Semin Liver Dis 2001; 21(3): 437-452
DOI: 10.1055/s-2001-17558
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Hepatic Stellate Cells as a Target for the Treatment of Liver Fibrosis

Ramón Bataller, David A. Brenner
  • University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
01. Oktober 2001 (online)

ABSTRACT

Following chronic liver injury of any etiology, there is progressive fibrosis. To date, removing the causative agent is the only effective therapy to stop or even reverse liver fibrosis. Therefore, the development of effective antifibrotic therapies represents a challenge for modern hepatology. In the past decade, dramatic advances have been made in the understanding of the cellular and molecular mechanisms underlying liver fibrogenesis. The identification of activated hepatic stellate cells (HSCs) as the major fibrogenic cell type in the injured liver, as well as the recognition of key cytokines involved in this process, have facilitated the design of promising new antifibrotic therapies. These therapies are aimed at inhibiting the accumulation of activated HSCs at the sites of liver injury and preventing the deposition of extracellular matrix. Although many of these approaches are effective in experimental models of liver fibrosis, their efficacy and safety in humans are still unknown. This review describes the current therapeutic approaches for liver fibrosis and discusses different features of activated HSCs as a target to design new treatments to inhibit scar formation in chronic liver diseases.

REFERENCES

  • 1 Friedman S L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.  J Biol Chem . 2000;  275 2247-2250
  • 2 Pinzani M. Liver fibrosis.  Immunopathol . 1999;  21 475-490
  • 3 Eng F J, Friedman S L. Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex.  Am J Physiol . 2000;  279 G7-G11
  • 4 Wu J, Zern M A. Hepatic stellate cells: a target for the treatment of liver fibrosis.  J Gastroenterol . 2000;  35 665-662
  • 5 Maher J J, Bissell D M, Friedman S L, Roll F J. Collagen measured in primary cultures of normal rat hepatocytes derives from lipocytes within the monolayer.  J Clin Invest . 1988;  82 450-459
  • 6 Friedman S L, Roll F J, Boyles J, Bissell D M. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver.  Proc Natl Acad Sci USA . 1985;  82 8681-8685
  • 7 Matsuoka M, Tsukamoto H. Stimulation of hepatic lipocyte collagen production by Kupffer cell-derived transforming growth factor beta: implication for a pathogenetic role in alcoholic liver fibrogenesis.  Hepatology . 1990;  11 599-605
  • 8 Milani S, Herbst H, Schuppan D. Cellular localization of type I III and IV procollagen gene transcripts in normal and fibrotic human liver.  Am J Pathol . 1990;  137 59-70
  • 9 Maher J J, Zia S, Tzagarakis C. Acetaldehyde-induced stimulation of collagen synthesis and gene expression is dependent on conditions of cell culture: studies with rat lipocytes and fibroblasts.  Alcohol Clin Exp Res . 1994;  18 403-409
  • 10 Stefanovic B, Hellerbrand C, Holcik M. Posttranscriptional regulation of collagen alpha1(I) mRNA in hepatic stellate cells.  Mol Cell Biol . 1997;  17 5201-5209
  • 11 Milani S, Herbst H, Schuppan D. Cellular sources of extracellular matrix proteins in normal and fibrotic liver. Studies of gene expression by in situ hybridization.  J Hepatol . 1995;  22(Suppl) 71-76
  • 12 Ballardini G, Degli Esposti S, Bianchi F B. Correlation between Ito cells and fibrogenesis in an experimental model of hepatic fibrosis. A sequential stereological study.  Liver . 1983;  3 58-63
  • 13 Knittel T, Kobold D, Piscaglia F. 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;  112 387-401
  • 14 Baroni G S, D'Ambrosio L, Curto P. Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis.  Hepatology . 1996;  23 1189-1199
  • 15 Bruck R, Genina O, Aeed H. Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats.  Hepatology . 2001;  33 379-386
  • 16 Lieber C S. Prevention and treatment of liver fibrosis based on pathogenesis.  Alcohol Clin Exp Res . 1999;  23 944-999
  • 17 Knittel T, Kobold D, Saile B. Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential.  Gastroenterology . 1999;  117 1205-1221
  • 18 Rockey D C, Housset C N, Friedman S L. Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo.  J Clin Invest . 1993;  92 1795-1804
  • 19 Blomhoff R, Wake K. Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis.  FASEB J . 1991;  5 271-277
  • 20 Friedman S L, Arthur M J. 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 . 1989;  84 1780-1785
  • 21 Maher J J. Leukocytes as modulators of stellate cell activation.  Alcohol Clin Exp Res . 1999;  23 917-921
  • 22 Gressner A M, Lahme B, Brenzel A. Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells.  Hepatology . 1995;  22 1507-1518
  • 23 Poli G. Pathogenesis of liver fibrosis: role of oxidative stress.  Mol Aspects Med . 2000;  21 49-98
  • 24 Britton R S, Bacon B R. Intracellular signaling pathways in stellate cell activation.  Alcohol Clin Exp Res . 1999;  23 922-925
  • 25 Kawada N, Seki S, Inoue M, Kuroki T. Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells.  Hepatology . 1998;  27 1265-1274
  • 26 Reimann T, Hempel U, Krautwald S. Transforming growth factor-beta1 induces activation of Ras, Raf-1, MEK and MAPK in rat hepatic stellate cells.  FEBS Lett . 1997;  403 57-60
  • 27 Pinzani M, Gesualdo L, Sabbah G M, Abboud H E. Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells.  Clin Invest . 1989;  84 1786-1793
  • 28 Rockey D C, Fouassier L, Chung J J. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells.  Hepatology . 1998;  27 472-480
  • 29 Marra F, Arrighi M C, Fazi M. Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor's actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat.  Hepatology . 1999;  30 951-958
  • 30 Friedman S L, Yamasaki G, Wong L. 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 . 1994;  269 10551-10558
  • 31 Nouchi T, Tanaka Y, Tsukada T. Appearance of alpha-smooth-muscle-actin-positive cells in hepatic fibrosis.  Liver . 1991;  11 100-105
  • 32 Schmitt-Graff A, Kruger S, Bochard F. Modulation of alpha smooth muscle actin and desmin expression in perisinusoidal cells of normal and diseased human livers.  Am J Pathol . 1991;  138 1233-1242
  • 33 Pinzani M, Marra F, Carloni V. Signal transduction in hepatic stellate cells.  Liver . 1998;  18 2-13
  • 34 Pinzani M, Milani S, Grappone C. Expression of platelet-derived growth factor in a model of acute liver injury.  Hepatology . 1994;  19 701-707
  • 35 Pinzani M, Milani S, Herbst H. Expression of platelet-derived growth factor and its receptors in normal human liver and during active hepatic fibrogenesis.  Am J Pathol . 1996;  148 785-800
  • 36 Marra F, Grandaliano G, Valente A J, Abboud H E. Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury.  Hepatology . 1995;  22 780-787
  • 37 Bataller R, Nicolás J M, Ginès P. Arginine vasopressin induces contraction and stimulates growth of cultured human hepatic stellate cells.  Gastroenterology . 1997;  113 615-624
  • 38 Bataller R, Ginés P, Nicolás J M. Angiotensin II induces contraction and proliferation of human hepatic stellate cells.  Gastroenterology . 2000;  118 1149-1156
  • 39 Mallat A, Fouassier L, Preaux A M. Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway.  J Clin Invest . 1995;  96 42-49
  • 40 Gallois C, Habib A, Tao J. Role of NF-kappaB in the antiproliferative effect of endothelin-1 and tumor necrosis factor-alpha in human hepatic stellate cells. Involvement of cyclooxygenase-2.  J Biol Chem . 1998;  273 23183-23190
  • 41 Davaille J, Gallois C, Habib A. Antiproliferative properties of sphingosine 1-phosphate in human hepatic myofibroblasts. A cyclooxygenase-2 mediated pathway.  J Biol Chem . 2000;  275 34628-34633
  • 42 Svegliati-Baroni G, Saccomanno S, van Goor H. Involvement of reactive oxygen species and nitric oxide radicals in activation and proliferation of rat hepatic stellate cells.  Liver . 2001;  21 1-12
  • 43 Failli P, DeFranco R M, Caligiuri A. Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells.  Gastroenterology . 2000;  119 479-492
  • 44 Failli P, Ruocco C, De Franco R. The mitogenic effect of platelet-derived growth factor in human hepatic stellate cells requires calcium influx.  Am J Physiol . 1995;  269 C1133-1139
  • 45 Di Sario A, Bendia E, Svegliati Baroni G. Intracellular pathways mediating Na+/H+ exchange activation by platelet-derived growth factor in rat hepatic stellate cells.  Gastroenterology . 1999;  116 1155-1166
  • 46 Iredale J P, Benyon R C, Pickering J. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.  J Clin Invest . 1998;  102 538-549
  • 47 Issa R, Williams E, Trim N. Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors.  Gut . 2001;  48 548-557
  • 48 Gressner A M, Aachen R U. The up-and-down of hepatic stellate cells in tissue injury: apoptosis restores cellular homeostasis.  Gastroenterology . 2001;  120 1285-1288
  • 49 Gentilini A, Marra F, Gentilini P, Pinzani M. Phosphatidylinositol-3 kinase and extracellular signal-regulated kinase mediate the chemotactic and mitogenic effects of insulin-like growth factor-I in human hepatic stellate cells.  J Hepatol . 2000;  32 227-234
  • 50 Ikeda K, Wakahara T, Wang Y Q. In vitro migratory potential of rat quiescent hepatic stellate cells and its augmentation by cell activation.  Hepatology . 1999;  29 1760-1767
  • 51 Marra F, Romanelli R G, Giannini C. Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells.  Hepatology . 1999;  29 140-148
  • 52 Neubauer K, Saile B, Ramadori G. Liver fibrosis and altered matrix synthesis.  Can J Gastroenterol . 2001;  15 187-193
  • 53 Breitkopf K, Lahme B, Tag C G, Gressner A M. Expression and matrix deposition of latent transforming growth factor beta binding proteins in normal and fibrotic rat liver and transdifferentiating hepatic stellate cells in culture.  Hepatology . 2001;  33 387-396
  • 54 George J, Wang S S, Sevcsik A M. Transforming growth factor-beta initiates wound repair in rat liver through induction of the EIIIA-fibronectin splice isoform.  Am J Pathol . 2000;  156 115-124
  • 55 Ikeda K, Lin C, Olaso E. Discoidin domain receptor 2 (DDR2) interacts with SRC and SHC following activation by collagen I.  Hepatology . 2000;  32 315[Abst]
  • 56 Schuppan D, Cho J J, Jia J D, Hahn E G. Interplay of matrix and myofibroblasts during hepatic fibrogenesis.  Curr Top Pathol . 1999;  93 205-218
  • 57 Carloni V, Romanelli R G, Pinzani M. Expression and function of integrin receptors for collagen and laminin in cultured human hepatic stellate cells.  Gastroenterology . 1996;  110 1127-1136
  • 58 Sato M, Kojima N, Miura M. Induction of cellular processes containing collagenase and retinoid by integrin-binding to interstitial collagen in hepatic stellate cell culture.  Cell Biol Int . 1998;  22 115-125
  • 59 Booz G W, Baker K M. Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts.  Cardiovasc Res . 1995;  30 537-543
  • 60 Bruck R, Hershkoviz R, Lider O. Inhibition of experimentally induced liver cirrhosis in rats by a nonpeptidic mimetic of the extracellular matrix-associated Arg-Gly-Asp epitope.  J Hepatol . 1996;  24 731-738
  • 61 Marra F. Hepatic stellate cells and the regulation of liver inflammation.  J Hepatol . 1999;  31 1120-1130
  • 62 Friedman S L. Cytokines and fibrogenesis.  Semin Liver Dis . 1999;  19 129-140
  • 63 Hellerbrand C, Jobin C, Imuro Y. Inhibition of NFκB in activated rat hepatic stellate cells by proteosome inhibitors and an IκB super-repressor.  Hepatology . 1998;  27 1285-1295
  • 64 Bonacchi A, Romagnani P, Romanelli R G. Signal transduction by the chemokine receptor cxcr3. Activation of ras/erk, src, and phosphatidylinositol 3-kinase/akt controls cell migration and proliferation in human vascular pericytes.  J Biol Chem . 2001;  276 9945-9954
  • 65 Bataller R, Viñas O, Ginès P. Activated human stellate cells express the cell machinery required for antigen presentation and modulate the proliferation of allogenic lymphocytes.  Hepatology . 2000;  32 314[Abst]
  • 66 Nelson D R, Lauwers G Y, Lau J Y, Davis G L. Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders.  Gastroenterology . 2000;  118 655-660
  • 67 Lindquist J N, Marzluff W F, Stefanovic B. Fibrogenesis. III. Posttranscriptional regulation of type I collagen.  Am J Physiol . 2000;  279 G471-476
  • 68 Stefanovic B, Lindquist J, Brenner D A. The 5′ stem-loop regulates expression of collagen alpha1(I) mRNA in mouse fibroblasts cultured in a three-dimensional matrix.  Nucleic Acids Res . 2000;  28 641-647
  • 69 Arthur M J. Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis.  Am J Physiol Physiol . 2000;  279 G245-249
  • 70 Benyon R C, Hovell C J, Da Gaca M. Progelatinase A is produced and activated by rat hepatic stellate cells and promotes their proliferation.  Hepatology . 1999;  30 977-986
  • 71 Knittel T, Mehde M, Kobold D. Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1.  J Hepatol . 1999;  30 48-60
  • 72 Knittel T, Mehde M, Grundmann A. Expression of matrix metalloproteinases and their inhibitors during hepatic tissue repair in the rat.  Histochem Cell Biol . 2000;  113 443-453
  • 73 Yoshiji H, Kuriyama S, Miyamoto Y. Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model.  Hepatology . 2000;  32 1248-1254
  • 74 Shiratori Y, Imazeki F, Moriyama M. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy.  Ann Intern Med . 2000;  132 517-524
  • 75 Hammel P, Couvelard A, O'Toole D. Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct.  N Engl J Med . 2001;  344 418-423
  • 76 Pares A, Caballeria J, Bruguera M. Histological course of alcoholic hepatitis.  Influence of abstinence, sex and extent of hepatic damage. J Hepatol . 1986;  2 33-42
  • 77 Ramm G A, Crawford D H, Powell L W. Hepatic stellate cell activation in genetic haemochromatosis. Lobular distribution, effect of increasing hepatic iron and response to phlebotomy.  J Hepatol . 1997;  26 584-592
  • 78 Schilsky M L, Scheinberg I H, Sternlieb I. Prognosis of wilsonian chronic active hepatitis.  Gastroenterology . 1991;  100 762-767
  • 79 Nieto N, Greenwel P, Friedman S L. Ethanol and arachidonic acid increase alpha 2(I) collagen expression in rat hepatic stellate cells overexpressing cytochrome P450 2E1. Role of H2O2 and cyclooxygenase-2.  J Biol Chem . 2000;  275 20136-20145
  • 80 Pietrangelo A, Gualdi R, Casalgrandi G. Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents.  J Clin Invest . 1995;  95 1824-1831
  • 81 Brady L M, Beno D W, Davis B H. Bile acid stimulation of early growth response gene and mitogen-activated protein kinase is protein kinase C-dependent.  Biochem J . 1996;  316 765-769
  • 82 Poynard T, Ratziu V, Benmanov Y. Fibrosis in patients with chronic hepatitis C: detection and significance.  Semin Liver Dis . 2000;  20 47-55
  • 83 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;  349 825-832
  • 84 Poynard T, McHutchison J, Davis G L. Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C.  Hepatology . 2000;  32 1131-1137
  • 85 Davis G L, Esteban-Mur R, Rustgi V. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group.  N Engl J Med . 1998;  339 1493-1499
  • 86 Poynard T, Moussali J, Ratziu V. Effects of interferon therapy in ``non responder'' patients with chronic hepatitis C.  J Hepatol . 1999;  31(suppl 1) 178-183
  • 87 Guerret S, Desmouliere A, Chossegros P. Long-term administration of interferon-alpha in non-responder patients with chronic hepatitis C: follow-up of liver fibrosis over 5 years.  J Viral Hepat . 1999;  6 125-133
  • 88 Mallat A, Preaux A M, Blazejewski S. Interferon alfa and gamma inhibit proliferation and collagen synthesis of human Ito cells in culture.  Hepatology . 1995;  21 1003-1010
  • 89 Bueno M R, Daneri A, Armendariz-Borunda J. Cholestasis-induced fibrosis is reduced by interferon alpha-2a and is associated with elevated liver metalloprotease activity.  J Hepatol . 2000;  33 915-925
  • 90 McCaughan G W, Gorrell M D, Bishop G A. Molecular pathogenesis of liver disease: an approach to hepatic inflammation, cirrhosis and liver transplant tolerance.  Immunol Rev . 2000;  174 172-191
  • 91 Mathurin P, Duchatelle V, Ramond M J. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone.  Gastroenterology . 1996;  110 1847-1853
  • 92 Rambaldi A, Gluud C. Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis.  Liver . 2000;  20 262-266
  • 93 Casini A, Ceni E, Salzano R. Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide.  Hepatology . 1997;  25 361-367
  • 94 Dufour J F, DeLellis R, Kaplan M M. Reversibility of hepatic fibrosis in autoimmune hepatitis.  Ann Intern Med . 1997;  127 981-985
  • 95 Schlichting P, Juhl E, Poulsen H, Winkel P. Alcoholic hepatitis superimposed on cirrhosis. Clinical significance and effect of long-term prednisone treatment.  Scand J Gastroenterol . 1976;  11 305-312
  • 96 Mitchison H C, Palmer J M, Bassendine M F. A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results.  J Hepatol . 1992;  15 336-344
  • 97 Lindor K D, Wiesner R H, Colwell L J. The combination of prednisone and colchicine in patients with primary sclerosing cholangitis.  Am J Gastroenterol . 1991;  86 57-61
  • 98 Kershenobich D, Vargas F, Garcia-Tsao G. Colchicine in the treatment of cirrhosis of the liver.  N Engl J Med . 1988;  318 1709-1713
  • 99 Poupon R E, Huet P M, Poupon R. A randomized trial comparing colchicine and ursodeoxycholic acid combination to ursodeoxycholic acid in primary biliary cirrhosis. UDCA-PBC Study Group.  Hepatology . 1996;  24 1098-1103
  • 100 Ryhanen L, Stenback F, Ala-Kokko L, Savolainen E R. The effect of malotilate on type III and type IV collagen, laminin and fibronectin metabolism in dimethylnitrosamine-induced liver fibrosis in the rat.  J Hepatol . 1996;  24 238-245
  • 101 Keiding S, Badsberg J H, Becker U. The prognosis of patients with alcoholic liver disease. An international randomized, placebo-controlled trial on the effect of malotilate on survival.  J Hepatol . 1994;  20 454-460
  • 102 Mancini R, Benedetti A, Jezequel A M. An interleukin-1 receptor antagonist decreases fibrosis induced by dimethylnitrosamine in rat liver.  Virchows Arch . 1994;  424 25-31
  • 103 Bruck R, Hershkoviz R, Lider O. The use of synthetic analogues of Arg-Gly-Asp (RGD) and soluble receptor of tumor necrosis factor to prevent acute and chronic experimental liver injury.  Yale J Biol Med . 1997;  70 391-402
  • 104 Louis H, Van Laethem L J, Wu W. Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice.  Hepatology . 1998;  28 1607-1615
  • 105 Kono H, Rusyn I, Yin M. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease.  J Clin Invest . 2000;  106 867-872
  • 106 Mi L J, Mak K M, Lieber C S. Attenuation of alcohol-induced apoptosis of hepatocytes in rat livers by polyenylphosphatidylcholine (PPC).  Alcohol Clin Exp Res . 2000;  24 207-212
  • 107 Lieber C S. Alcoholic liver disease: new insights in pathogenesis lead to new treatments.  J Hepatol . 2000;  32(Suppl) 113-128
  • 108 Deulofeu R, Parés A, Rubio M. S-adenosylmethionine prevents hepatic tocopherol depletion in carbon tetrachloride-injured rats.  Clin Sci (Colch) . 2000;  99 315-320
  • 109 Sokol R J. Antioxidant defenses in metal-induced liver damage.  Semin Liver Dis . 1996;  16 39-46
  • 110 Parola M, Leonarduzzi G, Biasi F. Vitamin E dietary supplementation protects against carbon tetrachloride-induced chronic liver damage and cirrhosis.  Hepatology . 1992;  16 1014-1021
  • 111 de la Maza P M, Petermann M, Bunout D, Hirsch S. Effects of long-term vitamin E supplementation in alcoholic cirrhotics.  J Am Coll Nutr . 1995;  14 192-196
  • 112 Boigk G, Stroedter L, Herbst H. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats.  Hepatology . 1997;  26 643-649
  • 113 Parés A, Planas R, Torres M. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial.  J Hepatol . 1998;  28 615-261
  • 114 Ma X, Zhao J, Lieber C S. Polyenylphosphatidylcholine attenuates non-alcoholic hepatic fibrosis and accelerates its regression.  J Hepatol . 1996;  24 604-613
  • 115 Aleynik S I, Leo M A, Ma X. Polyenylphosphatidylcholine prevents carbon tetrachloride-induced lipid peroxidation while it attenuates liver fibrosis.  J Hepatol . 1997;  27 554-661
  • 116 Poniachik J, Baraona E, Zhao J, Lieber C S. Dilinoleoylphosphatidylcholine decreases hepatic stellate cell activation.  J Lab Clin Med . 1999;  133 342-348
  • 117 Lieber C S. Role of S-adenosyl-L-methionine in the treatment of liver diseases.  J Hepatol . 1999;  30 1155-1159
  • 118 Cutrin C, Menino M J, Otero X. Effect of nifedipine and S-adenosylmethionine in the liver of rats treated with CCl4 and ethanol for one month.  Life Sci . 1992;  51 PL113-118
  • 119 Muriel P, Castro V. Effects of S-adenosyl-L-methionine and interferon-alpha2b on liver damage induced by bile duct ligation in rats.  J Appl Toxicol . 1998;  18 143-147
  • 120 Mato J M, Camara J, Fernández de Paz J. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.  J Hepatol . 1999;  30 1081-1089
  • 121 Mizobuchi Y, Shimizu I, Yasuda M. Retinyl palmitate reduces hepatic fibrosis in rats induced by dimethylnitrosamine or pig serum.  J Hepatol . 1998;  29 933-943
  • 122 Godichaud S, Krisa S, Couronne B. Deactivation of cultured human liver myofibroblasts by trans-resveratrol, a grapevine-derived polyphenol.  Hepatology . 2000;  31 922-931
  • 123 Klahr S, Morrissey J J. The role of growth factors, cytokines, and vasoactive compounds in obstructive nephropathy.  Semin Nephrol . 1998;  18 622-632
  • 124 Wells R G. Fibrogenesis. V. TGF-beta signaling pathways.  Am J Physiol . 2000;  279 G845-580
  • 125 Okuno M, Moriwaki H, Muto Y, Kojima S. Protease inhibitors suppress TGF-beta generation by hepatic stellate cells.  J Hepatol . 1998;  29 1031-1032
  • 126 Nakamura T, Sakata R, Ueno T. Inhibition of transforming growth factor beta prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats.  Hepatology . 2000;  32 247-255
  • 127 George J, Roulot D, Koteliansky V E, Bissell D M. In vivo inhibition of rat stellate cell activation by soluble transforming growth factor beta type II receptor: a potential new therapy for hepatic fibrosis.  Proc Natl Acad Sci U S A . 1999;  96 12719-12724
  • 128 Qi Z, Atsuchi N, Ooshima A. Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat.  Proc Natl Acad Sci U S A . 1999;  96 2345-2349
  • 129 Ikeda H, Nagoshi S, Ohno A. Activated rat stellate cells express c-met and respond to hepatocyte growth factor to enhance transforming growth factor beta1 expression and DNA synthesis.  Biochem Biophys Res Commun . 1998;  250 769-775
  • 130 Ueki T, Kaneda Y, Tsutsui H. Hepatocyte growth factor gene therapy of liver cirrhosis in rats.  Nat Med . 1999;  5 226-230
  • 131 Rockey D C, Maher J J, Jarnagin W R. Inhibition of rat hepatic lipocyte activation in culture by interferon-gamma.  Hepatology . 1992;  16 776-784
  • 132 Baroni G S, D'Ambrosio L, Curto P. Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis.  Hepatology . 1996;  23 1189-1199
  • 133 Shi Z, Wakil A E, Rockey D C. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses.  Proc Natl Acad Sci USA . 1997;  94 10663-10668
  • 134 Preaux A M, Mallat A, Rosenbaum J. Pentoxifylline inhibits growth and collagen synthesis of cultured human hepatic myofibroblast-like cells.  Hepatology . 1997;  26 315-322
  • 135 Pinzani M, Marra F, Caligiuri A. Inhibition by pentoxifylline of extracellular signal-regulated kinase activation by platelet-derived growth factor in hepatic stellate cells.  Br J Pharmacol . 1996;  119 1117-1124
  • 136 Windmeier C, Gressner A M. Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis.  Gen Pharmacol . 1997;  29 181-196
  • 137 Svegliati-Baroni G, Di Sario A, Casini A. The Na+/H+ exchanger modulates the fibrogenic effect of oxidative stress in rat hepatic stellate cells.  J Hepatol . 1999;  30 868-875
  • 138 Benedetti A, Di Sario A, Casini A. Inhibition of the Na(+)/H(+) exchanger reduces rat hepatic stellate cell activity and liver fibrosis: an in vitro and in vivo study.  Gastroenterology . 2001;  120 545-556
  • 139 Reif S, Weis B, Aeed H. The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats.  J Hepatol . 1999;  31 1053-1061
  • 140 Miyahara T, Schrum L, Rippe R. Peroxisome proliferator-activated receptors and hepatic stellate cell activation.  J Biol Chem . 2000;  275 35715-35722
  • 141 Marra F, Efsen E, Romanelli R G. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells.  Gastroenterology . 2000;  119 466-478
  • 142 Niki T, Rombouts K, De Bleser P. A histone deacetylase inhibitor, trichostatin A, suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture.  Hepatology . 1999;  29 858-867
  • 143 Wang Y Q, Ikeda K, Ikebe T. Inhibition of hepatic stellate cell proliferation and activation by the semisynthetic analogue of fumagillin TNP-470 in rats.  Hepatology . 2000;  32 980-989
  • 144 Klahr S, Morrissey J J. The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease.  Kidney Int . 2000;  57(Suppl 75) 7-14
  • 145 Matsusaka T, Katori H, Homma T, Ichikawa I. Mechanism of cardiac fibrosis by angiotensin. New insight revealed by genetic engineering.  Trends Cardiovasc Med . 1999;  9 180-184
  • 146 Jonsson J R, Ando Y, Keleman L. Angiotensin converting enzyme inhibition attenuates the development of hepatic fibrosis in the rat bile duct ligation model.  Hepatology . 2000;  32 191[Abst]
  • 147 Rockey D C. Vasoactive agents in intrahepatic portal hypertension and fibrogenesis: implications for therapy.  Gastroenterology . 2000;  118 1261-1265
  • 148 Pinzani M, Milani S, De Franco R. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells.  Gastroenterology . 1996;  110 534-548
  • 149 Cho J J, Hocher B, Herbst H. An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis.  Gastroenterology . 2000;  118 1169-1178
  • 150 Buko V, Lukivskaya O, Nikitin V. Antioxidative effect of prostaglandin E2 in thioacetamide-induced liver cirrhosis.  Exp Toxicol Pathol . 1997;  49 141-146
  • 151 Kitamoto S, Egashira K, Kataoka C. Increased activity of nuclear factor-kappaB participates in cardiovascular remodeling induced by chronic inhibition of nitric oxide synthesis in rats.  Circulation . 2000;  102 806-812
  • 152 Koyanagi M, Egashira K, Kitamoto S. Role of monocyte chemoattractant protein-1 in cardiovascular remodeling induced by chronic blockade of nitric oxide synthesis.  Circulation . 2000;  102 2243-2248
  • 153 Rockey D C, Chung J J. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension.  Gastroenterology . 1998;  114 344-351
  • 154 Criado M, Flores O, Vazquez M J, Esteller A. Role of prostanoids and nitric oxide inhibition in rats with experimental hepatic fibrosis.  J Physiol Biochem . 2000;  56 181-188
  • 155 Fort J, Oberti F, Pilette C. Antifibrotic and hemodynamic effects of the early and chronic administration of octreotide in two models of liver fibrosis in rats.  Hepatology . 1998;  28 1525-1531
  • 156 Mansy S S, Yehia H A, Hassan M M. Octreotide decreases connective tissue formation and improves vascular changes associated with hepatic schistosomiasis.  J Egypt Soc Parasitol . 1998;  28 23-44
  • 157 Hernández-Muñoz R, Díaz-Muñoz M, López V. Balance between oxidative damage and proliferative potential in an experimental rat model of CCl4-induced cirrhosis: protective role of adenosine administration.  Hepatology . 1997;  26 1100-1110
  • 158 Fernández M I, Torres M I, Gil A, Ríos A. Steatosis and collagen content in experimental liver cirrhosis are affected by dietary monounsaturated and polyunsaturated fatty acids.  Scand J Gastroenterol . 1997;  32 350-356
  • 159 Fernández I, Torres I, Moreira E. Influence of administration of long-chain polyunsaturated fatty acids on process of histological recovery in liver cirrhosis produced by oral intake of thioacetamide.  Dig Dis Sci . 1996;  41 197-207
  • 160 Nanji A A, Zakim D, Rahemtulla A. Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat.  Hepatology . 1997;  26 1538-1545
  • 161 Giménez A, Caballería J, Parés A. Influence of dietary zinc on hepatic collagen and prolyl hydroxylase activity in alcoholic rats.  Hepatology . 1992;  16 815-819
  • 162 Giménez A, Parés A, Alie S. Fibrogenic and collagenolytic activity in carbon-tetrachloride-injured rats: beneficial effects of zinc administration.  J Hepatol . 1994;  21 292-298
  • 163 Shimizu I, Ma Y R, Mizobuchi Y. Effects of Sho-saiko-to, a Japanese herbal medicine, on hepatic fibrosis in rats.  Hepatology . 1999;  29 149-160
  • 164 Miyamura M, Ono M, Kyotani S, Nishioka Y. Effects of sho-saiko-to extract on fibrosis and regeneration of the liver in rats.  J Pharm Pharmacol . 1998;  50 97-105
  • 165 Park E J, Ko G, Kim J, Sohn D H. Antifibrotic effects of a polysaccharide extracted from Ganoderma lucidum, glycyrrhizin, and pentoxifylline in rats with cirrhosis induced by biliary obstruction.  Biol Pharm Bull . 1997;  20 417-420
  • 166 Nan J X, Park E J, Kang H C. Anti-fibrotic effects of a hot-water extract from Salvia miltiorrhiza roots on liver fibrosis induced by biliary obstruction in rats.  J Pharm Pharmacol . 2001;  53 197-204
  • 167 Sakaida I, Uchida K, Hironaka K, Okita K. Prolyl 4-hydroxylase inhibitor (HOE 077) prevents TIMP-1 gene expression in rat liver fibrosis.  J Gastroenterol . 1999;  34 376-377
  • 168 Wang Y J, Wang S S, Bickel M. Two novel antifibrotics, HOE 077 and Safironil, modulate stellate cell activation in rat liver injury: differential effects in males and females.  Am J Pathol . 1998;  152 279-287
  • 169 Sakaida I, Matsumura Y, Kubota M. The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells, reducing procollagen gene expression in rat liver fibrosis induced by choline-deficient L-amino acid-defined diet.  Hepatology . 1996;  23 755-763
  • 170 Matsumura Y, Sakaida I, Uchida K. Prolyl 4-hydroxylase inhibitor (HOE 077) inhibits pig serum-induced rat liver fibrosis by preventing stellate cell activation.  J Hepatol . 1997;  27 185-192
  • 171 Bickel M, Baringhaus K H, Gerl M. Selective inhibition of hepatic collagen accumulation in experimental liver fibrosis in rats by a new prolyl 4-hydroxylase inhibitor.  Hepatology . 1998;  28 404-411
  • 172 Nagler A, Gofrit O, Ohana M. The effect of halofuginone, an inhibitor of collagen type I synthesis, on urethral stricture formation: in vivo and in vitro study in a rat model.  J Urol . 2000;  164 1776-1780
  • 173 Pines M, Knopov V, Genina O. Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis.  J Hepatol . 1997;  27 391-398
  • 174 Salgado S, García J, Vera J. Liver cirrhosis is reverted by urokinase-type plasminogen activator gene therapy.  Mol Ther . 2000;  2 545-551
  • 175 Iimuro Y, Nishio T, Morimoto T. Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat.  J Clin Invest 2001 (in press).
  • 176 Beljaars L, Molema G, Weert B. Albumin modified with mannose 6-phosphate: A potential carrier for selective delivery of antifibrotic drugs to rat and human hepatic stellate cells.  Hepatology . 1999;  29 1486-1493
  • 177 Beljaars L, Molema G, Schuppan D. Successful targeting to rat hepatic stellate cells using albumin modified with cyclic peptides that recognize the collagen type VI receptor.  J Biol Chem . 2000;  275 12743-12751