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Animal Models in Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

  • Marion J. Pollheimer
  • Peter FickertEmail author
Article

Abstract

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are immune-mediated cholangiopathies with enigmatic etiology and pathogenesis. They have distinct clinical, laboratory, immunological, and histomorphological characteristics. Well-characterized animal models for PBC and PSC are utterly needed to develop novel pathogenetic concepts and to study innovative treatment strategies. The aim of the current paper is to outline the characteristics of ideal PBC and PSC animal models and to contrast this with a real-life up-to-date overview of currently available mouse models. Although some of this models show several individual characteristics of PBC and PSC, it is obvious that all of them have substantial and important limitations. Nevertheless, some may be beneficial to study certain pathophysiological aspects. Potential cholangiopathy animal models should be systematically investigated in regard to elevated serum alkaline phosphatase, bilirubin, and bile acid levels; immunological abnormalities; and longitudinal studies in regard to their liver phenotype. We herein propose a common systematic workup for potential models based on the fact that there are some intriguing disease combinations in specific genetically modified mice and recommend a stepwise process in regard to model characterization with methodical harvesting and screening of numerous organs for potential concomitant diseases. Due to the complex nature of both cholangiopathies, it seems to be very likely that no single perfect PBC or PSC model will ever be generated. The models outlined herein will certainly help to clarify specific pathogenetic aspects and even more important may turn out to be suitable to test potential drugs for treatment.

Keywords

Animal model Biliary fibrosis Cholangiopathies Cholestasis Cholestatic liver disease Primary biliary cirrhosis Primary sclerosing cholangitis 

References

  1. 1.
    Loftus EV Jr, Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister AR et al (2005) PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 54:91–96PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Broome U, Olsson R, Lööf L, Bodemar G, Hultcrantz R, Danielsson A et al (1996) Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 38:610–615PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Fausa O, Schrumpf E, Elgjo K (1991) Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis 11:31–39PubMedCrossRefGoogle Scholar
  4. 4.
    Hirschfield GM, Gershwin ME (2013) The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol 24:303–330CrossRefGoogle Scholar
  5. 5.
    Hirschfield GM (2011) Diagnosis of primary biliary cirrhosis. Best Pract Res Clin Gastroenterol 25:701–712PubMedCrossRefGoogle Scholar
  6. 6.
    Hirschfield GM, Gershwin ME (2011) Primary biliary cirrhosis: one disease with many faces. Isr Med Assoc J 13:55–59PubMedGoogle Scholar
  7. 7.
    Hirschfield GM, Heathcote EJ, Gershwin ME (2010) Pathogenesis of cholestatic liver disease and therapeutic approaches. Gastroenterology 139:1481–1496PubMedCrossRefGoogle Scholar
  8. 8.
    Hohenester S, Oude-Elferink RP, Beuers U (2009) Primary biliary cirrhosis. Semin Immunopathol 31:283–307PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y et al (2009) Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 360:2544–2555PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Weismüller TJ, Wedemeyer J, Kubicka S, Strassburg CP, Manns MP (2008) The challenges in primary sclerosing cholangitis—aetiopathogenesis, autoimmunity, management and malignancy. J Hepatol 1:S38–S57CrossRefGoogle Scholar
  11. 11.
    Karlsen TH, Schrumpf E, Boberg KM (2010) Update on primary sclerosing cholangitis. Dig Liver Dis 42:390–400PubMedCrossRefGoogle Scholar
  12. 12.
    Vierling JM (2001) Animal models for primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 15:591–610PubMedCrossRefGoogle Scholar
  13. 13.
    Edwards DF, McCracken MD, Richardson DC (1983) Sclerosing cholangitis in a cat. J Am Vet Med Assoc 182:710–712PubMedGoogle Scholar
  14. 14.
    Nakayama H, Uchida K, Lee SK, Uetsuka K, Hasegawa A, Goto N (1992) Three cases of feline sclerosing lymphocytic cholangitis. J Vet Med Sci 54:769–771PubMedCrossRefGoogle Scholar
  15. 15.
    Arenas-Gamboa AM, Bearss JJ, Hubbard GB, Porter BF, Owston MA, Dick EJ Jr (2012) Sclerosing cholangitis in baboons (Papio spp) resembling primary sclerosing cholangitis of humans. Vet Pathol 49:524–527PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A, Delaney ML, Punit S et al (2010) Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8:292–300Google Scholar
  17. 17.
    Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE et al (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134:743–756Google Scholar
  18. 18.
    Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS et al (2006) Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 177:1655–1660PubMedCrossRefGoogle Scholar
  19. 19.
    Yang GX, Lian ZX, Chuang YH, Moritoki Y, Lan RY, Wakabayashi K et al (2008) Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice. Hepatology 47:1974–1982PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Moritoki Y, Zhang W, Tsuneyama K, Yoshida K, Wakabayashi K, Yang GX et al (2009) B cells suppress the inflammatory response in a mouse model of primary biliary cirrhosis. Gastroenterology 136:1037–1047PubMedCrossRefGoogle Scholar
  21. 21.
    Chuang YH, Lian ZX, Yang GX, Shu SA, Moritoki Y, Ridgway WM et al (2008) Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology 47:571–580PubMedCrossRefGoogle Scholar
  22. 22.
    Tsuda M, Zhang W, Yang GX, Tsuneyama K, Ando Y, Kawata K et al (2013) Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFβ receptor type II mice. Hepatology 57:806–816PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH et al (2006) IL-2 receptor alpha(−/−) mice and the development of primary biliary cirrhosis. Hepatology 44:1240–1249PubMedCrossRefGoogle Scholar
  24. 24.
    Hsu W, Zhang W, Tsuneyama K, Moritoki Y, Ridgway WM, Ansari AA et al (2009) Differential mechanisms in the pathogenesis of autoimmune cholangitis versus inflammatory bowel disease in interleukin-2Ralpha(−/−) mice. Hepatology 49:133–140PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Yao Y, Yang W, Yang YQ, Ma HD, Lu FT, Li L et al (2014) Distinct from its canonical effects, deletion of IL-12p40 induces cholangitis and fibrosis in interleukin-2Rα(−/−) mice. J Autoimmun 51:99–108PubMedCrossRefGoogle Scholar
  26. 26.
    Irie J, Wu Y, Wicker LS, Rainbow D, Nalesnik MA, Hirsch R et al (2006) NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. Exp Med 203:1209–1219CrossRefGoogle Scholar
  27. 27.
    Nakagome Y, Ueno Y, Kogure T, Fukushima K, Moritoki Y, Ridgway WM et al (2007) Autoimmune cholangitis in NOD.c3c4 mice is associated with cholangiocyte-specific Fas antigen deficiency. J Autoimmun 29:20–29PubMedCrossRefGoogle Scholar
  28. 28.
    Moritoki Y, Tsuda M, Tsuneyama K, Zhang W, Yoshida K, Lian ZX et al (2011) B cells promote hepatic inflammation, biliary cyst formation, and salivary gland inflammation in the NOD.c3c4 model of autoimmune cholangitis. Cell Immunol 268:16–23PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Salas JT, Banales JM, Sarvide S, Recalde S, Ferrer A, Uriarte I et al (2008) Ae2a, b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology 134:1482–1493PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang W, Sharma R, Ju ST, He XS, Tao Y, Tsuneyama K et al (2009) Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. Hepatology 49:545–552PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Tsuneyama K, Nose M, Nisihara M, Katayanagi K, Harada K, Nakanuma Y (2001) Spontaneous occurrence of chronic non-suppurative destructive cholangitis and antimitochondrial autoantibodies in MRL/lpr mice: possible animal model for primary biliary cirrhosis. Pathol Int 51:418–424PubMedCrossRefGoogle Scholar
  32. 32.
    Ohba K, Omagari K, Murase K, Hazama H, Masuda J, Kinoshita H et al (2002) A possible mouse model for spontaneous cholangitis: serological and histological characteristics of MRL/lpr mice. Pathology 34:250–256PubMedCrossRefGoogle Scholar
  33. 33.
    Masanaga T, Watanabe Y, Van de Water J, Leung PS, Nakanishi T, Kajiyama G et al (1998) Induction and persistence of immune-mediated cholangiohepatitis in neonatally thymectomized mice. Clin Immunol Immunopathol 89:141–149PubMedCrossRefGoogle Scholar
  34. 34.
