Mouse Models of Liver Fibrosis

 

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Zusammenfassung

Leberfibrose ist der gemeinsame Endweg einer Vielzahl von Lebererkrankungen. Mausmodelle der Leberfibrose werden bemüht, um die Mechanismen der Fibrogenese und Fibrolyse genau zu charakterisieren und potenzielle Therapien zu testen. Es sind verschiedene Mausmodelle verfügbar, die Leberfibrose entwickeln: Induziert über 1. Verabreichung von Hepatotoxinen, 2. durch Gallengangsligatur oder über 3. immunologische Mechanismen sowie, in jüngerer Zeit zunehmend, auch 4. transgene Mausmodelle mit spontaner oder induzierbarer Fibroseentwicklung. Sie stellen wichtige Instrumente dar, mit deren Hilfe die Mechanismen der Fibrogenese untersucht werden können. Weiterhin bieten die unterschiedlichen Modelle die Möglichkeit, die ätiologisch unterschiedlichen Lebererkrankungen des Menschen nachzuvollziehen. In neueren Ansätzen wird versucht, Leberfibrose durch ein therapeutisches Eingreifen in den Signaltransduktionsweg zu inhibieren beziehungsweise rückgängig zu machen.

Abstract

Liver fibrosis is the final common pathway in a variety of liver diseases. To model liver fibrosis in mice is important as mechanisms not only of fibrogenesis, but also of fibrolysis, need to be clearly defined. Also, small rodents present a possibility to test potential treatments in vivo. Today, there are several mouse models of liver fibrosis available - induced by administration of hepatotoxins, by bile duct ligation or by immunological mechanisms - and, more and more widespread, transgenic animal models elucidating pathogenesis and common pathways in liver fibrosis. These different mouse models are complementary as they represent different pathways to fibrosis - as also seen in human disease. Recently, several promising treatment methods interfering with cytokine signaling have been published, offering new potential therapeutic interventions. This review seeks to summarize the different methods of fibrosis induction as well as to briefly review some promising new treatment options for fibrosis in the mouse model.

