Semin Liver Dis
DOI: 10.1055/a-2358-9505
Review Article

Necrotic Liver Lesion Resolution: Another Mode of Liver Regeneration

Cheng Chen
1   Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
,
Dechun Feng
1   Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
,
Yang Wang
1   Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
,
Tiantian Yao
1   Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
,
Bryan Mackowiak
1   Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
,
Bin Gao
1   Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
› Author Affiliations
Funding The work described in the authors' lab was supported by the Intramural Program of the NIAAA, NIH (B.G.).


Abstract

The liver has the great ability to regenerate after partial resection or injury, and the mechanisms underlying liver regeneration have been extensively investigated. Interestingly, acute liver injuries triggered by various etiologies are associated with the formation of necrotic lesions, and such necrotic lesions are also rapidly resolved. However, how necrotic liver lesions are repaired has not been carefully investigated until recently. In this review, we briefly summarize the spatiotemporal process of necrotic liver lesion resolution in several liver injury models including immune-mediated liver injury and drug-induced liver injury. The roles of liver nonparenchymal cells and infiltrating immune cells in controlling necrotic liver lesion resolution are discussed, which may help identify potential therapies for acute liver injury and failure.



Publication History

Accepted Manuscript online:
02 July 2024

Article published online:
11 July 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Grant DM. Detoxification pathways in the liver. J Inherit Metab Dis 1991; 14 (04) 421-430
  • 2 Losser M-R, Payen D. Mechanisms of liver damage. Semin Liver Dis 1996; 16 (04) 357-367
  • 3 D'Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 2019; 43 (06) 582-592
  • 4 Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol 2010; (196) 369-405
  • 5 Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths?. Hepatology 2006; 43 (2, Suppl 1): S31-S44
  • 6 Nagata S. Apoptosis and clearance of apoptotic cells. Annu Rev Immunol 2018; 36: 489-517
  • 7 Savitskaya MA, Onishchenko GE. Mechanisms of apoptosis. Biochemistry (Mosc) 2015; 80 (11) 1393-1405
  • 8 Arienti S, Barth ND, Dorward DA, Rossi AG, Dransfield I. Regulation of apoptotic cell clearance during resolution of inflammation. Front Pharmacol 2019; 10: 891
  • 9 Feng D, Xiang X, Guan Y. et al. Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models. J Clin Invest 2023; 133 (15) e166954
  • 10 Opie EL. Zonal necrosis of the liver. J Med Res 1904; 12 (01) 147-168.1
  • 11 Wells HG. Chloroform necrosis of the liver. Arch Intern Med 1908; I (VI): 589-601
  • 12 Davis NC, Whipple GH. The influence of drugs and chemical agents on the liver necrosis of chloroform anesthesia: paper II. Arch Intern Med 1919; 23 (05) 636-654
  • 13 Goodhart GW. Chloroform necrosis of the liver. BMJ 1910; 2 (2601): 1425-1427
  • 14 Dice WG. The indications for interference in preeclamptic toxemia. In: Transactions of the American Association of Obstetricians and Gynecologists for the Year 1918. 30:251
  • 15 Flexner S. The histological changes produced by ricin and abrin intoxications. J Exp Med 1897; 2 (02) 197-216
  • 16 Krishna M. Patterns of necrosis in liver disease. Clin Liver Dis (Hoboken) 2017; 10 (02) 53-56
  • 17 Guicciardi ME, Malhi H, Mott JL, Gores GJ. Apoptosis and necrosis in the liver. Compr Physiol 2013; 3 (02) 977-1010
  • 18 Sumner JB, Howell SF. Identification of hemagglutinin of jack bean with concanavalin A. J Bacteriol 1936; 32 (02) 227-237
  • 19 Douglas SD, Kamin RM, Fudenberg HH. Human lymphocyte response to phytomitogens in vitro: normal, agammaglobulinemic and paraproteinemic individuals. J Immunol 1969; 103 (06) 1185-1195
  • 20 Inbar M, Sachs L. Interaction of the carbohydrate-binding protein concanavalin A with normal and transformed cells. Proc Natl Acad Sci U S A 1969; 63 (04) 1418-1425
