Hepatic Fibrosis and Cirrhosis

  • Rebecca G. Wells
Part of the Molecular Pathology Library book series (MPLB, volume 5)


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].


Hepatic Stellate Cell Biliary Atresia Sinusoidal Endothelial Cell Fibrillar Collagen Hepatic Venous Pressure Gradient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 3.
    Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology. 2004;39(6):1477–87.PubMedCrossRefGoogle Scholar
  4. 4.
    Greenbaum LE, Wells RG. The role of stem cells in liver repair and fibrosis. Int J Biochem Cell Biol. 2009.Google Scholar
  5. 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. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 9.
    Mallat A, Hezode C, Lotersztajn S. Environmental factors as disease accelerators during chronic hepatitis C. J Hepatol. 2008;48(4):657–65.PubMedCrossRefGoogle Scholar
  10. 10.
    Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38(6):1449–57.PubMedGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 12.
    Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol. 2007;47(4):598–607.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 14.
    Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22(6):696–9.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 18.
    Scheuer P. Primary biliary cirrhosis. Proc R Soc Med. 1967;60(12):1257–60.PubMedGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 21.
    Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol. 2004;99(6):1160–74.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 24.
    Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655–69.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Brenner DA, Waterboer T, Choi SK, et al. New aspects of hepatic fibrosis. J Hepatol. 2000;32(1 Suppl):32–8.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 33.
    Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis. 2001;21(3):351–72.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 35.
    Schaffner F, Popper H. Capillarization of the hepatic sinusoids in man. Gastroenterology. 1963;44:239–42.PubMedGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 43.
    Gressner OA, Weiskirchen R, Gressner AM. Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options. Comp Hepatol. 2007;6:7.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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. 46.
    Kivirikko KI, Myllyla R. Post-translational processing of procollagens. Ann N Y Acad Sci. 1985;460:187–201.PubMedCrossRefGoogle Scholar
  47. 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. 48.
    Mehta K, Fok JY, Mangala LS. Tissue transglutaminase: from biological glue to cell survival cues. Front Biosci. 2006;11:173–85.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.PubMedGoogle Scholar
  53. 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.PubMedCrossRefGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 55.
    Fiume L, Favilli G. Inhibition of experimental cirrhosis by carbon tetrachloride following treatment with aminoacetonitrile. Nature. 1961;189:71–2.PubMedCrossRefGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 60.
    Ramadori G, Knittel T, Saile B. Fibrosis and altered matrix synthesis. Digestion. 1998;59(4):372–5.PubMedCrossRefGoogle Scholar
  61. 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.PubMedCrossRefGoogle Scholar
  62. 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.PubMedGoogle Scholar
  63. 63.
    Knupp C, Squire JM. Molecular packing in network-forming collagens. Adv Protein Chem. 2005;70:375–403.PubMedCrossRefGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 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.PubMedCrossRefGoogle Scholar
  68. 68.
    Shuttleworth CA. Type VIII collagen. Int J Biochem Cell Biol. 1997;29(10):1145–8.PubMedCrossRefGoogle Scholar
  69. 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.PubMedGoogle Scholar
  70. 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.PubMedCrossRefGoogle Scholar
  71. 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.PubMedCrossRefGoogle Scholar
  72. 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.PubMedCrossRefGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. 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.PubMedCrossRefGoogle Scholar
  75. 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.PubMedCrossRefGoogle Scholar
  76. 76.
    Iozzo RV. Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol. 2005;6(8):646–56.PubMedCrossRefGoogle Scholar
  77. 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.PubMedCrossRefGoogle Scholar
  78. 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.PubMedCrossRefGoogle Scholar
  79. 79.
    White ES, Baralle FE, Muro AF. New insights into form and function of fibronectin splice variants. J Pathol. 2008;216(1):1–14.PubMedCrossRefGoogle Scholar
  80. 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.PubMedCrossRefGoogle Scholar
  81. 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.PubMedCrossRefGoogle Scholar
  82. 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.PubMedCrossRefGoogle Scholar
  83. 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.PubMedCrossRefGoogle Scholar
  84. 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.PubMedCrossRefGoogle Scholar
  85. 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.PubMedGoogle Scholar
  86. 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.PubMedCrossRefGoogle Scholar
  87. 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.PubMedCrossRefGoogle Scholar
  88. 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.PubMedCrossRefGoogle Scholar
  89. 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.PubMedCrossRefGoogle Scholar
  90. 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.PubMedCrossRefGoogle Scholar
  91. 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.PubMedCrossRefGoogle Scholar
  92. 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.PubMedGoogle Scholar
  93. 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.PubMedCrossRefGoogle Scholar
  94. 94.
