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Optimized Mouse Models for Liver Fibrosis

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Inflammation

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1559))

Abstract

Fibrosis is the excessive accumulation of extracellular matrix components due to chronic injury, with collagens as predominant structural components. Liver fibrosis can progress to cirrhosis, which is characterized by a severe distortion of the delicate hepatic vascular architecture, the shunting of the blood supply away from hepatocytes and the resultant functional liver failure. Cirrhosis is associated with a highly increased morbidity and mortality and represents the major hard endpoint in clinical studies of chronic liver diseases. Moreover, cirrhosis is a strong cofactor of primary liver cancer. In vivo models are indispensable tools to study the cellular and molecular mechanisms of liver fibrosis and to develop specific antifibrotic therapies towards clinical translation. Here, we provide a detailed description of select optimized mouse models of liver fibrosis and state-of-the-art fibrosis readouts.

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References

  1. Mehal WZ, Schuppan D (2015) Antifibrotic therapies in the liver. Semin Liver Dis 35:184–198

    Article  CAS  PubMed  Google Scholar 

  2. Schuppan D, Kim YO (2013) Evolving therapies for liver fibrosis. J Clin Invest 123:1887–1901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schuppan D, Afdhal NH (2008) Liver cirrhosis. Lancet 371:838–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Friedman SL (2010) Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 7:425–436

    Article  PubMed  Google Scholar 

  5. Friedman SL, Sheppard D, Duffield JS et al (2013) Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 5:167sr161

    Article  Google Scholar 

  6. D’ambrosio R, Aghemo A, Rumi MG et al (2012) A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology 56:532–543

    Article  PubMed  Google Scholar 

  7. Marcellin P, Gane E, Buti M et al (2013) Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 381:468–475

    Article  CAS  PubMed  Google Scholar 

  8. Schuppan D, Pinzani M (2012) Anti-fibrotic therapy: lost in translation? J Hepatol 56(Suppl 1):S66–S74

    Article  CAS  PubMed  Google Scholar 

  9. Popov Y, Schuppan D (2009) Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 50:1294–1306

    Article  CAS  PubMed  Google Scholar 

  10. Schuppan D (2015) Liver fibrosis: common mechanisms and antifibrotic therapies. Clin Res Hepatol Gastroenterol 39(Suppl 1):S51–S59

    Article  CAS  PubMed  Google Scholar 

  11. Liedtke C, Luedde T, Sauerbruch T et al (2013) Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair 6:19

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ikenaga N, Liu SB, Sverdlov DY et al (2015) A new Mdr2(−/−) mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset portal hypertension, and liver cancer. Am J Pathol 185:325–334

    Article  CAS  PubMed  Google Scholar 

  13. Popov Y, Patsenker E, Fickert P et al (2005) Mdr2 (Abcb4)−/− mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol 43:1045–1054

    Article  CAS  PubMed  Google Scholar 

  14. Popov Y, Sverdlov DY, Sharma AK et al (2011) Tissue transglutaminase does not affect fibrotic matrix stability or regression of liver fibrosis in mice. Gastroenterology 140:1642–1652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jimenez Calvente C, Sehgal A, Popov Y et al (2015) Specific hepatic delivery of procollagen alpha1(I) small interfering RNA in lipid-like nanoparticles resolves liver fibrosis. Hepatology 62:1285–1297

    Article  CAS  PubMed  Google Scholar 

  16. Patsenker E, Popov Y, Stickel F et al (2008) Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 135:660–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Patsenker E, Popov Y, Stickel F et al (2009) Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology 50:1501–1511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Popov Y, Patsenker E, Stickel F et al (2008) Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J Hepatol 48:453–464

    Article  CAS  PubMed  Google Scholar 

  19. Schattenberg JM, Nagel M, Kim YO et al (2012) Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP. Am J Physiol Gastrointest Liver Physiol 303:G498–G506

    Article  CAS  PubMed  Google Scholar 

  20. Sedlaczek N, Jia JD, Bauer M et al (2001) Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis. Am J Pathol 158:1239–1244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yoshida S, Ikenaga N, Liu SB et al (2014) Extrahepatic platelet-derived growth factor-beta, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice. Gastroenterology 147:1378–1392

    Article  CAS  PubMed  Google Scholar 

  22. Fickert P, Zollner G, Fuchsbichler A et al (2002) Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 123:1238–1251

    Article  CAS  PubMed  Google Scholar 

  23. Smit JJ, Schinkel AH, Oude Elferink RP 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 75:451–462

    Article  CAS  PubMed  Google Scholar 

  24. Shi J, Aisaki K, Ikawa Y et al (1998) Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am J Pathol 153:515–525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Slater TF, Cheeseman KH, Ingold KU (1985) Carbon tetrachloride toxicity as a model for studying free-radical mediated liver injury. Philos Trans R Soc Lond B Biol Sci 311:633–645