    Aisaka Y, Watanabe Y, Kamiyasu M, Masanaga T, Tsuji K, Nakanishi T et al (2000) Immune-mediated cholangiohepatitis in neonatally thymectomized mice: the role of T cells and analysis of T-cell receptor Vbeta usage. J Autoimmun 14:239–246PubMedCrossRefGoogle Scholar
  35. 35.
    Wakabayashi K, Lian ZX, Leung PS, Moritoki Y, Tsuneyama K, Kurth MJ et al (2008) Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology 48:531–540PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Wakabayashi K, Yoshida K, Leung PS, Moritoki Y, Yang GX, Tsuneyama K et al (2009) Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol 155:577–586PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Dhirapong A, Lleo A, Yang GX, Tsuneyama K, Dunn R, Kehry M et al (2011) B cell depletion therapy exacerbates murine primary biliary cirrhosis. Hepatology 53:527–535PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Wu SJ, Yang YH, Tsuneyama K, Leung PS, Illarionov P, Gershwin ME et al (2011) Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. Hepatology 53:915–925PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Ambrosini YM, Yang GX, Zhang W, Tsuda M, Shu S, Tsuneyama K et al (2011) The multi-hit hypothesis of primary biliary cirrhosis: polyinosinic-polycytidylic acid (poly I:C) and murine autoimmune cholangitis. Clin Exp Immunol 166:110–120PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Ide T, Sata M, Suzuki H, Uchimura Y, Murashima S, Shirachi M et al (1996) An experimental animal model of primary biliary cirrhosis induced by lipopolysaccharide and pyruvate dehydrogenase. Kurume Med J 43:185–188PubMedCrossRefGoogle Scholar
  41. 41.
    Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O et al (2008) Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe 3:304–315PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Wang J, Shan Y, Jiang Z, Feng J, Li C, Ma L et al (2013) High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin Exp Immunol 174:212–220PubMedCentralPubMedGoogle Scholar
  43. 43.
    Koarada S, Wu Y, Fertig N, Sass DA, Nalesnik M, Todd JA et al (2004) Genetic control of autoimmunity: protection from diabetes, but spontaneous autoimmune biliary disease in a nonobese diabetic congenic strain. J Immunol 173:2315–2323PubMedCrossRefGoogle Scholar
  44. 44.
    Melero S, Spirlì C, Zsembery A, Medina JF, Joplin RE, Duner E et al (2002) Defective regulation of cholangiocyte Cl/HCO3 (−) and Na+/H+ exchanger activities in primary biliary cirrhosis. Hepatology 35:1513–1521PubMedCrossRefGoogle Scholar
  45. 45.
    Prieto J, García N, Martí-Climent JM, Peñuelas I, Richter JA, Medina JF (1999) Assessment of biliary bicarbonate secretion in humans by positron emission tomography. Gastroenterology 117:167–172PubMedCrossRefGoogle Scholar
  46. 46.
    Medina JF, Martínez-Ansó VJJ, Prieto J (1997) Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology 25:12–17PubMedCrossRefGoogle Scholar
  47. 47.
    Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA et al (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68–73PubMedCrossRefGoogle Scholar
  48. 48.
    Amano K, Leung PS, Rieger R, Quan C, Wang X, Marik J et al (2005) Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. J Immunol 174:5874–5883PubMedCrossRefGoogle Scholar
  49. 49.
    Leung PS, Park O, Tsuneyama K, Kurth MJ, Lam KS, Ansari AA et al (2007) Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization. J Immunol 179:2651–2657PubMedCrossRefGoogle Scholar
  50. 50.
    Pollheimer MJ, Trauner M, Fickert P (2011) Will we ever model PSC?—"it's hard to be a PSC model!". Clin Res Hepatol Gastroenterol 35:792–804PubMedCrossRefGoogle Scholar
  51. 51.
    Mourelle M, Salas A, Vilaseca J, Guarner F, Malagelada JR (1995) Induction of chronic cholangitis in the rat by trinitrobenzenesulfonic acid. J Hepatol 22:219–225PubMedCrossRefGoogle Scholar
  52. 52.