References

• 1 Arthur M J. Collagenases and liver fibrosis.  J Hepatol. 1995;  22 43-48
  Google Scholar
• 2 Friedman S L. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies.  N Engl J Med. 1993;  328 1828-1835
  Google Scholar
• 3 Knittel T, Kobold D, Piscaglia F. et al . Localization of liver myofibroblasts and hepatic stellate cells in normal and diseased rat livers: distinct roles of (myo-)fibroblast subpopulations in hepatic tissue repair.  Histochem Cell Biol. 1999;  112 387-401
  Google Scholar
• 4 Knittel T, Kobold D, Saile B. et al . Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential.  Gastroenterology. 1999;  117 1205-1221
  Google Scholar
• 5 Mitaka T, Sato F, Mizuguchi T. et al . Reconstruction of hepatic organoid by rat small hepatocytes and hepatic nonparenchymal cells.  Hepatology. 1999;  29 111-125
  Google Scholar
• 6 Bedossa P, Paradis V. Liver extracellular matrix in health and disease.  J Pathol. 2003;  200 504-515
  Google Scholar
• 7 Lalazar A, Wong L, Yamasaki G. et al . Early genes induced in hepatic stellate cells during wound healing.  Gene. 1997;  195 235-243
  Google Scholar
• 8 Eng F J, Friedman S L. Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex.  Am J Physiol Gastrointest Liver Physiol. 2000;  279 G7-G11
  Google Scholar
• 9 Ramadori G, Veit T, Schwogler S. et al . Expression of the gene of the alpha-smooth muscle-actin isoform in rat liver and in rat fat-storing (ITO) cells.  Virchows Arch B Cell Pathol Incl Mol Pathol. 1990;  59 349-357
  Google Scholar
• 10 Knittel T, Schuppan D, Meyer zum Buschenfelde K H. et al . Differential expression of collagen types I, III, and IV by fat-storing (Ito) cells in vitro.  Gastroenterology. 1992;  102 1724-1735
  Google Scholar
• 11 Ramadori G, Rieder H, Knittel T. et al . Fat storing cells (FSC) of rat liver synthesize and secrete fibronectin. Comparison with hepatocytes.  J Hepatol. 1987;  4 190-197
  Google Scholar
• 12 Olaso E, Friedman S L. Molecular regulation of hepatic fibrogenesis.  J Hepatol. 1998;  29 836-847
  Google Scholar
• 13 Blobe G C, Schiemann W P, Lodish H F. Role of transforming growth factor beta in human disease.  N Engl J Med. 2000;  342 1350-1358
  Google Scholar
• 14 Zhou S, Kinzler K W, Vogelstein B. Going mad with Smads.  N Engl J Med. 1999;  341 1144-1146
  Google Scholar
• 15 Knittel T, Mehde M, Kobold D. et al . Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1.  J Hepatol. 1999;  30 48-60
  Google Scholar
• 16 Arthur M J, Mann D A, Iredale J P. Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis.  J Gastroenterol Hepatol. 1998;  13 (Suppl) S33-S38
  Google Scholar
• 17 Iredale J P, Benyon R C, Arthur M J. et al . Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis.  Hepatology. 1996;  24 176-184
  Google Scholar
• 18 Irie J, Wu Y, Wicker L S. et al . NOD. c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis.  J Exp Med. 2006;  203 1209-1219
  Google Scholar
• 19 Oertelt S, Lian Z X, Cheng C M. et al . Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice.  J Immunol. 2006;  177 1655-1660
  Google Scholar
• 20 Duffield J S, Forbes S J, Constandinou C M. et al . Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.  J Clin Invest. 2005;  115 56-65
  Google Scholar
• 21 Radaeva S, Sun R, Jaruga B. et al . Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners.  Gastroenterology. 2006;  130 435-452
  Google Scholar
• 22 Safadi R, Ohta M, Alvarez C E. et al . Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes.  Gastroenterology. 2004;  127 870-882
  Google Scholar
• 23 Stavitsky A B. Regulation of granulomatous inflammation in experimental models of schistosomiasis.  Infect Immun. 2004;  72 1-12
  Google Scholar
• 24 Pearce E J. Priming of the immune response by schistosome eggs.  Parasite Immunol. 2005;  27 265-270
  Google Scholar
• 25 Bartley P B, Ramm G A, Jones M K. et al . A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis.  Int J Parasitol. 2006;  36 993-1001
  Google Scholar
• 26 Singh K P, Gerard H C, Hudson A P. et al . Dynamics of collagen, MMP and TIMP gene expression during the granulomatous, fibrotic process induced by Schistosoma mansoni eggs.  Ann Trop Med Parasitol. 2004;  98 581-593
  Google Scholar
• 27 Kresina T F, He Q, Degli Esposti S. et al . Gene expression of transforming growth factor beta 1 and extracellular matrix proteins in murine Schistosoma mansoni infection.  Gastroenterology. 1994;  107 773-780
  Google Scholar
• 28 Chiaramonte M G, Donaldson D D, Cheever A W. et al . An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response.  J Clin Invest. 1999;  104 777-785
  Google Scholar
• 29 Kimura K, Ando K, Ohnishi H. et al . Immunopathogenesis of hepatic fibrosis in chronic liver injury induced by repeatedly administered concanavalin A.  Int Immunol. 1999;  11 1491-1500
  Google Scholar
• 30 Louis H, Le Moine A, Quertinmont E. et al . Repeated concanavalin A challenge in mice induces an interleukin 10-producing phenotype and liver fibrosis.  Hepatology. 2000;  31 381-390
  Google Scholar
• 31 Reinehr R, Becker S, Keitel V. et al . Bile salt-induced apoptosis involves NADPH oxidase isoform activation.  Gastroenterology. 2005;  129 2009-2031
  Google Scholar
• 32 Accatino L, Contreras A, Fernandez S. et al . The effect of complete biliary obstruction on bile flow and bile acid excretion: postcholestatic choleresis in the rat.  J Lab Clin Med. 1979;  93 706-717
  Google Scholar
• 33 Chang M L, Yeh C T, Chang P Y. et al . Comparison of murine cirrhosis models induced by hepatotoxin administration and common bile duct ligation.  World J Gastroenterol. 2005;  11 4167-4172
  Google Scholar
• 34 Arias M, Sauer-Lehnen S, Treptau J. et al . Adenoviral expression of a transforming growth factor-beta1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats.  BMC Gastroenterol. 2003;  3 29
  Google Scholar
• 35 Uchinami H, Seki E, Brenner D A. et al . Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis.  Hepatology. 2006;  44 420-429
  Google Scholar
• 36 Canbay A, Guicciardi M E, Higuchi H. et al . Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis.  J Clin Invest. 2003;  112 152-159
  Google Scholar
• 37 Canbay A, Feldstein A E, Higuchi H. et al . Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression.  Hepatology. 2003;  38 1188-1198
  Google Scholar
• 38 Yoshiji H, Kuriyama S, Yoshii J. et al . Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis.  Gut. 2003;  52 1347-1354
  Google Scholar
• 39 Ogata H, Chinen T, Yoshida T. et al . Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production.  Oncogene. 2006;  25 2520-2530
  Google Scholar
• 40 Kovalovich K, DeAngelis R A, Li W. et al . Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice.  Hepatology. 2000;  31 149-159
  Google Scholar
• 41 Hillebrandt S, Goos C, Matern S. et al . Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15.  Gastroenterology. 2002;  123 2041-2051
  Google Scholar
• 42 Muriel P, Escobar Y. Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride.  J Appl Toxicol. 2003;  23 103-108
  Google Scholar
• 43 Nakatsukasa H, Nagy P, Evarts R P. et al . Cellular distribution of transforming growth factor-beta 1 and procollagen types I, III, and IV transcripts in carbon tetrachloride-induced rat liver fibrosis.  J Clin Invest. 1990;  85 1833-1843
  Google Scholar
• 44 Kim K H, Kim H C, Hwang M Y. et al . The antifibrotic effect of TGF-beta1 siRNAs in murine model of liver cirrhosis.  Biochem Biophys Res Commun. 2006;  343 1072-1078
  Google Scholar
• 45 Yu C, Wang F, Jin C. et al . Increased carbon tetrachloride-induced liver injury and fibrosis in FGFR4-deficient mice.  Am J Pathol. 2002;  161 2003-2010
  Google Scholar
• 46 Sanz S, Pucilowska J B, Liu S. et al . Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury.  Gut. 2005;  54 134-141
  Google Scholar
• 47 Nabeshima Y, Tazuma S, Kanno K. et al . Anti-fibrogenic function of angiotensin II type 2 receptor in CCl4-induced liver fibrosis.  Biochem Biophys Res Commun. 2006;  346 658-664
  Google Scholar
• 48 Bataller R, Schwabe R F, Choi Y H. et al . NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis.  J Clin Invest. 2003;  112 1383-1394
  Google Scholar
• 49 Yeh C N, Maitra A, Lee K F. et al . Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma.  Carcinogenesis. 2004;  25 631-636
