Skip to main content
SpringerLink
Log in

Hepatic Fibrosis and Cirrhosis

  • Chapter
  • First Online:
Molecular Pathology of Liver Diseases

Part of the book series: Molecular Pathology Library ((MPLB,volume 5))

  • 3811 Accesses

Abstract

Liver fibrosis is the presence of scar tissue in the liver. Although it varies in location within the liver, especially in early disease, the liver scar uniformly represents both an excess of extracellular matrix (ECM) and a shift in the quality of that matrix. Cirrhosis is the term applied to the final stage of fibrosis, the common end result of progressive fibrosis from all etiologies. Although it is in one sense the far end of the fibrosis spectrum, the term cirrhosis reflects architectural rearrangements rather than the quantity of abnormal matrix, specifically the formation of parenchymal nodules surrounded by scar tissue [1].

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    MELD score (rounded to the nearest whole number), with United Network for Organ Sharing modifications, for patients age 12 and older: [260]

    3.78[Ln serum bilirubin (mg/dl)] + 11.2[Ln INR] + 9.57[Ln serum creatinine (mg/dl)] + 6.43.

    (Modifications: if patient has been dialyzed twice within previous 7 days, serum creatinine is set at 4.0 mg/dl; any value below 1.0 is rounded up to 1.0.)

References

  1. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol. 1978;31(5):395–414.

    Article  PubMed  CAS  Google Scholar 

  2. Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, Albrecht J. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C. J Hepatol. 2001;34(5):730–9.

    Article  PubMed  CAS  Google Scholar 

  3. Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology. 2004;39(6):1477–87.

    Article  PubMed  Google Scholar 

  4. Greenbaum LE, Wells RG. The role of stem cells in liver repair and fibrosis. Int J Biochem Cell Biol. 2009.

    Google Scholar 

  5. Lim YS, Kim WR. The global impact of hepatic fibrosis and end-stage liver disease. Clin Liver Dis. 2008;12(4):733–46, vii.

    Google Scholar 

  6. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: liver, biliary tract, and pancreas. Gastroenterology. 2009;136(4):1134–44.

    Article  PubMed  Google Scholar 

  7. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387–95.

    Article  PubMed  Google Scholar 

  8. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825–32.

    Article  PubMed  CAS  Google Scholar 

  9. Mallat A, Hezode C, Lotersztajn S. Environmental factors as disease accelerators during chronic hepatitis C. J Hepatol. 2008;48(4):657–65.

    Article  PubMed  CAS  Google Scholar 

  10. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38(6):1449–57.

    PubMed  Google Scholar 

  11. Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol. 2003;39(2):239–44.

    Article  PubMed  Google Scholar 

  12. Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol. 2007;47(4):598–607.

    Article  PubMed  Google Scholar 

  13. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24(2):289–93.

    Article  PubMed  CAS  Google Scholar 

  14. Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22(6):696–9.

    Article  PubMed  CAS  Google Scholar 

  15. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19(6):1513–20.

    Article  PubMed  CAS  Google Scholar 

  16. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.

    Article  PubMed  Google Scholar 

  17. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94(9):2467–74.

    Article  PubMed  CAS  Google Scholar 

  18. Scheuer P. Primary biliary cirrhosis. Proc R Soc Med. 1967;60(12):1257–60.

    PubMed  CAS  Google Scholar 

  19. Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol. 1978;379(2):103–12.

    Article  PubMed  CAS  Google Scholar 

  20. Goodman ZD, Becker Jr RL, Pockros PJ, Afdhal NH. Progression of fibrosis in advanced chronic hepatitis C: evaluation by morphometric image analysis. Hepatology. 2007;45(4):886–94.

    Article  PubMed  CAS  Google Scholar 

  21. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol. 2004;99(6):1160–74.

    Article  PubMed  Google Scholar 

  22. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217–31.

    Article  PubMed  Google Scholar 

  23. de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2005;43(1):167–76.

    Article  PubMed  Google Scholar 

  24. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655–69.

    Article  PubMed  CAS  Google Scholar 

  25. Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology. 2010;51(4):1445–9.

    Article  PubMed  Google Scholar 

  26. Nagula S, Jain D, Groszmann RJ, Garcia-Tsao G. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol. 2006;44(1):111–7.

    Article  PubMed  Google Scholar 

  27. Kumar M, Sakhuja P, Kumar A, et al. Histological subclassification of cirrhosis based on histological-haemodynamic correlation. Aliment Pharmacol Ther. 2008;27(9):771–9.

    Article  PubMed  CAS  Google Scholar 

  28. Issa R, Zhou X, Constandinou CM, et al. Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. Gastroenterology. 2004;126(7):1795–808.

    Article  PubMed  CAS  Google Scholar 

  29. Brenner DA, Waterboer T, Choi SK, et al. New aspects of hepatic fibrosis. J Hepatol. 2000;32(1 Suppl):32–8.

    Article  PubMed  CAS  Google Scholar 

  30. Hahn E, Wick G, Pencev D, Timpl R. Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV, laminin, and fibronectin. Gut. 1980;21(1):63–71.

    Article  PubMed  CAS  Google Scholar 

  31. Loreal O, Clement B, Schuppan D, Rescan PY, Rissel M, Guillouzo A. Distribution and cellular origin of collagen VI during development and in cirrhosis. Gastroenterology. 1992;102(3):980–7.

    PubMed  CAS  Google Scholar 

  32. Martinez-Hernandez A, Amenta PS. The hepatic extracellular matrix. I. Components and distribution in normal liver. Virchows Arch A Pathol Anat Histopathol. 1993;423(1):1–11.

    Article  PubMed  CAS  Google Scholar 

  33. Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis. 2001;21(3):351–72.

    Article  PubMed  CAS  Google Scholar 

  34. Reid LM, Fiorino AS, Sigal SH, Brill S, Holst PA. Extracellular matrix gradients in the space of Disse: relevance to liver biology. Hepatology. 1992;15(6):1198–203.

    Article  PubMed  CAS  Google Scholar 

  35. Schaffner F, Popper H. Capillarization of the hepatic sinusoids in man. Gastroenterology. 1963;44:239–42.

    PubMed  CAS  Google Scholar 

  36. Mori T, Okanoue T, Sawa Y, Hori N, Ohta M, Kagawa K. Defenestration of the sinusoidal endothelial cell in a rat model of cirrhosis. Hepatology. 1993;17(5):891–7.

    Article  PubMed  CAS  Google Scholar 

  37. Martinez-Hernandez A, Amenta PS. The hepatic extracellular matrix. II. Ontogenesis, regeneration and cirrhosis. Virchows Arch A Pathol Anat Histopathol. 1993;423(2):77–84.