    Orth T, Neurath M, Schirmacher P, Galle PR, Mayet WJ (2000) A novel rat model of chronic fibrosing cholangitis induced by local administration of a hapten reagent into the dilated BD is associated with increased TNF-alpha production and autoantibodies. J Hepatol 33:862–872PubMedCrossRefGoogle Scholar
  53. 53.
    Tjandra K, Sharkey KA, Swain MG (2000) Progressive development of a Th1-type hepatic cytokine profile in rats with experimental cholangitis. Hepatology 31:280–290PubMedCrossRefGoogle Scholar
  54. 54.
    Fickert P, Stöger U, Fuchsbichler A, Moustafa T, Marschall HU, Weiglein AH et al (2007) A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis. Am J Pathol 171:525–536PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Marzioni M, Saccomanno S, Agostinelli L, Rychlicki C, De Minicis S, Pierantonelli I et al (2013) PDX-1/Hes-1 interactions determine cholangiocyte proliferative response to injury in rodents: possible implications for sclerosing cholangitis. J Hepatol 58:750–756PubMedCrossRefGoogle Scholar
  56. 56.
    Fickert P, Fuchsbichler A, Marschall HU, Wagner M, Zollner G, Krause R et al (2006) Lithocholic acid feeding induces segmental BD obstruction and destructive cholangitis in mice. Am J Pathol 168:410–422PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Weiglein AH, Lammert F et al (2002) Ursodeoxycholic acid aggravates bile infarcts in BD-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 123:1238–1251PubMedCrossRefGoogle Scholar
  58. 58.
    Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H et al (2004) Regurgitation of bile acids from leaky BDs causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127:261–274PubMedCrossRefGoogle Scholar
  59. 59.
    Popov Y, Patsenker E, Fickert P, Trauner M, Schuppan D et al (2005) Mdr2 (Abcb4)−/− mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol 43:1045–1054PubMedCrossRefGoogle Scholar
  60. 60.
    Durie PR, Kent G, Phillips MJ, Ackerley CA (2004) Characteristic multiorgan pathology of cystic fibrosis in a long-living cystic fibrosis transmembrane regulator knockout murine model. Am J Pathol 164:1481–1493PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Meerman L, Koopen NR, Bloks V, Van Goor H, Havinga R, Wolthers BG et al (1999) Biliary fibrosis associated with altered bile composition in a mouse model of erythropoietic protoporphyria. Gastroenterology 117:696–705PubMedCrossRefGoogle Scholar
  62. 62.
    Libbrecht L, Meerman L, Kuipers F, Roskams T, Desmet V, Jansen P (2003) Liver pathology and hepatocarcinogenesis in a long-term mouse model of erythropoietic protoporphyria. J Pathol 199:191–200PubMedCrossRefGoogle Scholar
  63. 63.
    Jochum W, David JP, Elliott C, Wutz A, Plenk H Jr, Matsuo K et al (2000) Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nat Med 6:980–984PubMedCrossRefGoogle Scholar
  64. 64.
    Kireva T, Erhardt A, Tiegs G, Tilg H, Denk H, Haybaeck J et al (2011) Transcription factor Fra-1 induces cholangitis and liver fibrosis. Hepatology 53:1259–1269PubMedCrossRefGoogle Scholar
  65. 65.
    Nakagawa H, Hikiba Y, Hirata Y, Font-Burgada J, Sakamoto K, Hayakawa Y et al (2014) Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis. Proc Natl Acad Sci U S A 111:1090–1095PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Stephens J, Cosyns M, Jones M, Hayward A (1999) Liver and bile duct pathology following Cryptosporidium parvum infection of immunodeficient mice. Hepatology 30:27–35PubMedCrossRefGoogle Scholar
  67. 67.
    Ungar BL, Burris JA, Quinn CA, Finkelman FD (1990) New mouse models for chronic Cryptosporidium infection in immunodeficient hosts. Infect Immun 58:961–969PubMedCentralPubMedGoogle Scholar
  68. 68.
    Mead JR, Arrowood MJ, Sidwell RW, Healey MC (1991) Chronic Cryptosporidium parvum infections in congenitally immunodeficient SCID and nude mice. J Infect Dis 163:1297–1304PubMedCrossRefGoogle Scholar
  69. 69.