    Article  CAS  PubMed  Google Scholar 

  26. Hajovsky H, Hu G, Koen Y et al (2012) Metabolism and toxicity of thioacetamide and thioacetamide S-oxide in rat hepatocytes. Chem Res Toxicol 25:1955–1963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ishak K, Baptista A, Bianchi L et al (1995) Histological grading and staging of chronic hepatitis. J Hepatol 22:696–699

    Article  CAS  PubMed  Google Scholar 

  28. Standish RA, Cholongitas E, Dhillon A et al (2006) An appraisal of the histopathological assessment of liver fibrosis. Gut 55:569–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. De Meijer VE, Sverdlov DY, Popov Y et al (2010) Broad-spectrum matrix metalloproteinase inhibition curbs inflammation and liver injury but aggravates experimental liver fibrosis in mice. PLoS One 5:e11256

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kornek M, Lynch M, Mehta SH et al (2012) Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. Gastroenterology 143:448–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Popov Y, Patsenker E, Bauer M et al (2006) Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NFkappaB. J Biol Chem 281:15090–15098

    Article  CAS  PubMed  Google Scholar 

  32. Popov Y, Sverdlov DY, Bhaskar KR et al (2010) Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis. Am J Physiol Gastrointest Liver Physiol 298:G323–G334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Neuman RE, Logan MA (1950) The determination of hydroxyproline. J Biol Chem 184:299–306

    CAS  PubMed  Google Scholar 

  34. Schuppan D (1990) Structure of the extracellular matrix in normal and fibrotic liver: collagens and glycoproteins. Semin Liver Dis 10:1–10

    Article  CAS  PubMed  Google Scholar 

  35. Schuppan D, Ruehl M, Somasundaram R et al (2001) Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 21:351–372

    Article  CAS  PubMed  Google Scholar 

  36. Prockop DJ, Udenfriend S (1960) A specific method for the analysis of hydroxyproline in tissues and urine. Anal Biochem 1:228–239

    Article  CAS  PubMed  Google Scholar 

  37. Boigk G, Stroedter L, Herbst H et al (1997) Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats. Hepatology 26:643–649

    Article  CAS  PubMed  Google Scholar 

  38. Cho JJ, Hocher B, Herbst H et al (2000) An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology 118:1169–1178

    Article  CAS  PubMed  Google Scholar 

  39. Gerling B, Becker M, Staab D et al (1997) Prediction of liver fibrosis according to serum collagen VI level in children with cystic fibrosis. N Engl J Med 336:1611–1612

    Article  CAS  PubMed  Google Scholar 

  40. Fujita M, Shannon JM, Irvin CG et al (2001) Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 280:L39–L49

    CAS  PubMed  Google Scholar 

  41. Junqueira LC, Bignolas G, Brentani RR (1979) Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J 11:447–455

    Article  CAS  PubMed  Google Scholar 

  42. Whittaker P, Kloner RA, Boughner DR et al (1994) Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light. Basic Res Cardiol 89:397–410

    Article  CAS  PubMed  Google Scholar 

  43. Knodell RG, Ishak KG, Black WC et al (1981) Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1:431–435

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by NIH U19 AI066313-04 Hepatitis C Cooperative Research Centers, EU ERC Advanced Grant titled “Quantitative Imaging of Liver Fibrosis and Fibrogenesis,” and a grant within the EU Project “European Study of Steatohepatitis” to DS.

Author information

Authors and Affiliations

  1. Institute of Translational Immunology and Research Center for Immune Therapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany

    Yong Ook Kim & Detlef Schuppan M.D., Ph.D.

  2. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Yury Popov & Detlef Schuppan M.D., Ph.D.

Authors
  1. Yong Ook Kim
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  2. Yury Popov
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  3. Detlef Schuppan M.D., Ph.D.
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Corresponding author

Correspondence to Detlef Schuppan M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Björn E. Clausen

  2. Section Medical Physiology Department of Neuroscience, University of Groningen University Medical Center Groningen, Groningen, The Netherlands

    Jon D. Laman

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Kim, Y.O., Popov, Y., Schuppan, D. (2017). Optimized Mouse Models for Liver Fibrosis. In: Clausen, B., Laman, J. (eds) Inflammation. Methods in Molecular Biology, vol 1559. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6786-5_19

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  • DOI: https://doi.org/10.1007/978-1-4939-6786-5_19

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6784-1

  • Online ISBN: 978-1-4939-6786-5

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