    Article  PubMed  CAS  Google Scholar 

  38. Zeisberg M, Kramer K, Sindhi N, Sarkar P, Upton M, Kalluri R. De-differentiation of primary human hepatocytes depends on the composition of specialized liver basement membrane. Mol Cell Biochem. 2006;283(1–2):181–9.

    Article  PubMed  CAS  Google Scholar 

  39. Odenthal M, Neubauer K, Meyer zum Buschenfelde KH, Ramadori G. Localization and mRNA steady-state level of cellular fibronectin in rat liver undergoing a CCl4-induced acute damage or fibrosis. Biochim Biophys Acta. 1993;1181(3):266–72.

    Article  PubMed  CAS  Google Scholar 

  40. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349–63.

    Article  PubMed  CAS  Google Scholar 

  41. George J, Wang SS, Sevcsik AM, et al. Transforming growth factor-beta initiates wound repair in rat liver through induction of the EIIIA-fibronectin splice isoform. Am J Pathol. 2000;156(1):115–24.

    Article  PubMed  CAS  Google Scholar 

  42. Zeitlin L, Resnick MB, Konikoff F, et al. Divergent patterns of extracellular matrix protein expression in neonatal versus adult liver fibrosis. Pediatr Pathol Mol Med. 2003;22(4):349–62.

    Article  PubMed  CAS  Google Scholar 

  43. Gressner OA, Weiskirchen R, Gressner AM. Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options. Comp Hepatol. 2007;6:7.

    Article  PubMed  CAS  Google Scholar 

  44. Tatrai P, Egedi K, Somoracz A, et al. Quantitative and qualitative alterations of heparan sulfate in fibrogenic liver diseases and hepatocellular cancer. J Histochem Cytochem. 2010;58:429–41.

    Article  PubMed  CAS  Google Scholar 

  45. Hanauske-Abel HM. Fibrosis of the liver: representative molecular elements and their emerging role as anti-fibrotic targets. In: Zakim D, Boyer TD, editors. Hepatology. A textbook of liver disease, vol. 1. 4th ed. Philadelphia: Saunders; 2003. p. 347–94.

    Google Scholar 

  46. Kivirikko KI, Myllyla R. Post-translational processing of procollagens. Ann N Y Acad Sci. 1985;460:187–201.

    Article  PubMed  CAS  Google Scholar 

  47. Crockett SD, Kaltenbach T, Keeffe EB. Do we still need a liver biopsy? Are the serum fibrosis tests ready for prime time? Clin Liver Dis. 2006;10(3):513–34, viii.

    Google Scholar 

  48. Mehta K, Fok JY, Mangala LS. Tissue transglutaminase: from biological glue to cell survival cues. Front Biosci. 2006;11:173–85.

    Article  PubMed  Google Scholar 

  49. Nardacci R, Lo Iacono O, Ciccosanti F, et al. Transglutaminase type II plays a protective role in hepatic injury. Am J Pathol. 2003;162(4):1293–303.

    Article  PubMed  CAS  Google Scholar 

  50. Grenard P, Bresson-Hadni S, El Alaoui S, Chevallier M, Vuitton DA, Ricard-Blum S. Transglutaminase-mediated cross-linking is involved in the stabilization of extracellular matrix in human liver fibrosis. J Hepatol. 2001;35(3):367–75.

    Article  PubMed  CAS  Google Scholar 

  51. Mirza A, Liu SL, Frizell E, et al. A role for tissue transglutaminase in hepatic injury and fibrogenesis, and its regulation by NF-kappaB. Am J Physiol. 1997;272(2 Pt 1):G281–8.

    PubMed  CAS  Google Scholar 

  52. Desmouliere A, Darby I, Costa AM, et al. Extracellular matrix deposition, lysyl oxidase expression, and myofibroblastic differentiation during the initial stages of cholestatic fibrosis in the rat. Lab Invest. 1997;76(6):765–78.

    PubMed  CAS  Google Scholar 

  53. Kim Y, Peyrol S, So CK, Boyd CD, Csiszar K. Coexpression of the lysyl oxidase-like gene (LOXL) and the gene encoding type III procollagen in induced liver fibrosis. J Cell Biochem. 1999;72(2):181–8.

    Article  PubMed  Google Scholar 

  54. Fiume L. Inhibition by aminoacetonitrile of early lesions induced in the liver of rats by carbon tetrachloride. J Pathol Bacteriol. 1962;83:291–3.

    Article  PubMed  CAS  Google Scholar 

  55. Fiume L, Favilli G. Inhibition of experimental cirrhosis by carbon tetrachloride following treatment with aminoacetonitrile. Nature. 1961;189:71–2.

    Article  PubMed  CAS  Google Scholar 

  56. Vater CA, Harris Jr ED, Siegel RC. Native cross-links in collagen fibrils induce resistance to human synovial collagenase. Biochem J. 1979;181(3):639–45.

    PubMed  CAS  Google Scholar 

  57. Georges PC, Hui JJ, Gombos Z, et al. Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am J Physiol Gastrointest Liver Physiol. 2007;293(6):G1147–54.

    Article  PubMed  CAS  Google Scholar 

  58. Ricard-Blum S, Bresson-Hadni S, Vuitton DA, Ville G, Grimaud JA. Hydroxypyridinium collagen cross-links in human liver fibrosis: study of alveolar echinococcosis. Hepatology. 1992;15(4):599–602.

    Article  PubMed  CAS  Google Scholar 

  59. van der Slot AJ, Zuurmond AM, van den Bogaerdt AJ, et al. Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon. Matrix Biol. 2004;23(4):251–7.

    Article  PubMed  CAS  Google Scholar 

  60. Ramadori G, Knittel T, Saile B. Fibrosis and altered matrix synthesis. Digestion. 1998;59(4):372–5.

    Article  PubMed  CAS  Google Scholar 

  61. Geerts A, Schuppan D, Lazeroms S, De Zanger R, Wisse E. Collagen type I and III occur together in hybrid fibrils in the space of Disse of normal rat liver. Hepatology. 1990;12(2):233–41.

    Article  PubMed  CAS  Google Scholar 

  62. Romanic AM, Adachi E, Kadler KE, Hojima Y, Prockop DJ. Copolymerization of pNcollagen III and collagen I. pNcollagen III decreases the rate of incorporation of collagen I into fibrils, the amount of collagen I incorporated, and the diameter of the fibrils formed. J Biol Chem. 1991;266(19):12703–9.

    PubMed  CAS  Google Scholar 

  63. Knupp C, Squire JM. Molecular packing in network-forming collagens. Adv Protein Chem. 2005;70:375–403.

    Article  PubMed  CAS  Google Scholar 

  64. Herbst H, Frey A, Heinrichs O, et al. Heterogeneity of liver cells expressing procollagen types I and IV in vivo. Histochem Cell Biol. 1997;107(5):399–409.