    Ponnuraj EM, Hayward AR (2002) Requirement for TNF-Tnfrsf1 signalling for sclerosing cholangitis in mice chronically infected by Cryptosporidium parvum. Clin Exp Immunol 128:416–420PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Ward JM, Anver MR, Haines DC, Benveniste RE (1994) Chronic active hepatitis in mice caused by Helicobacter hepaticus. Am J Pathol 145:959–968PubMedCentralPubMedGoogle Scholar
  71. 71.
    Avenaud P, Le Bail B, Mayo K, Marais A, Fawaz R, Bioulac-Sage P et al (2003) Natural history of Helicobacter hepaticus infection in conventional A/J mice, with special reference to liver involvement. Infect Immun 71:3667–3672PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Georgiev P, Jochum W, Heinrich S, Jang JH, Nocito A, Dahm F et al (2008) Characterization of time-related changes after experimental bile duct ligation. Br J Surg 95:646–656PubMedCrossRefGoogle Scholar
  73. 73.
    Lichtman SN, Sartor RB (1991) Hepatobiliary injury associated with experimental small-bowel bacterial overgrowth in rats. Immunol Res 10:528–531PubMedCrossRefGoogle Scholar
  74. 74.
    Lichtman SN, Wang J, Clark RL (1995) A microcholangiographic study of liver disease models in rats. Acad Radiol 2:515–521PubMedCrossRefGoogle Scholar
  75. 75.
    Yamada S, Ishii M, Liang LS, Yamamoto T, Toyota T (1994) Small duct cholangitis induced by N-formyl L-methionine L-leucine L-tyrosine in rats. J Gastroenterol 29:631–636PubMedCrossRefGoogle Scholar
  76. 76.
    Yamada S, Ishii M, Kisara N, Nagatomi R, Toyota T (1999) Macrophages are essential for lymphocyte infiltration in formyl peptide-induced cholangitis in rat liver. Liver 19:253–258PubMedCrossRefGoogle Scholar
  77. 77.
    Numata Y, Tazuma S, Nishioka T, Ueno Y, Chayama K (2004) Immune response in mouse experimental cholangitis associated with colitis induced by dextran sulfate sodium. J Gastroenterol Hepatol 19:910–915PubMedCrossRefGoogle Scholar
  78. 78.
    Tjandra K, Le T, Swain MG (2002) Experimental colitis attenuates development of toxin-induced cholangitis in rats. Dig Dis Sci 47:1216–1223PubMedCrossRefGoogle Scholar
  79. 79.
    Nonomura A, Kono N, Minato H (1998) Nakanuma Y (1998) Diffuse biliary tract involvement mimicking primary sclerosing cholangitis in an experimental model of chronic graft-versus-host disease in mice. Pathol Int 48:421–427PubMedCrossRefGoogle Scholar
  80. 80.
    Orth T, Neurath M, Schirmacher P, Treichel U, Meyer zum Büschenfelde KH, Mayet W (1999) Anti-neutrophil cytoplasmic antibodies in a rat model of trinitrobenzenesulphonic acid-induced liver injury. Eur J Clin Invest 29:929–939PubMedCrossRefGoogle Scholar
  81. 81.
    Beaussier M, Wendum D, Fouassier L, Rey C, Barbu V, Lasnier E et al (2005) Adaptative bile duct proliferative response in experimental bile duct ischemia. J Hepatol 42:257–265PubMedCrossRefGoogle Scholar
  82. 82.
    Buxbaum J, Qian P, Khuu C, Shneider BL, Daikh DI, Gershwin ME et al (2006) Novel model of antigen-specific induction of bile duct injury. Gastroenterology 131:1899–1906PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Seidel D, Eickmeier I, Kühl AA, Hamann A, Loddenkemper C, Schott E (2014) CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice. Hepatology 59:601–611PubMedCrossRefGoogle Scholar
  84. 84.
    Ernst TM, Schwinge D, Raabe N, Daubmann A, Kaul MG, Adam G, et al (2014) Imaging of the murine biliopancreatic tract at 7 tesla: technique and results in a model of primary sclerosing cholangitis. J Magn Reson Imaging. doi: 10.1002/jmri.24475
  85. 85.
    Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L et al (1993) Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75:451–462PubMedCrossRefGoogle Scholar
  86. 86.