    Kielty CM, Sherratt MJ, Shuttleworth CA. Elastic fibres. J Cell Sci. 2002;115(Pt 14):2817–28.PubMedGoogle Scholar
  95. 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.PubMedCrossRefGoogle Scholar
  96. 96.
    Ramirez F, Sakai LY. Biogenesis and function of fibrillin assemblies. Cell Tissue Res. 2010;339(1):71–82.PubMedCrossRefGoogle Scholar
  97. 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.PubMedCrossRefGoogle Scholar
  98. 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.PubMedGoogle Scholar
  99. 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.PubMedGoogle Scholar
  100. 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.PubMedCrossRefGoogle Scholar
  101. 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.PubMedGoogle Scholar
  102. 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.PubMedCrossRefGoogle Scholar
  103. 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.PubMedCrossRefGoogle Scholar
  104. 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.PubMedCrossRefGoogle Scholar
  105. 105.
    Kalamajski S, Oldberg A. The role of small leucine-rich proteoglycans in collagen fibrillogenesis. Matrix Biol. 2010;29(4):248–53.PubMedCrossRefGoogle Scholar
  106. 106.
    Chakravarti S. Functions of lumican and fibromodulin: lessons from knockout mice. Glycoconj J. 2002;19(4–5):287–93.PubMedCrossRefGoogle Scholar
  107. 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.PubMedCrossRefGoogle Scholar
  108. 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.PubMedCrossRefGoogle Scholar
  109. 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.PubMedCrossRefGoogle Scholar
  110. 110.
    Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003;200(4):500–3.PubMedCrossRefGoogle Scholar
  111. 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.PubMedCrossRefGoogle Scholar
  112. 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.PubMedCrossRefGoogle Scholar
  113. 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.PubMedCrossRefGoogle Scholar
  114. 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.PubMedCrossRefGoogle Scholar
  115. 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.PubMedGoogle Scholar
  116. 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.PubMedCrossRefGoogle Scholar
  117. 117.
    Russo FP, Alison MR, Bigger BW, et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology. 2006;130(6):1807–21.PubMedCrossRefGoogle Scholar
  118. 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.PubMedCrossRefGoogle Scholar
  119. 119.
    Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88(1):125–72.PubMedCrossRefGoogle Scholar
  120. 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.PubMedCrossRefGoogle Scholar
  121. 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.PubMedCrossRefGoogle Scholar
  122. 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.PubMedCrossRefGoogle Scholar
  123. 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.PubMedCrossRefGoogle Scholar
  124. 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.PubMedCrossRefGoogle Scholar
  125. 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.PubMedCrossRefGoogle Scholar
  126. 126.
    Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209–18.PubMedGoogle Scholar
  127. 127.
    Wallace K, Burt AD, Wright MC. Liver fibrosis. Biochem J. 2008;411(1):1–18.PubMedCrossRefGoogle Scholar
  128. 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.PubMedCrossRefGoogle Scholar
  129. 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.PubMedCrossRefGoogle Scholar
  130. 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.PubMedCrossRefGoogle Scholar
  131. 131.
    Dranoff JA, Wells RG. Portal fibroblasts: underappreciated mediators of biliary fibrosis. Hepatology. 2010;51(4):1438–44.PubMedCrossRefGoogle Scholar
  132. 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.PubMedCrossRefGoogle Scholar
  133. 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.PubMedCrossRefGoogle Scholar
  134. 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.PubMedCrossRefGoogle Scholar
  135. 135.
    Kinnman N, Housset C. Peribiliary myofibroblasts in biliary type liver fibrosis. Front Biosci. 2002;7:d496–503.PubMedCrossRefGoogle Scholar
  136. 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.PubMedCrossRefGoogle Scholar
  137. 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.PubMedGoogle Scholar
  138. 138.
    Alpini G, McGill JM, Larusso NF. The pathobiology of biliary epithelia. Hepatology. 2002;35(5):1256–68.PubMedCrossRefGoogle Scholar
  139. 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.PubMedCrossRefGoogle Scholar
  140. 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.PubMedCrossRefGoogle Scholar
  141. 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.PubMedCrossRefGoogle Scholar
  142. 142.
    Kallis YN, Forbes SJ. The bone marrow and liver fibrosis: friend or foe? Gastroenterology. 2009;137(4):1218–21.PubMedCrossRefGoogle Scholar
  143. 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.PubMedCrossRefGoogle Scholar
  144. 144.