    Article  PubMed  CAS  Google Scholar 

  65. Griffiths MR, Shepherd M, Ferrier R, Schuppan D, James OF, Burt AD. Light microscopic and ultrastructural distribution of type VI collagen in human liver: alterations in chronic biliary disease. Histopathology. 1992;21(4):335–44.

    Article  PubMed  CAS  Google Scholar 

  66. Keene DR, Engvall E, Glanville RW. Ultrastructure of type VI collagen in human skin and cartilage suggests an anchoring function for this filamentous network. J Cell Biol. 1988;107(5):1995–2006.

    Article  PubMed  CAS  Google Scholar 

  67. Freise C, Erben U, Muche M, et al. The alpha 2 chain of collagen type VI sequesters latent proforms of matrix-metalloproteinases and modulates their activation and activity. Matrix Biol. 2009;28(8):480–9.

    Article  PubMed  CAS  Google Scholar 

  68. Shuttleworth CA. Type VIII collagen. Int J Biochem Cell Biol. 1997;29(10):1145–8.

    Article  PubMed  CAS  Google Scholar 

  69. Schuppan D, Cantaluppi MC, Becker J, et al. Undulin, an extracellular matrix glycoprotein associated with collagen fibrils. J Biol Chem. 1990;265(15):8823–32.

    PubMed  CAS  Google Scholar 

  70. Milani S, Grappone C, Pellegrini G, et al. Undulin RNA and protein expression in normal and fibrotic human liver. Hepatology. 1994;20(4 Pt 1):908–16.

    Article  PubMed  CAS  Google Scholar 

  71. Berthod F, Germain L, Guignard R, et al. Differential expression of collagens XII and XIV in human skin and in reconstructed skin. J Invest Dermatol. 1997;108(5):737–42.

    Article  PubMed  CAS  Google Scholar 

  72. Ansorge HL, Meng X, Zhang G, et al. Type XIV Collagen Regulates Fibrillogenesis: premature collagen fibril growth and tissue dysfunction in null mice. J Biol Chem. 2009;284(13):8427–38.

    Article  PubMed  CAS  Google Scholar 

  73. Ruehl M, Erben U, Schuppan D, et al. The elongated first fibronectin type III domain of collagen XIV is an inducer of quiescence and differentiation in fibroblasts and preadipocytes. J Biol Chem. 2005;280(46):38537–43.

    Article  PubMed  CAS  Google Scholar 

  74. Tomono Y, Naito I, Ando K, et al. Epitope-defined monoclonal antibodies against multiplexin collagens demonstrate that type XV and XVIII collagens are expressed in specialized basement membranes. Cell Struct Funct. 2002;27(1):9–20.

    Article  PubMed  CAS  Google Scholar 

  75. Halfter W, Dong S, Schurer B, Cole GJ. Collagen XVIII is a basement membrane heparan sulfate proteoglycan. J Biol Chem. 1998;273(39):25404–12.

    Article  PubMed  CAS  Google Scholar 

  76. Iozzo RV. Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol. 2005;6(8):646–56.

    Article  PubMed  CAS  Google Scholar 

  77. Musso O, Rehn M, Saarela J, et al. Collagen XVIII is localized in sinusoids and basement membrane zones and expressed by hepatocytes and activated stellate cells in fibrotic human liver. Hepatology. 1998;28(1):98–107.

    Article  PubMed  CAS  Google Scholar 

  78. Jia JD, Bauer M, Sedlaczek N, et al. Modulation of collagen XVIII/endostatin expression in lobular and biliary rat liver fibrogenesis. J Hepatol. 2001;35(3):386–91.

    Article  PubMed  CAS  Google Scholar 

  79. White ES, Baralle FE, Muro AF. New insights into form and function of fibronectin splice variants. J Pathol. 2008;216(1):1–14.

    Article  PubMed  CAS  Google Scholar 

  80. Muro AF, Moretti FA, Moore BB, et al. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am J Respir Crit Care Med. 2008;177(6):638–45.

    Article  PubMed  CAS  Google Scholar 

  81. Muro AF, Chauhan AK, Gajovic S, et al. Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan. J Cell Biol. 2003;162(1):149–60.

    Article  PubMed  CAS  Google Scholar 

  82. Williams SA, Schwarzbauer JE. A shared mechanism of adhesion modulation for tenascin-C and fibulin-1. Mol Biol Cell. 2009;20(4):1141–9.

    Article  PubMed  CAS  Google Scholar 

  83. Van Eyken P, Sciot R, Desmet VJ. Expression of the novel extracellular matrix component tenascin in normal and diseased human liver. An immunohistochemical study. J Hepatol. 1990;11(1):43–52.

    Article  PubMed  Google Scholar 

  84. Van Eyken P, Geerts A, De Bleser P, et al. Localization and cellular source of the extracellular matrix protein tenascin in normal and fibrotic rat liver. Hepatology. 1992;15(5):909–16.

    Article  PubMed  Google Scholar 

  85. Yamada S, Ichida T, Matsuda Y, et al. Tenascin expression in human chronic liver disease and in hepatocellular carcinoma. Liver. 1992;12(1):10–6.

    PubMed  CAS  Google Scholar 

  86. Miyazaki H, Van Eyken P, Roskams T, De Vos R, Desmet VJ. Transient expression of tenascin in experimentally induced cholestatic fibrosis in rat liver: an immunohistochemical study. J Hepatol. 1993;19(3):353–66.

    Article  PubMed  CAS  Google Scholar 

  87. El-Karef A, Yoshida T, Gabazza EC, et al. Deficiency of tenascin-C attenuates liver fibrosis in immune-mediated chronic hepatitis in mice. J Pathol. 2007;211(1):86–94.

    Article  PubMed  CAS  Google Scholar 

  88. Piscaglia F, Dudas J, Knittel T, et al. Expression of ECM proteins fibulin-1 and -2 in acute and chronic liver disease and in cultured rat liver cells. Cell Tissue Res. 2009;337(3):449–62.

    Article  PubMed  CAS  Google Scholar 

  89. de Vega S, Iwamoto T, Yamada Y. Fibulins: multiple roles in matrix structures and tissue functions. Cell Mol Life Sci. 2009;66(11–12):1890–902.

    Article  PubMed  CAS  Google Scholar 

  90. Lorena D, Darby IA, Reinhardt DP, Sapin V, Rosenbaum J, Desmouliere A. Fibrillin-1 expression in normal and fibrotic rat liver and in cultured hepatic fibroblastic cells: modulation by mechanical stress and role in cell adhesion. Lab Invest. 2004;84(2):203–12.

    Article  PubMed  CAS  Google Scholar 

  91. Dubuisson L, Lepreux S, Bioulac-Sage P, et al. Expression and cellular localization of fibrillin-1 in normal and pathological human liver. J Hepatol. 2001;34(4):514–22.