    Halilbasic E, Fiorotto R, Fickert P, Marschall HU, Moustafa T, Spirli C et al (2009) Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2−/− mice. Hepatology 49:1972–1981PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Baghdasaryan A, Claudel T, Kosters A, Gumhold J, Silbert D, Thüringer A et al (2010) Curcumin improves sclerosing cholangitis in Mdr2−/− mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation. Gut 59:521–530PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, Roda A et al (2011) Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2−/− (Abcb4−/−) mouse cholangiopathy model by promoting biliary HCO3 output. Hepatology 54:1303–1312PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Moustafa T, Fickert P, Magnes C, Guelly C, Thueringer A, Frank S et al (2012) Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 142:140–151PubMedCrossRefGoogle Scholar
  90. 90.
    Ehlken H, Kondylis V, Heinrichsdorff J, Ochoa-Callejero L, Roskams T, Pasparakis M (2011) Hepatocyte IKK2 protects Mdr2−/− mice from chronic liver failure. PLoS One 6:e25942PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Barikbin R, Neureiter D, Wirth J, Erhardt A, Schwinge D, Kluwe J et al (2012) Induction of heme oxygenase 1 prevents progression of liver fibrosis in Mdr2 knockout mice. Hepatology 55:553–562PubMedCrossRefGoogle Scholar
  92. 92.
    Strack I, Schulte S, Varnholt H, Schievenbusch S, Töx U, Wendland K et al (2011) β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis. Lab Invest 91:252–261PubMedCrossRefGoogle Scholar
  93. 93.
    Blaas L, Kornfeld JW, Schramek D, Musteanu M, Zollner G, Gumhold J et al (2010) Disruption of the growth hormone–signal transducer and activator of transcription 5–insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis. Hepatology 51:1319–1326PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Trauner M, Fickert P, Wagner M (2007) MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis 27:77–98PubMedCrossRefGoogle Scholar
  95. 95.
    Henckaerts L, Jaspers M, Van Steenbergen W, Vliegen L, Fevery J, Nuytten H et al (2009) Cystic fibrosis transmembrane conductance regulator gene polymorphisms in patients with primary sclerosing cholangitis. J Hepatol 50:150–157PubMedCrossRefGoogle Scholar
  96. 96.
    Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O et al (1992) An animal model for cystic fibrosis made by gene targeting. Science 257:1083–1088PubMedCrossRefGoogle Scholar
  97. 97.
    Dorin JR, Dickinson P, Alton EW, Smith SN, Geddes DM, Stevenson BJ et al (1992) Cystic fibrosis in the mouse by targeted insertional mutagenesis. Nature 359:211–215PubMedCrossRefGoogle Scholar
  98. 98.
    Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Zeiher BG, Eichwald E, Zabner J, Smith JJ, Puga AP, McCray PB Jr et al (1995) A mouse model for the delta F508 allele of cystic fibrosis. J Clin Invest 96:2051–2064PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Lyoumi S, Abitbol M, Rainteau D, Karim Z, Bernex F, Oustric V et al (2011) Protoporphyrin retention in hepatocytes and Kupffer cells prevents sclerosing cholangitis in erythropoietic protoporphyria mouse model. Gastroenterology 141:1509–1519PubMedCrossRefGoogle Scholar
  101. 101.
    Fickert P (2014) Time to say goodbye to the drug or the model?—why do drugs fail to live up to their promise in bile duct ligated mice? J Hepatol 60:12–15PubMedCrossRefGoogle Scholar
  102. 102.
    Colledge WH, Abella BS, Southern KW, Ratcliff R, Jiang C, Cheng SH et al (1995) Generation and characterization of a delta F508 cystic fibrosis mouse model. Nat Genet 10:445–452PubMedCrossRefGoogle Scholar
  103. 103.
    Lichtman SN, Keku J, Schwab JH, Sartor RB (1991) Evidence for peptidoglycan absorption in rats with experimental small bowel bacterial overgrowth. Infect Immun 59:555–562PubMedCentralPubMedGoogle Scholar
  104. 104.
    Lichtman SN, Sartor RB (1991) Duct proliferation following biliary obstruction in the rat. Gastroenterology 100:1785–1787PubMedGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and HepatologyDepartment of Internal MedicineGrazAustria
  2. 2.Institute of PathologyMedical University of GrazGrazAustria

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