    Tamkun JW, Hynes RO. Plasma fibronectin is synthesized and secreted by hepatocytes. J Biol Chem. 1983;258(7):4641–7.PubMedGoogle Scholar
  145. 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.PubMedCrossRefGoogle Scholar
  146. 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.PubMedCrossRefGoogle Scholar
  147. 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.PubMedGoogle Scholar
  148. 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.PubMedCrossRefGoogle Scholar
  149. 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.PubMedCrossRefGoogle Scholar
  150. 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.PubMedCrossRefGoogle Scholar
  151. 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.PubMedCrossRefGoogle Scholar
  152. 152.
    Bardadin KA, Desmet VJ. Ultrastructural observations on sinusoidal endothelial cells in chronic active hepatitis. Histopathology. 1985;9(2):171–81.PubMedCrossRefGoogle Scholar
  153. 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.PubMedGoogle Scholar
  154. 154.
    DeLeve LD. Hepatic microvasculature in liver injury. Semin Liver Dis. 2007;27(4):390–400.PubMedCrossRefGoogle Scholar
  155. 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.PubMedCrossRefGoogle Scholar
  156. 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.PubMedCrossRefGoogle Scholar
  157. 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.PubMedCrossRefGoogle Scholar
  158. 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.PubMedCrossRefGoogle Scholar
  159. 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.PubMedCrossRefGoogle Scholar
  160. 160.
    Tan J, Hytiroglou P, Wieczorek R, et al. Immunohistochemical evidence for hepatic progenitor cells in liver diseases. Liver. 2002;22(5):365–73.PubMedCrossRefGoogle Scholar
  161. 161.
    Thorgeirsson SS. Hepatic stem cells in liver regeneration. FASEB J. 1996;10(11):1249–56.PubMedGoogle Scholar
  162. 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.PubMedCrossRefGoogle Scholar
  163. 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.PubMedCrossRefGoogle Scholar
  164. 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.PubMedCrossRefGoogle Scholar
  165. 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.PubMedCrossRefGoogle Scholar
  166. 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.PubMedGoogle Scholar
  167. 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.PubMedCrossRefGoogle Scholar
  168. 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.PubMedCrossRefGoogle Scholar
  169. 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.PubMedCrossRefGoogle Scholar
  170. 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.PubMedCrossRefGoogle Scholar
  171. 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. 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.PubMedCrossRefGoogle Scholar
  173. 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.PubMedCrossRefGoogle Scholar
  174. 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.PubMedCrossRefGoogle Scholar
  175. 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.PubMedCrossRefGoogle Scholar
  176. 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.PubMedCrossRefGoogle Scholar
  177. 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.PubMedCrossRefGoogle Scholar
  178. 178.
    Wu J, Norton PA. Animal models of liver fibrosis. Scand J Gastroenterol. 1996;31(12):1137–43.PubMedCrossRefGoogle Scholar
  179. 179.
    Weiler-Normann C, Herkel J, Lohse AW. Mouse models of liver fibrosis. Z Gastroenterol. 2007;45(1):43–50.PubMedCrossRefGoogle Scholar
  180. 180.
    Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci. 2002;7:d793–807.PubMedCrossRefGoogle Scholar
  181. 181.
    Inagaki Y, Okazaki I. Emerging insights into Transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut. 2007;56(2):284–92.PubMedCrossRefGoogle Scholar
  182. 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.PubMedCrossRefGoogle Scholar
  183. 183.
    Flanders KC. Smad3 as a mediator of the fibrotic response. Int J Exp Pathol. 2004;85(2):47–64.PubMedCrossRefGoogle Scholar
  184. 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.PubMedCrossRefGoogle Scholar
  185. 185.
    Pinzani M. PDGF and signal transduction in hepatic stellate cells. Front Biosci. 2002;7:d1720–6.PubMedCrossRefGoogle Scholar
  186. 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.PubMedCrossRefGoogle Scholar
  187. 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.PubMedCrossRefGoogle Scholar
  188. 188.
    Gressner OA, Gressner AM. Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int. 2008;28(8):1065–79.PubMedCrossRefGoogle Scholar
  189. 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.PubMedCrossRefGoogle Scholar
  190. 190.
    Seki E, de Minicis S, Inokuchi S, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50(1):185–97.PubMedCrossRefGoogle Scholar
  191. 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.PubMedGoogle Scholar
  192. 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.PubMedCrossRefGoogle Scholar
  193. 193.
    Marra F, Bertolani C. Adipokines in liver diseases. Hepatology. 2009;50(3):957–69.PubMedCrossRefGoogle Scholar
  194. 194.
    She H, Xiong S, Hazra S, Tsukamoto H. Adipogenic transcriptional regulation of hepatic stellate cells. J Biol Chem. 2005;280(6):4959–67.PubMedCrossRefGoogle Scholar
  195. 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.PubMedCrossRefGoogle Scholar
  196. 196.
    Rockey DC. Vascular mediators in the injured liver. Hepatology. 2003;37(1):4–12.PubMedCrossRefGoogle Scholar
  197. 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. 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. 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.PubMedCrossRefGoogle Scholar
  200. 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.PubMedCrossRefGoogle Scholar
  201. 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.PubMedCrossRefGoogle Scholar
  202. 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.PubMedCrossRefGoogle Scholar
  203. 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.PubMedCrossRefGoogle Scholar
  204. 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.PubMedCrossRefGoogle Scholar
  205. 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.PubMedCrossRefGoogle Scholar
  206. 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.PubMedCrossRefGoogle Scholar
  207. 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.PubMedCrossRefGoogle Scholar
  208. 208.
    Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology. 2008;47(4):1394–400.PubMedCrossRefGoogle Scholar
  209. 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.PubMedCrossRefGoogle Scholar
  210. 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.PubMedCrossRefGoogle Scholar
  211. 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.PubMedGoogle Scholar
  212. 212.
    Marra F, Aleffi S, Galastri S, Provenzano A. Mononuclear cells in liver fibrosis. Semin Immunopathol. 2009;31(3):345–58.PubMedCrossRefGoogle Scholar
  213. 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.PubMedCrossRefGoogle Scholar
  214. 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.PubMedCrossRefGoogle Scholar
  215. 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.PubMedGoogle Scholar
  216. 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.PubMedCrossRefGoogle Scholar
  217. 217.
    Mencin A, Kluwe J, Schwabe RF. Toll-like receptors as targets in chronic liver diseases. Gut. 2009;58(5):704–20.PubMedCrossRefGoogle Scholar
  218. 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.PubMedCrossRefGoogle Scholar
  219. 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.PubMedCrossRefGoogle Scholar
  220. 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.PubMedGoogle Scholar
  221. 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.PubMedCrossRefGoogle Scholar
  222. 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.PubMedGoogle Scholar
  223. 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. 224.
    Desmet VJ, Roskams T. Cirrhosis reversal: a duel between dogma and myth. J Hepatol. 2004;40(5):860–7.PubMedCrossRefGoogle Scholar
  225. 225.
    Popper H. Pathologic aspects of cirrhosis. A review. Am J Pathol. 1977;87(1):228–64.PubMedGoogle Scholar
  226. 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. 227.
    Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009;50(3):604–20.PubMedCrossRefGoogle Scholar
  228. 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.PubMedCrossRefGoogle Scholar
  229. 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.PubMedCrossRefGoogle Scholar
  230. 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.PubMedCrossRefGoogle Scholar
  231. 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.PubMedCrossRefGoogle Scholar
  232. 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.PubMedGoogle Scholar
  233. 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.PubMedCrossRefGoogle Scholar
  234. 234.
    Benyon RC, Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis. 2001;21(3):373–84.PubMedCrossRefGoogle Scholar
  235. 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.PubMedCrossRefGoogle Scholar
  236. 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.PubMedCrossRefGoogle Scholar
  237. 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.PubMedCrossRefGoogle Scholar
  238. 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.PubMedGoogle Scholar
  239. 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.PubMedCrossRefGoogle Scholar
  240. 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.PubMedCrossRefGoogle Scholar
  241. 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.PubMedCrossRefGoogle Scholar
  242. 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.PubMedCrossRefGoogle Scholar
  243. 243.
    Friedman SL, Bansal MB. Reversal of hepatic fibrosis – fact or fantasy? Hepatology. 2006;43(2 Suppl 1):S82–8.PubMedCrossRefGoogle Scholar
  244. 244.
    Quinn PS, Higginson J. Reversible and irreversible changes in experimental cirrhosis. Am J Pathol. 1965;47:353–69.PubMedGoogle Scholar
  245. 245.
    Perez-Tamayo R. Cirrhosis of the liver: a reversible disease? Pathol Annu. 1979;14(Pt 2):183–213.PubMedGoogle Scholar
  246. 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.PubMedCrossRefGoogle Scholar
  247. 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. 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.PubMedCrossRefGoogle Scholar
  249. 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.PubMedCrossRefGoogle Scholar
  250. 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.PubMedGoogle Scholar
  251. 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.PubMedGoogle Scholar
  252. 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.PubMedGoogle Scholar
  253. 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.PubMedCrossRefGoogle Scholar
  254. 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.PubMedCrossRefGoogle Scholar
  255. 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.PubMedCrossRefGoogle Scholar
  256. 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.PubMedCrossRefGoogle Scholar
  257. 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.PubMedCrossRefGoogle Scholar
  258. 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.PubMedCrossRefGoogle Scholar
  259. 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.PubMedCrossRefGoogle Scholar
  260. 260.
  261. 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.PubMedCrossRefGoogle Scholar
  262. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations