Kubicka S, Manns M, Trautwein C . Hyperstimulation with interleukin 6 inhibits cell cycle progression after hepatectomy in mice. Hepatology. 2000; 32(3):514-22. DOI: 10.1053/jhep.2000.16604. View

Michalopoulos G . Hepatostat: Liver regeneration and normal liver tissue maintenance. Hepatology. 2016; 65(4):1384-1392. DOI: 10.1002/hep.28988. View

10.

Tsagianni A, Mars W, Bhushan B, Bowen W, Orr A, Stoops J . Combined Systemic Disruption of MET and Epidermal Growth Factor Receptor Signaling Causes Liver Failure in Normal Mice. Am J Pathol. 2018; 188(10):2223-2235. PMC: 6168971. DOI: 10.1016/j.ajpath.2018.06.009. View

11.

Simpson K, Hogaboam C, Kunkel S, Harrison D, Bone-Larson C, Lukacs N . Stem cell factor attenuates liver damage in a murine model of acetaminophen-induced hepatic injury. Lab Invest. 2003; 83(2):199-206. DOI: 10.1097/01.lab.0000057002.16935.84. View

12.

Papastefanou V, Bozas E, Mykoniatis M, Grypioti A, Garyfallidis S, Bartsocas C . VEGF isoforms and receptors expression throughout acute acetaminophen-induced liver injury and regeneration. Arch Toxicol. 2007; 81(10):729-41. DOI: 10.1007/s00204-007-0201-x. View

13.

Masubuchi Y, Bourdi M, Reilly T, Graf M, George J, Pohl L . Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease. Biochem Biophys Res Commun. 2003; 304(1):207-12. DOI: 10.1016/s0006-291x(03)00572-2. View

14.

Hughes R, Zhang L, Tsubouchi H, Daikuhara Y, Williams R . Plasma hepatocyte growth factor and biliprotein levels and outcome in fulminant hepatic failure. J Hepatol. 1994; 20(1):106-11. DOI: 10.1016/s0168-8278(05)80475-1. View

15.

James L, McCullough S, Lamps L, Hinson J . Effect of N-acetylcysteine on acetaminophen toxicity in mice: relationship to reactive nitrogen and cytokine formation. Toxicol Sci. 2003; 75(2):458-67. DOI: 10.1093/toxsci/kfg181. View

16.

Huang M, Williams J, Kong B, Zhu Y, Li G, Zhu Z . Fibroblast growth factor 15 deficiency increases susceptibility but does not improve repair to acetaminophen-induced liver injury in mice. Dig Liver Dis. 2017; 50(2):175-180. DOI: 10.1016/j.dld.2017.08.023. View

17.

Paranjpe S, Bowen W, Mars W, Orr A, Haynes M, DeFrances M . Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology. 2016; 64(5):1711-1724. PMC: 5074871. DOI: 10.1002/hep.28721. View

18.

Mehendale H . Tissue repair: an important determinant of final outcome of toxicant-induced injury. Toxicol Pathol. 2005; 33(1):41-51. DOI: 10.1080/01926230590881808. View

19.

James L, Kurten R, Lamps L, McCullough S, Hinson J . Tumour necrosis factor receptor 1 and hepatocyte regeneration in acetaminophen toxicity: a kinetic study of proliferating cell nuclear antigen and cytokine expression. Basic Clin Pharmacol Toxicol. 2005; 97(1):8-14. DOI: 10.1111/j.1742-7843.2005.pto_97102.x. View

20.

Chang W, Song L, Chang X, Ji M, Wang H, Qin X . Early activated hepatic stellate cell-derived paracrine molecules modulate acute liver injury and regeneration. Lab Invest. 2016; 97(3):318-328. DOI: 10.1038/labinvest.2016.130. View