  • 21 Sharon N, Lis H. Lectins: cell-agglutinating and sugar-specific proteins. Science 1972; 177 (4053): 949-959
  • 22 Barth RF, Singla O. Differential effects of concanavalin A on T helper dependent and independent antibody responses. Cell Immunol 1973; 9 (01) 96-103
  • 23 Gantner F, Leist M, Lohse AW, Germann PG, Tiegs G. Concanavalin A-induced T-cell-mediated hepatic injury in mice: the role of tumor necrosis factor. Hepatology 1995; 21 (01) 190-198
  • 24 Miethke T, Wahl C, Heeg K, Echtenacher B, Krammer PH, Wagner H. T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of tumor necrosis factor. J Exp Med 1992; 175 (01) 91-98
  • 25 Trautwein C, Rakemann T, Brenner DA. et al. Concanavalin A-induced liver cell damage: activation of intracellular pathways triggered by tumor necrosis factor in mice. Gastroenterology 1998; 114 (05) 1035-1045
  • 26 Tyan ML. In vivo toxicity of concanavalin A. Proc Soc Exp Biol Med 1974; 146 (04) 1163-1165
  • 27 Ballegeer M, Libert C. Different cell types involved in mediating concanavalin A induced liver injury: a comprehensive overview. J Gastroenterol Hepatol Res 2016; 1 (01) 1-13
  • 28 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest 1992; 90 (01) 196-203
  • 29 Rodrigues RM, Boeckmans J, Vanhaecke T. Macrophages clear out necrotic liver lesions: a new magic trick revealed. eGastroenterology 2023; 1 (02) 1-3
  • 30 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 (04) G583-G589
  • 31 Wang Y, Rodrigues RM, Chen C, Feng D, Maccioni L, Gao B. Macrophages in necrotic liver lesion repair: opportunities for therapeutical applications. Am J Physiol Cell Physiol 2024; 326 (05) C1556-C1562
  • 32 Galvan MD, Greenlee-Wacker MC, Bohlson SS. C1q and phagocytosis: the perfect complement to a good meal. J Leukoc Biol 2012; 92 (03) 489-497
  • 33 Lee WM. Acetaminophen-related acute liver failure in the United States. Hepatol Res 2008; 38 (Suppl. 01) S3-S8
  • 34 Reuben A, Tillman H, Fontana RJ. et al. Outcomes in Adults with acute liver failure between 1998 and 2013: an observational cohort study. Ann Intern Med 2016; 164 (11) 724-732
  • 35 Boyd E-M, Bereczky GM. Liver necrosis from paracetamol. Br J Pharmacol Chemother 1966; 26 (03) 606-614
  • 36 Luyendyk JP, Morozova E, Copple BL. Good cells go bad: immune dysregulation in the transition from acute liver injury to liver failure after acetaminophen overdose. Drug Metab Dispos 2023; 52 (07) 25
  • 37 Ni HM, Williams JA, Jaeschke H, Ding WX. Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen-induced necrosis in the liver. Redox Biol 2013; 1 (01) 427-432
  • 38 Mazaleuskaya LL, Sangkuhl K, Thorn CF, FitzGerald GA, Altman RB, Klein TE. PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics 2015; 25 (08) 416-426
  • 39 Fisher K, Vuppalanchi R, Saxena R. Drug-induced liver injury. Arch Pathol Lab Med 2015; 139 (07) 876-887
  • 40 Ben-Moshe S, Veg T, Manco R. et al. The spatiotemporal program of zonal liver regeneration following acute injury. Cell Stem Cell 2022; 29 (06) 973-989.e10
  • 41 Kolodziejczyk AA, Federici S, Zmora N. et al. Acute liver failure is regulated by MYC- and microbiome-dependent programs. Nat Med 2020; 26 (12) 1899-1911
  • 42 Zigmond E, Samia-Grinberg S, Pasmanik-Chor M. et al. Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury. J Immunol 2014; 193 (01) 344-353
  • 43 Mossanen JC, Krenkel O, Ergen C. et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology 2016; 64 (05) 1667-1682
  • 44 Jaeschke H, Ramachandran A. Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity. Food Chem Toxicol 2020; 138: 111240
  • 45 Wang J, Kubes P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell 2016; 165 (03) 668-678
  • 46 Starkey Lewis P, Campana L, Aleksieva N. et al. Alternatively activated macrophages promote resolution of necrosis following acute liver injury. J Hepatol 2020; 73 (02) 349-360
  • 47 Triantafyllou E, Gudd CL, Mawhin MA. et al. PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury. J Clin Invest 2021; 131 (04) e140196
  • 48 Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol 2016; 13 (03) 316-327
  • 49 Lopes ME, Nakagaki BN, Mattos MS. et al. Susceptibility to infections during acute liver injury depends on transient disruption of liver macrophage niche. Front Immunol 2022; 13: 892114
  • 50 Matchett KP, Wilson-Kanamori JR, Portman JR. et al. Multimodal decoding of human liver regeneration. Nature 2024; 630 (8015): 158-165
  • 51 Nguyen NT, Umbaugh DS, Sanchez-Guerrero G, Ramachandran A, Jaeschke H. Kupffer cells regulate liver recovery through induction of chemokine receptor CXCR2 on hepatocytes after acetaminophen overdose in mice. Arch Toxicol 2022; 96 (01) 305-320
  • 52 Hu S, Liu S, Bian Y. et al. Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b. Cell Rep Med 2022; 3 (10) 100754
  • 53 Pritchard DJ, Wright MG, Sulsh S, Butler WH. The assessment of chemically induced liver injury in rats. J Appl Toxicol 1987; 7 (04) 229-236
  • 54 Ito Y, Watanabe T, Nagatomo S, Seki T, Niimi S, Ariga T. Annexin A3-expressing cellular phenotypes emerge from necrotic lesion in the pericentral area in 2-acetylaminofluoren/carbon tetrachloride-treated rat livers. Biosci Biotechnol Biochem 2007; 71 (12) 3082-3089
  • 55 Simeonova PP, Gallucci RM, Hulderman T. et al. The role of tumor necrosis factor-α in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride. Toxicol Appl Pharmacol 2001; 177 (02) 112-120
  • 56 Pritchard DJ, Butler WH. Apoptosis–the mechanism of cell death in dimethylnitrosamine-induced hepatotoxicity. J Pathol 1989; 158 (03) 253-260
  • 57 Ezhilarasan D. Molecular mechanisms in thioacetamide-induced acute and chronic liver injury models. Environ Toxicol Pharmacol 2023; 99: 104093
  • 58 Hossain M, Kubes P. Innate immune cells orchestrate the repair of sterile injury in the liver and beyond. Eur J Immunol 2019; 49 (06) 831-841
  • 59 McDonald B, Pittman K, Menezes GB. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 2010; 330 (6002): 362-366
  • 60 Wang J, Hossain M, Thanabalasuriar A, Gunzer M, Meininger C, Kubes P. Visualizing the function and fate of neutrophils in sterile injury and repair. Science 2017; 358 (6359): 111-116
  • 61 Dal-Secco D, Wang J, Zeng Z. et al. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J Exp Med 2015; 212 (04) 447-456
  • 62 Liew PX, Lee WY, Kubes P. iNKT cells orchestrate a switch from inflammation to resolution of sterile liver injury. Immunity 2017; 47 (04) 752-765.e5
  • 63 Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia-reperfusion injury. Am J Surg 2001; 181 (02) 160-166
  • 64 Xin J, Yang T, Wu X. et al. Spatial transcriptomics analysis of zone-dependent hepatic ischemia-reperfusion injury murine model. Commun Biol 2023; 6 (01) 194
  • 65 Konishi T, Lentsch AB. Hepatic ischemia/reperfusion: mechanisms of tissue injury, repair, and regeneration. Gene Expr 2017; 17 (04) 277-287
  • 66 Kuboki S, Shin T, Huber N. et al. Hepatocyte signaling through CXC chemokine receptor-2 is detrimental to liver recovery after ischemia/reperfusion in mice. Hepatology 2008; 48 (04) 1213-1223
  • 67 Barone S, Okaya T, Rudich S. et al. Distinct and sequential upregulation of genes regulating cell growth and cell cycle progression during hepatic ischemia-reperfusion injury. Am J Physiol Cell Physiol 2005; 289 (04) C826-C835
  • 68 Wang L, Li J, He S. et al. Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution. Cell Death Dis 2021; 12 (06) 589
  • 69 Kang JW, Lee SM. Resolvin D1 protects the liver from ischemia/reperfusion injury by enhancing M2 macrophage polarization and efferocytosis. Biochim Biophys Acta 2016; 1861 (9 Pt A): 1025-1035
  • 70 Schlegel M, Köhler D, Körner A. et al. The neuroimmune guidance cue netrin-1 controls resolution programs and promotes liver regeneration. Hepatology 2016; 63 (05) 1689-1705
  • 71 Hu H, Cheng X, Li F. et al. Defective efferocytosis by aged macrophages promotes STING signaling mediated inflammatory liver injury. Cell Death Discov 2023; 9 (01) 236
  • 72 Siu LK, Yeh KM, Lin JC, Fung CP, Chang FY. Klebsiella pneumoniae liver abscess: a new invasive syndrome. Lancet Infect Dis 2012; 12 (11) 881-887
  • 73 Chen SC, Wu WY, Yeh CH. et al. Comparison of Escherichia coli and Klebsiella pneumoniae liver abscesses. Am J Med Sci 2007; 334 (02) 97-105
  • 74 Wanford JJ, Hames RG, Carreno D. et al. Interaction of Klebsiella pneumoniae with tissue macrophages in a mouse infection model and ex-vivo pig organ perfusions: an exploratory investigation. Lancet Microbe 2021; 2 (12) e695-e703
  • 75 Guillot A, Guerri L, Feng D. et al. Bile acid-activated macrophages promote biliary epithelial cell proliferation through integrin αvβ6 upregulation following liver injury. J Clin Invest 2021; 131 (09) e132305
  • 76 Woolbright BL, Jaeschke H. Therapeutic targets for cholestatic liver injury. Expert Opin Ther Targets 2016; 20 (04) 463-475
  • 77 Mariotti V, Cadamuro M, Spirli C, Fiorotto R, Strazzabosco M, Fabris L. Animal models of cholestasis: an update on inflammatory cholangiopathies. Biochim Biophys Acta Mol Basis Dis 2019; 1865 (05) 954-964
  • 78 Ghallab A, Hofmann U, Sezgin S. et al. Bile microinfarcts in cholestasis are initiated by rupture of the apical hepatocyte membrane and cause shunting of bile to sinusoidal blood. Hepatology 2019; 69 (02) 666-683
  • 79 Heinrich S, Georgiev P, Weber A, Vergopoulos A, Graf R, Clavien PA. Partial bile duct ligation in mice: a novel model of acute cholestasis. Surgery 2011; 149 (03) 445-451
  • 80 Mackowiak B, Fu Y, Maccioni L, Gao B. Alcohol-associated liver disease. J Clin Invest 2024; 134 (03) e176345
  • 81 Cui M, Chen F, Shao L. et al. Mesenchymal stem cells and ferroptosis: clinical opportunities and challenges. Heliyon 2024; 10 (03) e25251
  • 82 Guillot A, Kohlhepp MS, Bruneau A, Heymann F, Tacke F. Deciphering the immune microenvironment on a single archival formalin-fixed paraffin-embedded tissue section by an immediately implementable multiplex fluorescence immunostaining protocol. Cancers (Basel) 2020; 12 (09) 2449
  • 83 Yasuda M, Okabe T, Itoh J. et al. Differentiation of necrotic cell death with or without lysosomal activation: application of acute liver injury models induced by carbon tetrachloride (CCL4) and dimethylnitrosamine (DMN). J Histochem Cytochem 2000; 48 (10) 1331-1339
  • 84 Tsai CF, Hsu YW, Chen WK. et al. Hepatoprotective effect of electrolyzed reduced water against carbon tetrachloride-induced liver damage in mice. Food Chem Toxicol 2009; 47 (08) 2031-2036
  • 85 Miyagi T, Takehara T, Tatsumi T. et al. Concanavalin a injection activates intrahepatic innate immune cells to provoke an antitumor effect in murine liver. Hepatology 2004; 40 (05) 1190-1196
  • 86 Yan M, Huo Y, Yin S, Hu H. Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol 2018; 17: 274-283
  • 87 Jaeschke H, Ramachandran A. Acetaminophen hepatotoxicity: paradigm for understanding mechanisms of drug-induced liver injury. Annu Rev Pathol 2024; 19: 453-478
  • 88 Son G, Iimuro Y, Seki E, Hirano T, Kaneda Y, Fujimoto J. Selective inactivation of NF-kappaB in the liver using NF-kappaB decoy suppresses CCl4-induced liver injury and fibrosis. Am J Physiol Gastrointest Liver Physiol 2007; 293 (03) G631-G639
  • 89 Kalinichenko VV, Bhattacharyya D, Zhou Y. et al. Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury. Hepatology 2003; 37 (01) 107-117
  • 90 George J, Rao KR, Stern R, Chandrakasan G. Dimethylnitrosamine-induced liver injury in rats: the early deposition of collagen. Toxicology 2001; 156 (2–3): 129-138
  • 91 Kupiec-Weglinski JW, Busuttil RW. Ischemia and reperfusion injury in liver transplantation. Transplant Proc 2005; 37 (04) 1653-1656
  • 92 Diya Adawi GMSA. Modulation of the colonic bacterial flora affects differently bacterial translocation and liver injury in an acute liver injury model. Microb Ecol Health Dis 2009; 11 (01) 47-54
  • 93 Nolan JP. The role of endotoxin in liver injury. Gastroenterology 1975; 69 (06) 1346-1356
  • 94 Zhang Y, Cai W, Huang Q. et al. Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells. Hepatology 2014; 59 (02) 671-682