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Abstract

Knowledge on the development and progression of liver fibrosis has grown exponentially in the past decade. At present, liver fibrogenesis is referred to as a dynamic process involving complex cellular and molecular mechanisms, resulting from the chronic activation of the tissue repair mechanisms that follows reiterated liver tissue injury. The identification and characterization of the cell types and of the different mediators involved in this process has allowed a “re-visitation” of several issues related to liver cirrhosis and its immediate consequences. Among these, evaluation of the relationships occurring between fibrogenesis and portal hypertension, cholestasis and the development of hepatocellular carcinoma, represent some of the hottest areas of research in this field of hepatology. The elucidation of many of the cellular and molecular mechanisms responsible for the progression of liver fibrosis has provided a sound basis for the development of pharmacological strategies able to modulate this important pathophysiological process.

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References

  1. Armendariz-Borunda J, Seyer JM, Kang AH, Raghow R (1990) Regulation of transforming growth factor-β expression in rat liver intoxicated with carbon tetrachloride. FASEB J 4:215

    PubMed  CAS  Google Scholar 

  2. Arthur MJP, Friedman SL, Roll FJ, Bissell DM (1989) Lipocytes from normal rat liver release a neutral metalloproteinase that degrades basement membrane (type IV) collagen. J Clin Invest 84:1076

    Article  PubMed  CAS  Google Scholar 

  3. Bachem MG, Meyer D, Melchior R, Sell K-M, Gressner AM (1992) Activation of rat liver perisinusoidal lipocytes by transforming growth factors derived from myofibroblast-like cells. J Clin Invest 89:19

    Article  PubMed  CAS  Google Scholar 

  4. Bataller R, Nicolas JM, Gines P, Esteve A, Gorbig N, Garcia-Ramallo E, Pinzani M, Ros J, Jimenez W, Thomas AP, Arroyo V, Rodes J (1997) Arginine vasopressin induces contraction and stimulates growth of cultured human hepatic stellate cells. Gastroenterology 113:615

    Article  PubMed  CAS  Google Scholar 

  5. Bataller R, Nicolas JM, Gines P, Gorbig N, Garcia-Ramallo E, Lario S, Tobias E, Pinzani M, Thomas AP, Arroyo V, Rodes J (1998) Contraction of human hepatic stellate cells activated in culture: a role for voltage-operated calcium channels. J Hepatol 29:398

    Article  PubMed  CAS  Google Scholar 

  6. Bhatal PS, Grossmann HJ (1985) Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1:325

    Article  Google Scholar 

  7. Bhunchet E, Wake K (1992) Role of mesenchymal cell populations in porcine serum-induced rat liver fibrosis. Hepatology 16:1452

    Article  PubMed  CAS  Google Scholar 

  8. Blomhoff R, Green MH, Berg T, Norum KR (1990) Transport and storage of vitamin A. Science 250: 399

    Article  PubMed  CAS  Google Scholar 

  9. Blomhoff R., Wake K (1991) Perisinusoidal stellate cell of the liver: important roles in retinol metabolism and fibrosis. FASEB J 5:271

    PubMed  CAS  Google Scholar 

  10. Burt AD, Robertson JL, Heir J, Macsween RNM (1986) Desmin-containing stellate cells in rat liver; distribution in normal animals and response to experimental acute liver injury. J Pathol 150:29

    Article  PubMed  CAS  Google Scholar 

  11. Casini A, Cunningham M, Rojkind M, Lieber CS (1991) Acetaldehyde increases procollagen type I and fibronectin gene transcription in cultured rat fat-storing cells through a protein synthesis-dependent mechanism. Hepatology 13:758

    PubMed  CAS  Google Scholar 

  12. Casini C, Galli G, Salzano R, Rotella CM, Surrenti C (1993) Acetaldehyde-protein adducts, but not lactate and pyruvate, stimulate gene transcription of collagen and fibronectin in hepatic fat-storing cells. J Hepatol 19:385

    Article  PubMed  CAS  Google Scholar 

  13. Casini A, Pinzani M, Milani S, Grappone C, Galli G, Jezequel AM, Schuppan D, Rotella CM, Surrenti C (1993) Regulation of transforming growth factor-β1 in human fat-storing cells. Gastroenterology 105:245

    PubMed  CAS  Google Scholar 

  14. Casini A, Ceni E, Salzano R, Schuppan D, Milani S, Pellegrini G, Surrend C (1994) Regulation of undulin synthesis and gene expression in human fat-storing cells by acetaldehyde and transforming growth factor-β1. Comparison with fibronectin. Biochem Biophys Res Commun 199:1019

    Article  PubMed  CAS  Google Scholar 

  15. Castilla A, Prieto J, Fausto N (1991) Transforming growth factor-β1 and α in chronic liver disease. N Engl J Med 324:933

    PubMed  CAS  Google Scholar 

  16. Carloni V, Romanelli RG, Pinzani M, Laffi G, Gentilini P (1996) Expression and function of integrins receptors for collagen and laminin in cultured human hepatic stellate cells. Gastroenterology 110:1127

    Article  PubMed  CAS  Google Scholar 

  17. Carloni V, Romanelli RG, Pinzani M, Laffi G, Gentilini P (1997) Focal adhesion kinase and phospholipase Cγ involvement in adhesion and migration of human hepatic stellate cells. Gastroenterology 112:522

    Article  PubMed  CAS  Google Scholar 

  18. Carr MW, Roth SJ, Luther E, Rose SS, Springer TA (1994) Monocyte chemoattractant protein 1 acts as a T -lymphocyte chemoattractant. Proc Natl Acad Sci USA 91:3652

    Article  PubMed  CAS  Google Scholar 

  19. Claesson-Welsh L (1994) Platelet-derived receptor signals. J Biol Chem 269:32023

    PubMed  CAS  Google Scholar 

  20. Czaja MJ, Weiner FR, Flanders KC, Giambrone MA, Wind R, Biempica L, Zern MA (1989) In vitro and in vivo association of transforming growth factor-β with hepatic fibrosis. J Cell Biol 108:2477

    Article  PubMed  CAS  Google Scholar 

  21. Davis BH, Pratt BM, Madri JA (1987) Retinol and extracellular collagen matrices modulate hepatic Ito cell collagen phenotype and cellular retinol binding proteins levels. J Biol Chem 262:10280

    PubMed  CAS  Google Scholar 

  22. Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Docherty AJ, Angel P, Heath JK (1987) Transforming growth factor-β modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J 6:1899

    PubMed  CAS  Google Scholar 

  23. Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11:81

    Article  PubMed  CAS  Google Scholar 

  24. Friedman SL, Arthur MJP (1989) Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium: direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. J Clin Invest 84:1780

    Article  PubMed  CAS  Google Scholar 

  25. Friedman SL (1993) The cellular basis of hepatic fibrosis: mechanisms and treatment strategies. N Engl J Med 328:1828

    Article  PubMed  CAS  Google Scholar 

  26. Friedman SL, Yamasaki G, Wong L (1994) Modulation of transforming growth factor beta receptors of rat lipocytes during the hepatic wound healing response. Enhanced binding and reduced gene expression accompany cellular activation in culture and in vivo. J Biol Chem 269:10551

    PubMed  CAS  Google Scholar 

  27. Gong WR, Pecci A, Roth S, Lahme B, Beato M, Gressner A (1998) Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble Fas ligand. Hepatology 28:492

    Article  PubMed  CAS  Google Scholar 

  28. Grappone C, Pinzani M, Parola M, Pellegrini G, Caligiuri A, DeFranco R, Marra F, Herbst H, Milani S (1999) Cholangiocytes contribute to cholestatic fibrosis in the rat through platelet-derived growth factor. J Hepatol 31:100

    Article  PubMed  CAS  Google Scholar 

  29. Gullberg D, Gehlsen KR, Turner DC, Ahlen K, Zijenah LS, Barnes MJ, Rubin K (1992) Analysis of α1β1, α2β1, α3β1 integrins in cell-collagen interactions: identification of conformation dependent α1β1 binding sites in collagen type I. EMBO J 11:3865

    PubMed  CAS  Google Scholar 

  30. Iredale JP, Murphy G, Hembry RM, Friedman SL, Arthur MJP (1992) Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinase-1: implication for regulation of matrix degradation in liver. J Clin Invest 90:282

    Article  PubMed  CAS  Google Scholar 

  31. Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur MJP (1998) Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cells apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 102:538

    Article  PubMed  CAS  Google Scholar 

  32. Hall DE, Reichardt LF, Crowley E, Holley B, Moezzi H, Sonnenberg A, Damsky CH (1990) The α1β1 and α6β1 integrin heterodimers mediate cell attachment to distinct sites on laminin. J Cell Biol 110:2175

    Article  PubMed  CAS  Google Scholar 

  33. Hellebrand C, Stefanovic B, Giordano F, Burchardt ER, Brenner DA (1999) The role of TGF-β1 in initiating hepatic stellate cell activation. J Hepatol 30:77

    Article  Google Scholar 

  34. Kamimura S, Gaal K, Britton RS, Bacon BR, Triadafilopoulos G, Tsukamoto H (1992) Increased 4-hydroxynonenal levels in experimental alcoholic liver disease: association of lipid peroxidation with liver fibrogenesis. Hepatology 16:448

    Article  PubMed  CAS  Google Scholar 

  35. Kavasaki ES, Ladner MB, Wang AM, Van Arsdell J, Warren MK, Coyne MY, Scweickart L, Lee M-T, Wilson KJ, Boosman A, Stanley ER, Ralph P, Mark DF (1985) Molecular cloning of a complementary DNA encoding human macrophage-colony stimulating factor (CSF-1). Science 230:291

    Article  Google Scholar 

  36. Kawada N, Klein H, Decker K (1992) Eicoesanoid-mediated contractility of hepatic stellate cells. Biochem J 285:367

    PubMed  CAS  Google Scholar 

  37. Knittel T, Aurisch S, Neubauer K, Eichhorst S, Ramadori G (1996) Cell-type-specific expression of neural cell adhesion molecule (N-CAM) in Ito cells of rat liver. Am J Pathol 149:449

    PubMed  CAS  Google Scholar 

  38. Lafon ME, Bioulac-Sage P, LeBail N (1989) Nerves and perisinusoidal cells in human liver. In: Wisse E, Knook DL, Decker K (eds) Cells of hepatic sinusoid. Kupffer Cell Foundation, Riswijk, pp 230–234

    Google Scholar 

  39. Lee KS, Buck M, Houglum K, Chojkier M (1995) Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest 96:2461

    Article  PubMed  CAS  Google Scholar 

  40. Loetscher P, Seitz M, Clark-Lewis I, Baggiolini M, Moser B (1994) Monocyte chemotactic proteins MCP-1, MCP-2, MCP-3 are major attractants for human CD4+ and CD8+ T lymphocytes. FASEB J 8:1055

    PubMed  CAS  Google Scholar 

  41. Maher JJ (1989) Fat-storing cells and myofibroblasts: one cell or two? Hepatology 6:903

    Article  Google Scholar 

  42. Mak KM, Lieber CS (1988) Lipocytes and transitional cells in alcoholic liver disease: a morphometric study. Hepatology 8:1027

    Article  PubMed  CAS  Google Scholar 

  43. Marra F, Valente AJ, Pinzani M, Abboud HE (1993) Cultured human liver fat-storing cells produce monocyte chemotactic protein-1. Regulation by proinflammatory cytokines. J Clin Invest 92:1674

    Article  PubMed  CAS  Google Scholar 

  44. Marra F, Ghosh Choudhury G, Pinzani M, Abboud HE (1994) Regulation of platelet-derived growth factor secretion and gene expression in human fat-storing cells. Gastroenterology 107:1110

    PubMed  CAS  Google Scholar 

  45. Marra F, Bonewald LF, Park-Snyder S, Park I-S, Woodruff KA, Abboud HE (1996) Characterization and regulation of the latent transforming growth factor-β complex secreted by vascular pericytes. J Cell Physiol 166:537

    Article  PubMed  CAS  Google Scholar 

  46. Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, Pinzani M, Romanelli RG, Laffi G, Gentilini P (1998) Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol 152:423

    PubMed  CAS  Google Scholar 

  47. Marra F, DeFranco R, Grappone C, Parola M, Milani S, Leonarduzzi G, Pastacaldi S, Wenzel UO, Pinzani M, Dianzani MU, Laffi G, Gentilini P (1999) Expression of monocyte chemotactic protein-1 precedes monocyte recruitment in a rat model of acute liver injury, is modulated by vitamin E. J Invest Med 47:66

    CAS  Google Scholar 

  48. Milani S, Herbst H, Schuppan D, Hahn EG, Stein H (1989) 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 10:84

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  50. Milani S, Herbst H, Schuppan D, Kim KY, Riecken EO, Stein H (1990) Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis. Gastroenterology 98:175

    PubMed  CAS  Google Scholar 

  51. Milani S, Herbst H, Schuppan D, Surrenti C, Riecken EO, Stein H (1990) Cellular localization of procollagen type I, III, IV gene transcripts in normal and fibrotic human liver. Am J Pathol 137:59

    PubMed  CAS  Google Scholar 

  52. Milani S, Herbst H, Shuppan D, Stein H, Surrenti C (1991) Transforming growth factor-β1 and -β2 are differentially expressed in fibrotic liver disease. Am J Pathol 139:1221

    PubMed  CAS  Google Scholar 

  53. Moshage H, Casini A, Lieber CS (1990) Acetaldehyde selectively stimulates collagen production in cultured rat liver fat-storing cells but not in hepatocytes. Hepatology 12:511

    Article  PubMed  CAS  Google Scholar 

  54. Niemela O, Parkkila S, Yla-Herttuala S, Villanueva J, Reubner B, Halsted C (1994) Sequential acetaldehyde production, lipid peroxidation and fibrogenesis in micropig model of alcohol induced liver injury. Hepatology 22:1208

    Article  Google Scholar 

  55. Niki T, Pekny M, Hellemans K, De Bleser P, Van Den Berg K, Vaeyens F, Quartier E, Schuit F, Geerts A (1999) Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells. Hepatology 29:520

    Article  PubMed  CAS  Google Scholar 

  56. Olaso E, Friedman SL (1998) Molecular regulation of hepatic fibrogenesis. J Hepatol 29:836

    Article  PubMed  CAS  Google Scholar 

  57. Parola M, Leonarduzzi G, Biasi F, Albano E, Biocca ME, Poli G, Dianzani MU (1992) Vitamin E dietary supplementation protects against carbon tetrachloride-induced chronic liver damage and cirrhosis. Hepatology 16:1014

    Article  PubMed  CAS  Google Scholar 

  58. Parola M, Pinzani M, Casini A, Leonarduzzi G, Marra F, Caligiuri A, Ceni E, Biondi P, Poli G, Dianzani MU (1996) Induction of procollagen type I gene expression and synthesis in human hepatic stellate cells by 4-hydroxy-2,3-nonenal and other 4-hydroxy-2,3-alkenals is related to their molecular structure. Biochem Biophys Res Common 222:261

    Article  CAS  Google Scholar 

  59. Parola M, Leonarduzzi G, Robino G, Albano E, Poli G, Dianzani MU (1996) On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis. Free Radic Biol Med 20:351

    Article  PubMed  CAS  Google Scholar 

  60. Parola M, Robino G, Marra F, Pinzani M, Bellomo G, Leonarduzzi G, Chiarugi P, Camandola S, Poli G, Waeg G, Gentilini P, Dianzani MU (1998) HNE interacts directly with JNK isoforms in human hepatic stellate cells. J Clin Invest 102:1942

    Article  PubMed  CAS  Google Scholar 

  61. Paradis V, Kollinger M, Fabre M, Holstege A, Poynard T, Bedossa P (1997) In situ detection of lipid peroxidation by-products in chronic liver diseases. Hepatology 26:135

    Article  PubMed  CAS  Google Scholar 

  62. Pietrangelo A (1996) Metals, oxidative stress, hepatic fibrogenesis. Semin Liver Dis 16:13

    Article  PubMed  CAS  Google Scholar 

  63. Pinzani M, Gesualdo L, Sabbah GM, Abboud HE (1989) Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Invest 84:1786

    Article  PubMed  CAS  Google Scholar 

  64. Pinzani M, Abboud HE, Gesualdo L, Abboud SL (1992) Regulation of macrophage-colony stimulating factor in liver fat-storing cells by peptide growth factors. Am J Physiol 262:C876

    PubMed  CAS  Google Scholar 

  65. Pinzani M, Failli P, Ruocco C, Casini A, Milani S, Baldi E, Giotti A, Gentilini P (1992) Fat-storing cells as liver-specific pericytes: spatial dynamics of agonist-stimulated intracellular calcium transients. J Clin Invest 90:642

    Article  PubMed  CAS  Google Scholar 

  66. Pinzani M, Milani S, Grappone C, Weber FL Jr, Gentilini P, Abboud HE (1994) Expression of platelet-derived growth factor in a model of acute liver injury. Hepatology 19:701

    Article  PubMed  CAS  Google Scholar 

  67. Pinzani M (1995) Novel insight into the biology and physiology of the Ito cell. Pharmac Ther 66:387

    Article  CAS  Google Scholar 

  68. Pinzani M, Gentilini A, Caligiuri A, DeFranco R, Pellegrini G, Milani S, Marra F, Gentilini P (1995) Transforming growth factor-1 regulates platelet-derived growth factor subunit in human liver fat-storing cells. Hepatology 21:232

    PubMed  CAS  Google Scholar 

  69. Pinzani M, Milani S, Herbst H, DeFranco R, Grappone C, Gentilini A, Caligiuri A, Pellegrini G, Vinh Ngo D, Romanelli RG, Gentilini P (1996) Expression of platelet-derived growth factor and its receptors in normal human liver and during active hepatic fibrogenesis. Am J Pathol 148:785

    PubMed  CAS  Google Scholar 

  70. Pinzani M, Marra F, Carloni V (1998) Signal transduction in hepatic stellate cells. Liver 18:2

    PubMed  CAS  Google Scholar 

  71. Racine-Samson L, Rockey DC, Bissell DM (1997) The role of alphalbetal integrin in wound contraction. A quantitative analysis of liver myofibroblasts in vivo and in primary culture. J Biol Chem 272:30911

    Article  PubMed  CAS  Google Scholar 

  72. Raghow R, Postlethwaite AE, Keski-Oja J, Moses HL., Kang AH (1987) Transforming growth factorB increases the steady state levels of type I procollagen and fibronectin mRNAs posttranscriptionally in cultured human dermal fibroblasts. J Clin Invest 79:1285

    Article  PubMed  CAS  Google Scholar 

  73. Reichen J, Le M (1986) Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver. J Clin Invest 78:448

    Article  PubMed  CAS  Google Scholar 

  74. Rockey DC, Housset CN, Friedman SL (1993) Activation- dependent contractility of rat hepatic lipocytes in culture and in vivo. J Clin Invest 92:1795

    Article  PubMed  CAS  Google Scholar 

  75. Rockey DC, Weisiger RA (1996) Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology 24:233

    Article  PubMed  CAS  Google Scholar 

  76. Rockey D (1997) The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, nitric oxide. Hepatology 25:2

    Article  PubMed  CAS  Google Scholar 

  77. Saile B, Knittel T, Matthes N, Schott P, Ramadori G (1997) CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair. Am J Pathol 151:1265

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  79. Slater TF (1982) Free radical mechanisms in tissue injury. Biochem J 222:1

    Google Scholar 

  80. Tsukamoto H, Horne W, Kamimura S, Niemela O, Parkkila S, Yla-Herttuala S, Brittenham GM (1995) Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest 96:620

    Article  PubMed  CAS  Google Scholar 

  81. Ueno T, Inuzuka S, Torimura T, Sakata R, Sakamoto M, Gondo K, Aoki T, Tanikawa K, Tsutsumi V (1991) Distribution of substance P and vasoactive intestinal peptide in the human liver. Light and electron immunoperoxidase methods of observation. Am J Gastroenterol 138:1233

    Google Scholar 

  82. Valente AJ, Graves DT, Vialle-Valentin CE, Delgado R, Schwartz CJ (1988) Purification of a monocyte chemotactic factor secreted by nonhuman primate vascular cells in culture. Biochemistry 27:4162

    Article  PubMed  CAS  Google Scholar 

  83. Wake K (1988) Liver perivascular cells revealed by gold and silver impregnation methods and electron microscopy. In: Motta P (ed) Biopathology of the liver, an ultrastructural approach. Kluwer, Dordrecht, pp 23–26

    Google Scholar 

  84. Weiner FR, Giambrone MA, Czaja MJ, Shah A, Annoni G, Takahashi S, Eghbali M, Zern MA (1990) Ito-cell gene expression and collagen regulation. Hepatology 11:111

    Article  PubMed  CAS  Google Scholar 

  85. Zhang JX, Pegoli W Jr, Clemens MG (1994) Endothelin-1 induces direct constriction of hepatic sinusoids. Am J Physiol 266:G624

    PubMed  CAS  Google Scholar 

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Pinzani, M. Liver fibrosis. Springer Semin Immunopathol 21, 475–490 (2000). https://doi.org/10.1007/s002810000037

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