    Article  PubMed  CAS  Google Scholar 

  92. Velebny V, Kasafirek E, Kanta J. Desmosine and isodesmosine contents and elastase activity in normal and cirrhotic rat liver. Biochem J. 1983;214(3):1023–5.

    PubMed  CAS  Google Scholar 

  93. Kanta J, Dooley S, Delvoux B, Breuer S, D’Amico T, Gressner AM. Tropoelastin expression is up-regulated during activation of hepatic stellate cells and in the livers of CCl(4)-cirrhotic rats. Liver. 2002;22(3):220–7.

    Article  PubMed  CAS  Google Scholar 

  94. Kielty CM, Sherratt MJ, Shuttleworth CA. Elastic fibres. J Cell Sci. 2002;115(Pt 14):2817–28.

    PubMed  CAS  Google Scholar 

  95. Porto LC, Chevallier M, Peyrol S, Guerret S, Grimaud JA. Elastin in human, baboon, and mouse liver: an immunohistochemical and immunoelectron microscopic study. Anat Rec. 1990;228(4):392–404.

    Article  PubMed  CAS  Google Scholar 

  96. Ramirez F, Sakai LY. Biogenesis and function of fibrillin assemblies. Cell Tissue Res. 2010;339(1):71–82.

    Article  PubMed  CAS  Google Scholar 

  97. Kovalszky II, Nagy JO, Gallai M, et al. Altered proteoglycan gene expression in human biliary cirrhosis. Pathol Oncol Res. 1997;3(1):51–8.

    Article  PubMed  Google Scholar 

  98. Gressner AM. Activation of proteoglycan synthesis in injured liver – a brief review of molecular and cellular aspects. Eur J Clin Chem Clin Biochem. 1994;32(4):225–37.

    PubMed  CAS  Google Scholar 

  99. Rescan PY, Loreal O, Hassell JR, Yamada Y, Guillouzo A, Clement B. Distribution and origin of the basement membrane component perlecan in rat liver and primary hepatocyte culture. Am J Pathol. 1993;142(1):199–208.

    PubMed  CAS  Google Scholar 

  100. Roskams T, Rosenbaum J, De Vos R, David G, Desmet V. Heparan sulfate proteoglycan expression in chronic cholestatic human liver diseases. Hepatology. 1996;24(3):524–32.

    Article  PubMed  CAS  Google Scholar 

  101. Gallai M, Kovalszky I, Knittel T, Neubauer K, Armbrust T, Ramadori G. Expression of extracellular matrix proteoglycans perlecan and decorin in carbon-tetrachloride-injured rat liver and in isolated liver cells. Am J Pathol. 1996;148(5):1463–71.

    PubMed  CAS  Google Scholar 

  102. Meyer DH, Krull N, Dreher KL, Gressner AM. Biglycan and decorin gene expression in normal and fibrotic rat liver: cellular localization and regulatory factors. Hepatology. 1992;16(1):204–16.

    Article  PubMed  CAS  Google Scholar 

  103. Krull NB, Gressner AM. Differential expression of keratan sulphate proteoglycans fibromodulin, lumican and aggrecan in normal and fibrotic rat liver. FEBS Lett. 1992;312(1):47–52.

    Article  PubMed  CAS  Google Scholar 

  104. Hogemann B, Edel G, Schwarz K, Krech R, Kresse H. Expression of biglycan, decorin and proteoglycan-100/CSF-1 in normal and fibrotic human liver. Pathol Res Pract. 1997;193(11–12):747–51.

    Article  PubMed  CAS  Google Scholar 

  105. Kalamajski S, Oldberg A. The role of small leucine-rich proteoglycans in collagen fibrillogenesis. Matrix Biol. 2010;29(4):248–53.

    Article  PubMed  CAS  Google Scholar 

  106. Chakravarti S. Functions of lumican and fibromodulin: lessons from knockout mice. Glycoconj J. 2002;19(4–5):287–93.

    Article  PubMed  CAS  Google Scholar 

  107. Webber J, Jenkins RH, Meran S, Phillips A, Steadman R. Modulation of TGFbeta1-dependent myofibroblast differentiation by hyaluronan. Am J Pathol. 2009;175(1):148–60.

    Article  PubMed  CAS  Google Scholar 

  108. Kikuchi S, Griffin CT, Wang SS, Bissell DM. Role of CD44 in epithelial wound repair: migration of rat hepatic stellate cells utilizes hyaluronic acid and CD44v6. J Biol Chem. 2005;280(15):15398–404.

    Article  PubMed  CAS  Google Scholar 

  109. Scott JE, Bosworth TR, Cribb AM, Gressner AM. The chemical morphology of extracellular matrix in experimental rat liver fibrosis resembles that of normal developing connective tissue. Virchows Arch. 1994;424(1):89–98.

    Article  PubMed  CAS  Google Scholar 

  110. Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003;200(4):500–3.

    Article  PubMed  CAS  Google Scholar 

  111. Taura K, Miura K, Iwaisako K, et al. Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology. 2010;51(3):1027–36.

    Article  PubMed  Google Scholar 

  112. Magness ST, Bataller R, Yang L, Brenner DA. A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations. Hepatology. 2004;40(5):1151–9.

    Article  PubMed  CAS  Google Scholar 

  113. Yamaoka K, Nouchi T, Marumo F, Sato C. Alpha-smooth-muscle actin expression in normal and fibrotic human livers. Dig Dis Sci. 1993;38(8):1473–9.

    Article  PubMed  CAS  Google Scholar 

  114. Novo E, di Bonzo LV, Cannito S, Colombatto S, Parola M. Hepatic myofibroblasts: a heterogeneous population of multifunctional cells in liver fibrogenesis. Int J Biochem Cell Biol. 2009;41(11):2089–93.

    Article  PubMed  CAS  Google Scholar 

  115. Guyot C, Lepreux S, Combe C, et al. Hepatic fibrosis and cirrhosis: the (myo)fibroblastic cell subpopulations involved. Int J Biochem Cell Biol. 2006;38(2):135–51.

    PubMed  CAS  Google Scholar 

  116. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170(6):1807–16.

    Article  PubMed  CAS  Google Scholar 

  117. Russo FP, Alison MR, Bigger BW, et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology. 2006;130(6):1807–21.

    Article  PubMed  Google Scholar 

  118. Asahina K, Tsai SY, Li P, et al. Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver development. Hepatology. 2009;49(3):998–1011.

    Article  PubMed  CAS  Google Scholar 

  119. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88(1):125–72.

    Article  PubMed  CAS  Google Scholar 

  120. Friedman SL, Roll FJ, Boyles J, Bissell DM. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci U S A. 1985;82(24):8681–5.

    Article  PubMed  CAS  Google Scholar 

  121. Maher JJ, McGuire RF. Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo. J Clin Invest. 1990;86(5):1641–8.

    Article  PubMed  CAS  Google Scholar 

  122. Nakatsukasa H, Nagy P, Evarts RP, Hsia CC, Marsden E, Thorgeirsson SS. 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(6):1833–43.

    Article  PubMed  CAS  Google Scholar 

  123. Knook DL, Seffelaar AM, de Leeuw AM. Fat-storing cells of the rat liver. Their isolation and purification. Exp Cell Res. 1982;139(2):468–71.

    Article  PubMed  CAS  Google Scholar 

  124. Friedman SL, Roll FJ. Isolation and culture of hepatic lipocytes, Kupffer cells, and sinusoidal endothelial cells by density gradient centrifugation with Stractan. Anal Biochem. 1987;161(1):207–18.

    Article  PubMed  CAS  Google Scholar 

  125. De Minicis S, Seki E, Uchinami H, et al. Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology. 2007;132(5):1937–46.

    Article  PubMed  CAS  Google Scholar 

  126. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209–18.

    PubMed  CAS  Google Scholar 

  127. Wallace K, Burt AD, Wright MC. Liver fibrosis. Biochem J. 2008;411(1):1–18.

    Article  PubMed  CAS  Google Scholar 

  128. Geerts A, Eliasson C, Niki T, Wielant A, Vaeyens F, Pekny M. Formation of normal desmin intermediate filaments in mouse hepatic stellate cells requires vimentin. Hepatology. 2001;33(1):177–88.

    Article  PubMed  CAS  Google Scholar 

  129. Van Rossen E, Vander Borght S, van Grunsven LA, et al. Vinculin and cellular retinol-binding protein-1 are markers for quiescent and activated hepatic stellate cells in formalin-fixed paraffin embedded human liver. Histochem Cell Biol. 2009;131(3):313–25.

    Article  PubMed  CAS  Google Scholar 

  130. Suzuki K, Tanaka M, Watanabe N, Saito S, Nonaka H, Miyajima A. p75 Neurotrophin receptor is a marker for precursors of stellate cells and portal fibroblasts in mouse fetal liver. Gastroenterology. 2008;135(1):270–81.

    Article  PubMed  CAS  Google Scholar 

  131. Dranoff JA, Wells RG. Portal fibroblasts: underappreciated mediators of biliary fibrosis. Hepatology. 2010;51(4):1438–44.

    Article  PubMed  Google Scholar 

  132. Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol. 2002;36(2):200–9.

    Article  PubMed  Google Scholar 

  133. 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(5):387–401.

    Article  PubMed  CAS  Google Scholar 

  134. 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(5):1205–21.

    Article  PubMed  CAS  Google Scholar 

  135. Kinnman N, Housset C. Peribiliary myofibroblasts in biliary type liver fibrosis. Front Biosci. 2002;7:d496–503.

    Article  PubMed  CAS  Google Scholar 

  136. Beaussier M, Wendum D, Schiffer E, et al. Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. Lab Invest. 2007;87(3):292–303.

    Article  PubMed  CAS  Google Scholar 

  137. Tuchweber B, Desmouliere A, Bochaton-Piallat ML, Rubbia-Brandt L, Gabbiani G. Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the rat. Lab Invest. 1996;74(1):265–78.

    PubMed  CAS  Google Scholar 

  138. Alpini G, McGill JM, Larusso NF. The pathobiology of biliary epithelia. Hepatology. 2002;35(5):1256–68.

    Article  PubMed  CAS  Google Scholar 

  139. Baba S, Fujii H, Hirose T, et al. Commitment of bone marrow cells to hepatic stellate cells in mouse. J Hepatol. 2004;40(2):255–60.

    Article  PubMed  Google Scholar 

  140. Forbes SJ, Russo FP, Rey V, et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology. 2004;126(4):955–63.

    Article  PubMed  Google Scholar 

  141. Kisseleva T, Uchinami H, Feirt N, et al. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol. 2006;45(3):429–38.

    Article  PubMed  CAS  Google Scholar 

  142. Kallis YN, Forbes SJ. The bone marrow and liver fibrosis: friend or foe? Gastroenterology. 2009;137(4):1218–21.

    Article  PubMed  CAS  Google Scholar 

  143. Milani S, Herbst H, Schuppan D, Hahn EG, Stein H. In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: evidence for predominant expression in nonparenchymal liver cells. Hepatology. 1989;10(1):84–92.

    Article  PubMed  CAS  Google Scholar 

  144. Tamkun JW, Hynes RO. Plasma fibronectin is synthesized and secreted by hepatocytes. J Biol Chem. 1983;258(7):4641–7.

    PubMed  CAS  Google Scholar 

  145. Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A. Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem. 2007;282(30):22089–101.

    Article  PubMed  CAS  Google Scholar 

  146. Zeisberg M, Yang C, Martino M, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem. 2007;282(32):23337–47.

    Article  PubMed  CAS  Google Scholar 

  147. Milani S, Herbst H, Schuppan D, Riecken EO, Stein H. Cellular localization of laminin gene transcripts in normal and fibrotic human liver. Am J Pathol. 1989;134(6):1175–82.

    PubMed  CAS  Google Scholar 

  148. Diaz R, Kim JW, Hui JJ, et al. Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis. Hum Pathol. 2008;39(1):102–15.

    Article  PubMed  CAS  Google Scholar 

  149. Rygiel KA, Robertson H, Marshall HL, et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest. 2008;88(2):112–23.

    Article  PubMed  CAS  Google Scholar 

  150. Xia JL, Dai C, Michalopoulos GK, Liu Y. Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation. Am J Pathol. 2006;168(5):1500–12.

    Article  PubMed  CAS  Google Scholar 

  151. Robertson H, Kirby JA, Yip WW, Jones DE, Burt AD. Biliary epithelial-mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis. Hepatology. 2007;45(4):977–81.

    Article  PubMed  CAS  Google Scholar 

  152. Bardadin KA, Desmet VJ. Ultrastructural observations on sinusoidal endothelial cells in chronic active hepatitis. Histopathology. 1985;9(2):171–81.

    Article  PubMed  CAS  Google Scholar 

  153. Horn T, Junge J, Christoffersen P. Early alcoholic liver injury: changes of the Disse space in acinar zone 3. Liver. 1985;5(6):301–10.

    PubMed  CAS  Google Scholar 

  154. DeLeve LD. Hepatic microvasculature in liver injury. Semin Liver Dis. 2007;27(4):390–400.

    Article  PubMed  CAS  Google Scholar 

  155. Clement B, Rescan PY, Baffet G, et al. Hepatocytes may produce laminin in fibrotic liver and in primary culture. Hepatology. 1988;8(4):794–803.

    Article  PubMed  CAS  Google Scholar 

  156. Geerts A, Greenwel P, Cunningham M, et al. Identification of connective tissue gene transcripts in freshly isolated parenchymal, endothelial, Kupffer and fat-storing cells by northern hybridization analysis. J Hepatol. 1993;19(1):148–58.