  Google Scholar
• 50 Li X, Benjamin I S, Alexander B. Reproducible production of thioacetamide-induced macronodular cirrhosis in the rat with no mortality.  J Hepatol. 2002;  36 488-493
  Google Scholar
• 51 Kornek M, Raskopf E, Guetgemann I. et al . Combination of systemic thioacetamide (TAA) injections and ethanol feeding accelerates hepatic fibrosis in C3H/He mice and is associated with intrahepatic up regulation of MMP-2, VEGF and ICAM-1.  J Hepatol. 2006;  45 370-376
  Google Scholar
• 52 Dai K, Qi J Y, Tian D Y. Leptin administration exacerbates thioacetamide-induced liver fibrosis in mice.  World J Gastroenterol. 2005;  11 4822-4826
  Google Scholar
• 53 Leclercq I A, Farrell G C, Schriemer R. et al . Leptin is essential for the hepatic fibrogenic response to chronic liver injury.  J Hepatol. 2002;  37 206-213
  Google Scholar
• 54 Honda H, Ikejima K, Hirose M. et al . Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver.  Hepatology. 2002;  36 12-21
  Google Scholar
• 55 Jenkins S A, Grandison A, Baxter J N. et al . A dimethylnitrosamine-induced model of cirrhosis and portal hypertension in the rat.  J Hepatol. 1985;  1 489-499
  Google Scholar
• 56 Kitamura K, Nakamoto Y, Akiyama M. et al . Pathogenic roles of tumor necrosis factor receptor p55-mediated signals in dimethylnitrosamine-induced murine liver fibrosis.  Lab Invest. 2002;  82 571-583
  Google Scholar
• 57 Yasuda M, Shimizu I, Shiba M. et al . Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats.  Hepatology. 1999;  29 719-727
  Google Scholar
• 58 Yoshida T, Ogata H, Kamio M. et al . SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis.  J Exp Med. 2004;  199 1701-1707
  Google Scholar
• 59 Xu J, Lee G, Wang H. et al . Limited role for CXC chemokines in the pathogenesis of alpha-naphthyl isothiocyanate-induced liver injury.  Am J Physiol Gastrointest Liver Physiol. 2004;  287 G734-G741
  Google Scholar
• 60 Ramadori G, Knittel T, Odenthal M. et al . Synthesis of cellular fibronectin by rat liver fat-storing (Ito) cells: regulation by cytokines.  Gastroenterology. 1992;  103 1313-1321
  Google Scholar
• 61 Bayer E M, Herr W, Kanzler S. et al . Transforming growth factor-beta1 in autoimmune hepatitis: correlation of liver tissue expression and serum levels with disease activity.  J Hepatol. 1998;  28 803-811
  Google Scholar
• 62 Roulot D, Durand H, Coste T. et al . Quantitative analysis of transforming growth factor beta 1 messenger RNA in the liver of patients with chronic hepatitis C: absence of correlation between high levels and severity of disease.  Hepatology. 1995;  21 298-304
  Google Scholar
• 63 Kanzler S, Baumann M, Schirmacher P. et al . Prediction of progressive liver fibrosis in hepatitis C infection by serum and tissue levels of transforming growth factor-beta.  J Viral Hepat. 2001;  8 430-437
  Google Scholar
• 64 Sanderson N, Factor V, Nagy P. et al . Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.  Proc Natl Acad Sci USA. 1995;  92 2572-2576
  Google Scholar
• 65 Kopp J B, Factor V M, Mozes M. et al . Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease.  Lab Invest. 1996;  74 991-1003
  Google Scholar
• 66 Clouthier D E, Comerford S A, Hammer R E. Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice.  J Clin Invest. 1997;  100 2697-2713
  Google Scholar
• 67 Kanzler S, Lohse A W, Keil A. et al . TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis.  Am J Physiol. 1999;  276 G1059-G1068
  Google Scholar
• 68 Ueberham E, Low R, Ueberham U. et al . Conditional tetracycline-regulated expression of TGF-beta1 in liver of transgenic mice leads to reversible intermediary fibrosis.  Hepatology. 2003;  37 1067-1078
  Google Scholar
• 69 Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms.  Cytokine Growth Factor Rev. 2004;  15 197-204
  Google Scholar
• 70 Breitkopf K, Roeyen C, Sawitza I. et al . Expression patterns of PDGF-A, -B, -C and -D and the PDGF-receptors alpha and beta in activated rat hepatic stellate cells (HSC).  Cytokine. 2005;  31 349-357
  Google Scholar
• 71 Pinzani M, Milani S, Grappone C. et al . Expression of platelet-derived growth factor in a model of acute liver injury.  Hepatology. 1994;  19 701-707
  Google Scholar
• 72 Wong L, Yamasaki G, Johnson R J. et al . Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture.  J Clin Invest. 1994;  94 1563-1569
  Google Scholar
• 73 Czochra P, Klopcic B, Meyer E. et al . Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice.  J Hepatol. 2006;  45 419-428
  Google Scholar
• 74 Borkham-Kamphorst E, Stoll D, Gressner A M. et al . Antisense strategy against PDGF B-chain proves effective in preventing experimental liver fibrogenesis.  Biochem Biophys Res Commun. 2004;  321 413-423
  Google Scholar
• 75 Campbell J S, Hughes S D, Gilbertson D G. et al . Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma.  Proc Natl Acad Sci USA. 2005;  102 3389-3394
  Google Scholar
• 76 Yoshiji H, Kuriyama S, Miyamoto Y. et al . Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model.  Hepatology. 2000;  32 1248-1254
  Google Scholar
• 77 Fernandez-Salguero P, Pineau T, Hilbert D M. et al . Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor.  Science. 1995;  268 722-726
  Google Scholar
• 78 Popov Y, Patsenker E, Fickert P. et al . Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes.  J Hepatol. 2005;  43 1045-1054
  Google Scholar
• 79 Rudolph K L, Chang S, Millard M. et al . Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery.  Science. 2000;  287 1253-1258
  Google Scholar
• 80 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;  55 415-424
  Google Scholar
• 81 Warskulat U, Borsch E, Reinehr R. et al . Chronic liver disease is triggered by taurine transporter knockout in the mouse.  FASEB0 J. 2006;  20 574-576
  Google Scholar
• 82 Issa R, Zhou X, Constandinou C M. et al . Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking.  Gastroenterology. 2004;  126 1795-1808
  Google Scholar
• 83 Liu X, Hu H, Yin J Q. Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis.  Liver Int. 2006;  26 8-22
  Google Scholar
• 84 Knittel T, Janneck T, Muller L. et al . Transforming growth factor beta 1-regulated gene expression of Ito cells.  Hepatology. 1996;  24 352-360
  Google Scholar
• 85 George J, Roulot D, Koteliansky V E. et al . In vivo inhibition of rat stellate cell activation by soluble transforming growth factor beta type II receptor: a potential new therapy for hepatic fibrosis.  Proc Natl Acad Sci USA. 1999;  96 12 719-12 724
  Google Scholar
• 86 Qi Z, Atsuchi N, Ooshima A. et al . Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat.  Proc Natl Acad Sci USA. 1999;  96 2345-2349
  Google Scholar
• 87 Nakamura T, Sakata R, Ueno T. et al . Inhibition of transforming growth factor beta prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats.  Hepatology. 2000;  32 247-255
  Google Scholar
• 88 Gouville A C, Boullay V de, Krysa G. et al . Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis.  Br J Pharmacol. 2005;  145 166-177
  Google Scholar
• 89 Henderson N C, Mackinnon A C, Farnworth S L. et al . Galectin-3 regulates myofibroblast activation and hepatic fibrosis.  Proc Natl Acad Sci USA. 2006;  103 5060-5065
  Google Scholar
• 90 Wang C H, Lee T H, Lu C N. et al . Electroporative alpha-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation.  Gene Ther. 2006;  13 1000-1009
  Google Scholar
• 91 Teixeira-Clerc F, Julien B, Grenard P. et al . CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis.  Nat Med. 2006;  12 671-676
  Google Scholar
• 92 Osei-Hyiaman D, DePetrillo M, Pacher P. et al . Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity.  J Clin Invest. 2005;  115 1298-1305
  Google Scholar
• 93 Xia J L, Dai C, Michalopoulos G K. et al . Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation.  Am J Pathol. 2006;  168 1500-1512
  Google Scholar
• 94 Novobrantseva T I, Majeau G R, Amatucci A. et al . Attenuated liver fibrosis in the absence of B cells.  J Clin Invest. 2005;  115 3072-3082
  Google Scholar

Ansgar W. Lohse, MD

I. Department of Medicine, University Clinic Hamburg, Germany

Martinistrasse 52

20246 Hamburg, Germany

Phone: ++49/40/4 28 03 39 10

Fax: ++49/40/4 28 03 85 31

Email: alohse@uke.uni-hamburg.de