    Article  PubMed  CAS  Google Scholar 

  157. Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology. 2008;48(3):920–30.

    Article  PubMed  CAS  Google Scholar 

  158. Jarnagin WR, Rockey DC, Koteliansky VE, Wang SS, Bissell DM. Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis. J Cell Biol. 1994;127(6 Pt 2):2037–48.

    Article  PubMed  CAS  Google Scholar 

  159. Thiele GM, Duryee MJ, Freeman TL, et al. Rat sinusoidal liver endothelial cells (SECs) produce pro-fibrotic factors in response to adducts formed from the metabolites of ethanol. Biochem Pharmacol. 2005;70(11):1593–600.

    Article  PubMed  CAS  Google Scholar 

  160. Tan J, Hytiroglou P, Wieczorek R, et al. Immunohistochemical evidence for hepatic progenitor cells in liver diseases. Liver. 2002;22(5):365–73.

    Article  PubMed  Google Scholar 

  161. Thorgeirsson SS. Hepatic stem cells in liver regeneration. FASEB J. 1996;10(11):1249–56.

    PubMed  CAS  Google Scholar 

  162. Alison M, Golding M, Lalani elN, Sarraf C. Wound healing in the liver with particular reference to stem cells. Philos Trans R Soc Lond B Biol Sci. 1998;353(1370):877–94.

    Article  PubMed  CAS  Google Scholar 

  163. Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology. 2005;41(4):809–18.

    Article  PubMed  CAS  Google Scholar 

  164. Richardson MM, Jonsson JR, Powell EE, et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology. 2007;133(1):80–90.

    Article  PubMed  Google Scholar 

  165. Fabris L, Cadamuro M, Guido M, et al. Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling. Am J Pathol. 2007;171(2):641–53.

    Article  PubMed  CAS  Google Scholar 

  166. Strick-Marchand H, Masse GX, Weiss MC, Di Santo JP. Lymphocytes support oval cell-dependent liver regeneration. J Immunol. 2008;181(4):2764–71.

    PubMed  CAS  Google Scholar 

  167. Ruddell RG, Knight B, Tirnitz-Parker JE, et al. Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury. Hepatology. 2009;49(1):227–39.

    Article  PubMed  CAS  Google Scholar 

  168. Parekkadan B, van Poll D, Megeed Z, et al. Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun. 2007;363(2):247–52.

    Article  PubMed  CAS  Google Scholar 

  169. Braun KM, Thompson AW, Sandgren EP. Hepatic microenvironment affects oval cell localization in albumin-urokinase-type plasminogen activator transgenic mice. Am J Pathol. 2003;162(1):195–202.

    Article  PubMed  Google Scholar 

  170. Knight B, Lim R, Yeoh GC, Olynyk JK. Interferon-gamma exacerbates liver damage, the hepatic progenitor cell response and fibrosis in a mouse model of chronic liver injury. J Hepatol. 2007;47(6):826–33.

    Article  PubMed  CAS  Google Scholar 

  171. Roskams T. Relationships among stellate cell activation, progenitor cells, and hepatic regeneration. Clin Liver Dis. 2008;12(4):853–60, ix.

    Google Scholar 

  172. Zhang W, Chen XP, Zhang WG, et al. Hepatic non-parenchymal cells and extracellular matrix participate in oval cell-mediated liver regeneration. World J Gastroenterol. 2009;15(5):552–60.

    Article  PubMed  CAS  Google Scholar 

  173. Van Hul NK, Abarca-Quinones J, Sempoux C, Horsmans Y, Leclercq IA. Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury. Hepatology. 2009;49(5):1625–35.

    Article  PubMed  CAS  Google Scholar 

  174. Kordes C, Sawitza I, Muller-Marbach A, et al. CD133+ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun. 2007;352(2):410–7.

    Article  PubMed  CAS  Google Scholar 

  175. Miyata E, Masuya M, Yoshida S, et al. Hematopoietic origin of hepatic stellate cells in the adult liver. Blood. 2008;111(4):2427–35.

    Article  PubMed  CAS  Google Scholar 

  176. Sicklick JK, Choi SS, Bustamante M, et al. Evidence for epithelial-mesenchymal transitions in adult liver cells. Am J Physiol Gastrointest Liver Physiol. 2006;291(4):G575–83.

    Article  PubMed  CAS  Google Scholar 

  177. Yang L, Jung Y, Omenetti A, et al. Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells. 2008;26(8):2104–13.

    Article  PubMed  CAS  Google Scholar 

  178. Wu J, Norton PA. Animal models of liver fibrosis. Scand J Gastroenterol. 1996;31(12):1137–43.

    Article  PubMed  CAS  Google Scholar 

  179. Weiler-Normann C, Herkel J, Lohse AW. Mouse models of liver fibrosis. Z Gastroenterol. 2007;45(1):43–50.

    Article  PubMed  CAS  Google Scholar 

  180. Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci. 2002;7:d793–807.

    Article  PubMed  CAS  Google Scholar 

  181. Inagaki Y, Okazaki I. Emerging insights into Transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut. 2007;56(2):284–92.

    Article  PubMed  CAS  Google Scholar 

  182. Breitkopf K, Godoy P, Ciuclan L, Singer MV, Dooley S. TGF-beta/Smad signaling in the injured liver. Z Gastroenterol. 2006;44(1):57–66.

    Article  PubMed  CAS  Google Scholar 

  183. Flanders KC. Smad3 as a mediator of the fibrotic response. Int J Exp Pathol. 2004;85(2):47–64.

    Article  PubMed  CAS  Google Scholar 

  184. Latella G, Vetuschi A, Sferra R, et al. Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice. Liver Int. 2009;29(7):997–1009.

    Article  PubMed  CAS  Google Scholar 

  185. Pinzani M. PDGF and signal transduction in hepatic stellate cells. Front Biosci. 2002;7:d1720–6.

    Article  PubMed  CAS  Google Scholar 

  186. 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(9):1347–54.

    Article  PubMed  CAS  Google Scholar 

  187. Czochra P, Klopcic B, Meyer E, et al. Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. J Hepatol. 2006;45(3):419–28.

    Article  PubMed  CAS  Google Scholar 

  188. Gressner OA, Gressner AM. Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int. 2008;28(8):1065–79.

    Article  PubMed  CAS  Google Scholar 

  189. Tong Z, Chen R, Alt DS, Kemper S, Perbal B, Brigstock DR. Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes. Hepatology. 2009;50(3):939–47.

    Article  PubMed  CAS  Google Scholar 

  190. Seki E, de Minicis S, Inokuchi S, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50(1):185–97.

    Article  PubMed  CAS  Google Scholar 

  191. Marra F, DeFranco R, Grappone C, et al. Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol. 1998;152(2):423–30.

    PubMed  CAS  Google Scholar 

  192. Ding X, Saxena NK, Lin S, Xu A, Srinivasan S, Anania FA. The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol. 2005;166(6):1655–69.

    Article  PubMed  CAS  Google Scholar 

  193. Marra F, Bertolani C. Adipokines in liver diseases. Hepatology. 2009;50(3):957–69.

    Article  PubMed  CAS  Google Scholar 

  194. She H, Xiong S, Hazra S, Tsukamoto H. Adipogenic transcriptional regulation of hepatic stellate cells. J Biol Chem. 2005;280(6):4959–67.

    Article  PubMed  CAS  Google Scholar 

  195. Yang L, Chan CC, Kwon OS, et al. Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2006;291(5):G902–11.

    Article  PubMed  CAS  Google Scholar 

  196. Rockey DC. Vascular mediators in the injured liver. Hepatology. 2003;37(1):4–12.

    Article  PubMed  CAS  Google Scholar 

  197. Soon RK Jr, Yee HF Jr. Stellate cell contraction: role, regulation, and potential therapeutic target. Clin Liver Dis. 2008;12(4):791–803, viii.

    Google Scholar 

  198. Urtasun R, Conde de la Rosa L, Nieto N. Oxidative and nitrosative stress and fibrogenic response. Clin Liver Dis. 2008;12(4):769–90, viii.

    Google Scholar 

  199. Canbay A, Feldstein AE, Higuchi H, et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology. 2003;38(5):1188–98.

    Article  PubMed  CAS  Google Scholar 

  200. Zhan SS, Jiang JX, Wu J, et al. Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology. 2006;43(3):435–43.

    Article  PubMed  CAS  Google Scholar 

  201. Mallat A, Lotersztajn S. Endocannabinoids and liver disease. I. Endocannabinoids and their receptors in the liver. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G9–12.

    Article  PubMed  CAS  Google Scholar 

  202. Siegmund SV, Schwabe RF. Endocannabinoids and liver disease. II. Endocannabinoids in the pathogenesis and treatment of liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2008;294(2): G357–62.

    Article  PubMed  CAS  Google Scholar 

  203. Ishida JH, Peters MG, Jin C, et al. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol. 2008;6(1):69–75.

    Article  PubMed  Google Scholar 

  204. Mallat A, Lotersztajn S. Cannabinoid receptors as novel therapeutic targets for the management of non-alcoholic steatohepatitis. Diabetes Metab. 2008;34(6 Pt 2):680–4.

    Article  PubMed  CAS  Google Scholar 

  205. Lubel JS, Herath CB, Burrell LM, Angus PW. Liver disease and the renin-angiotensin system: recent discoveries and clinical implications. J Gastroenterol Hepatol. 2008;23(9):1327–38.

    Article  PubMed  CAS  Google Scholar 

  206. Bataller R, Sancho-Bru P, Gines P, Brenner DA. Liver fibrogenesis: a new role for the renin-angiotensin system. Antioxid Redox Signal. 2005;7(9–10):1346–55.

    Article  PubMed  CAS  Google Scholar 

  207. Li Z, Dranoff JA, Chan EP, Uemura M, Sevigny J, Wells RG. Transforming growth factor-beta and substrate stiffness regulate portal­ fibroblast activation in culture. Hepatology. 2007;46(4):1246–56.

    Article  PubMed  CAS  Google Scholar 

  208. Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology. 2008;47(4):1394–400.

    Article  PubMed  CAS  Google Scholar 

  209. Wipff PJ, Hinz B. Integrins and the activation of latent transforming growth factor beta1 – an intimate relationship. Eur J Cell Biol. 2008;87(8–9):601–15.

    Article  PubMed  CAS  Google Scholar 

  210. Novobrantseva TI, Majeau GR, Amatucci A, et al. Attenuated liver fibrosis in the absence of B cells. J Clin Invest. 2005;115(11):3072–82.

    Article  PubMed  CAS  Google Scholar 

  211. Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol. 2009;86(3):513–28.

    PubMed  CAS  Google Scholar 

  212. Marra F, Aleffi S, Galastri S, Provenzano A. Mononuclear cells in liver fibrosis. Semin Immunopathol. 2009;31(3):345–58.

    Article  PubMed  CAS  Google Scholar 

  213. Winau F, Hegasy G, Weiskirchen R, et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity. 2007;26(1):117–29.

    Article  PubMed  CAS  Google Scholar 

  214. Watanabe A, Sohail MA, Gomes DA, et al. Inflammasome-mediated regulation of hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2009;296(6):G1248–57.

    Article  PubMed  CAS  Google Scholar 

  215. Connolly MK, Bedrosian AS, Mallen-St Clair J, et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J Clin Invest. 2009;119(11):3213–25.

    PubMed  CAS  Google Scholar 

  216. Seki E, De Minicis S, Osterreicher CH, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13(11):1324–32.

    Article  PubMed  CAS  Google Scholar 

  217. Mencin A, Kluwe J, Schwabe RF. Toll-like receptors as targets in chronic liver diseases. Gut. 2009;58(5):704–20.

    Article  PubMed  CAS  Google Scholar 

  218. Miele L, Beale G, Patman G, et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology. 2008;135(1):282–91.

    Article  PubMed  CAS  Google Scholar 

  219. Guo J, Loke J, Zheng F, et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology. 2009;49(3):960–8.

    Article  PubMed  CAS  Google Scholar 

  220. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis: definition, nomenclature, and classification. Bull World Health Organ. 1977;55(4):521–40.

    PubMed  CAS  Google Scholar 

  221. Fauerholdt L, Schlichting P, Christensen E, Poulsen H, Tygstrup N, Juhl E. Conversion of micronodular cirrhosis into macronodular cirrhosis. Hepatology. 1983;3(6):928–31.

    Article  PubMed  CAS  Google Scholar 

  222. Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med. 2000;124(11):1599–607.

    PubMed  CAS  Google Scholar 

  223. Pinzani M, Vizzutti F. Fibrosis and cirrhosis reversibility: clinical features and implications. Clin Liver Dis. 2008;12(4):901–13, x.

    Google Scholar 

  224. Desmet VJ, Roskams T. Cirrhosis reversal: a duel between dogma and myth. J Hepatol. 2004;40(5):860–7.

    Article  PubMed  Google Scholar 

  225. Popper H. Pathologic aspects of cirrhosis. A review. Am J Pathol. 1977;87(1):228–64.

    PubMed  CAS  Google Scholar 

  226. Gieling RG, Burt AD, Mann DA. Fibrosis and cirrhosis reversibility – molecular mechanisms. Clin Liver Dis. 2008;12(4):915–37, xi.

    Google Scholar 

  227. Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009;50(3):604–20.

    Article  PubMed  CAS  Google Scholar 

  228. Novo E, Cannito S, Zamara E, et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol. 2007;170(6):1942–53.

    Article  PubMed  CAS  Google Scholar 

  229. Semela D, Das A, Langer D, Kang N, Leof E, Shah V. Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterology. 2008;135(2):671–9.

    Article  PubMed  CAS  Google Scholar 

  230. Lee JS, Semela D, Iredale J, Shah VH. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? Hepatology. 2007;45(3):817–25.

    Article  PubMed  CAS  Google Scholar 

  231. Corpechot C, Barbu V, Wendum D, et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology. 2002;35(5):1010–21.

    Article  PubMed  CAS  Google Scholar 

  232. Wood AJ, Villeneuve JP, Branch RA, Rogers LW, Shand DG. Intact hepatocyte theory of impaired drug metabolism in experimental cirrhosis in the rat. Gastroenterology. 1979;76(6):1358–62.

    PubMed  CAS  Google Scholar 

  233. Racine-Samson L, Scoazec JY, D’Errico A, et al. The metabolic organization of the adult human liver: a comparative study of normal, fibrotic, and cirrhotic liver tissue. Hepatology. 1996;24(1):104–13.

    Article  PubMed  CAS  Google Scholar 

  234. Benyon RC, Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis. 2001;21(3):373–84.

    Article  PubMed  CAS  Google Scholar 

  235. Theret N, Lehti K, Musso O, Clement B. MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells. Hepatology. 1999;30(2):462–8.

    Article  PubMed  CAS  Google Scholar 

  236. Benyon RC, Iredale JP, Goddard S, Winwood PJ, Arthur MJ. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology. 1996;110(3):821–31.

    Article  PubMed  CAS  Google Scholar 

  237. Iredale JP, Benyon RC, Arthur MJ, 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(1):176–84.

    Article  PubMed  CAS  Google Scholar 

  238. Herbst H, Wege T, Milani S, et al. Tissue inhibitor of metalloproteinase-1 and -2 RNA expression in rat and human liver fibrosis. Am J Pathol. 1997;150(5):1647–59.

    PubMed  CAS  Google Scholar 

  239. Murawaki Y, Ikuta Y, Idobe Y, Kitamura Y, Kawasaki H. Tissue inhibitor of metalloproteinase-1 in the liver of patients with chronic liver disease. J Hepatol. 1997;26(6):1213–9.

    Article  PubMed  CAS  Google Scholar 

  240. 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(6):1248–54.

    Article  PubMed  CAS  Google Scholar 

  241. Takahara T, Furui K, Funaki J, et al. Increased expression of matrix metalloproteinase-II in experimental liver fibrosis in rats. Hepatology. 1995;21(3):787–95.

    Article  PubMed  CAS  Google Scholar 

  242. Takahara T, Furui K, Yata Y, et al. Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers. Hepatology. 1997;26(6):1521–9.

    Article  PubMed  CAS  Google Scholar 

  243. Friedman SL, Bansal MB. Reversal of hepatic fibrosis – fact or fantasy? Hepatology. 2006;43(2 Suppl 1):S82–8.

    Article  PubMed  CAS  Google Scholar 

  244. Quinn PS, Higginson J. Reversible and irreversible changes in experimental cirrhosis. Am J Pathol. 1965;47:353–69.

    PubMed  CAS  Google Scholar 

  245. Perez-Tamayo R. Cirrhosis of the liver: a reversible disease? Pathol Annu. 1979;14(Pt 2):183–213.

    PubMed  Google Scholar 

  246. Iredale JP, Benyon RC, Pickering J, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest. 1998;102(3):538–49.

    Article  PubMed  CAS  Google Scholar 

  247. Fallowfield JA, Kendall TJ, Iredale JP. Reversal of fibrosis: no longer a pipe dream? Clin Liver Dis. 2006;10(3):481–97, viii.

    Google Scholar 

  248. Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology. 2009;49(4):1245–56.

    Article  PubMed  CAS  Google Scholar 

  249. Tugues S, Fernandez-Varo G, Munoz-Luque J, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology. 2007;46(6):1919–26.

    Article  PubMed  CAS  Google Scholar 

  250. Issa R, Zhou X, Trim N, et al. Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. FASEB J. 2003;17(1):47–9.

    PubMed  CAS  Google Scholar 

  251. Duffield JS, Forbes SJ, Constandinou CM, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115(1):56–65.

    PubMed  CAS  Google Scholar 

  252. Fallowfield JA, Mizuno M, Kendall TJ, et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007;178(8):5288–95.

    PubMed  CAS  Google Scholar 

  253. Wright MC, Issa R, Smart DE, et al. Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology. 2001;121(3):685–98.

    Article  PubMed  CAS  Google Scholar 

  254. Kweon YO, Paik YH, Schnabl B, Qian T, Lemasters JJ, Brenner DA. Gliotoxin-mediated apoptosis of activated human hepatic stellate cells. J Hepatol. 2003;39(1):38–46.

    Article  PubMed  CAS  Google Scholar 

  255. Novo E, Marra F, Zamara E, et al. Overexpression of Bcl-2 by activated human hepatic stellate cells: resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans. Gut. 2006;55(8):1174–82.

    Article  PubMed  CAS  Google Scholar 

  256. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481–8.

    Article  PubMed  CAS  Google Scholar 

  257. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–9.

    Article  PubMed  CAS  Google Scholar 

  258. Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg. 1997;3(6):628–37.

    Article  PubMed  CAS  Google Scholar 

  259. Christensen E, Schlichting P, Fauerholdt L, et al. Prognostic value of Child-Turcotte criteria in medically treated cirrhosis. Hepatology. 1984;4(3):430–5.

    Article  PubMed  CAS  Google Scholar 

  260. http://www.unos.org/resources/meldpeldcalculator.asp. Accessed 5 March 2010.

  261. Boursier J, Cesbron E, Tropet AL, Pilette C. Comparison and improvement of MELD and Child-Pugh score accuracies for the prediction of 6-month mortality in cirrhotic patients. J Clin Gastroenterol. 2009;43(6):580–5.

    Article  PubMed  Google Scholar 

  262. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464–70.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Rebecca G. Wells

Authors
  1. Rebecca G. Wells
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rebecca G. Wells .

Editor information

Editors and Affiliations

  1. School of Medicine, Dept. Pathology, University of Pittsburgh, 200 Lothrop Street, S421-BST, Pittsburgh, 15261, Pennsylvania, USA

    Satdarshan P. S. Monga

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Wells, R.G. (2011). Hepatic Fibrosis and Cirrhosis. In: Monga, S. (eds) Molecular Pathology of Liver Diseases. Molecular Pathology Library, vol 5. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7107-4_30

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-7107-4_30

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4419-7106-7

  • Online ISBN: 978-1-4419-7107-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation