Inflammation, Damage Repair and Liver Fibrosis - Role of Cytokines and Different Cell Types

Zusammenfassung

Die Leberfibrose ist definiert als exzessive Ablagerung von extrazellulärer Matrix. Sie stellt die Hauptkomplikation einer chronischen Leberschädigung dar und das Endstadium, die Leberzirrhose ist mit einer ausgeprägten Morbidität und Mortalität vergesellschaftet. Für die Akkumulation von extrazellulärer Matrix im Rahmen der Leberfibrose und Leberzirrhose sind unterschiedliche Zelltypen verantwortlich, die einen myofibroblastenähnlichen Phänotyp annehmen - die im Disse’schen Raum lokalisierten hepatischen Sternzellen, portale Fibroblasten und Myofibroblasten aus den periportalen und perizentralen Gebieten. Weitere Studien legen auch eine besondere Rolle von Myofibroblasten aus dem Knochenmark nahe. Obwohl Unterschiede zwischen den Zelltypen hinsichtlich myofibroblastischer Differenzierung, Aktivierung und „Deaktivierung” beschrieben wurden, ist in den meisten Fällen eine weitere Sicherung der Daten erforderlich, insbesondere im Hinblick auf biologische und biochemische Charakterisierung, ihre Interaktionen mit inflammatorischen Zellen und der Zytokinzusammensetzung, die zu ihrer Aktivierung oder ihrem Zelltod führt. Diese Daten sind essenziell, um die Mechanismen der fortschreitenden Entwicklung einer exzessiven Vernarbung in der Leber wie auch die Fähigkeit der Leber zur Gewebereparatur und Regenration zu verstehen. Nur so kann der Stellenwert von möglichen Behandlungsschemata zur spezifischen und effizienten Beeinflussung der Zellen, die für die Entwicklung einer Leberfibrose/Leberzirrhose wie auch für die Leberregeneration verantwortlich sind, abgeschätzt werden.

Abstract

Liver fibrosis is defined as an excessive deposition of extracellular matrix. It is the main complication of chronic liver damage and its endpoint, the liver cirrhosis, is responsible for impressive morbidity and mortality. The accumulation of extracellular matrix proteins in liver fibrosis and cirrhosis is due to different cell types which acquire a myofibroblastic phenotype - the hepatic stellate cells, located in the space of Disse, portal fibroblasts as well as myofibroblasts of the portal and pericentral areas. Further studies also suggest an impressive role of bone marrow-derived myofibroblasts. Differences have been reported between the two cell populations with respect to myofibroblastic differentiation, activation and “deactivation”, proliferation and apoptosis. However, in most cases additional confirmation may be required; thus the biological and biochemical characterization of these cells, their interactions with inflammatory cells and the cytokine environment leading to their activation or cell death are essential to understand the mechanisms underlying the progressive development of excessive scarring in the liver as well as the ability of the liver for tissue repair and regeneration. All this information is required to estimate the value of already suggested possible treatments to specifically and efficiently target the cells responsible for the development of liver fibrosis/cirrhosis and as well as for liver regeneration.

Leber - Fibrose - Zirrhose - HSC - Myofibroblasten - Zytokine

liver - fibrosis - cirrhosis - HSC - myofibroblasts - cytokines

References

• 1 Batusic D S, Armbrust T, Saile B. et al . Induction of Mx-2 in rat liver by toxic injury.  J Hepatol. 2004;  40 446-453
• 2 Knittel T, Mehde M, Kobold D. et al . 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
• 3 Neubauer K, Ritzel A, Saile B. et al . Decrease of platelet-endothelial cell adhesion molecule 1-gene-expression in inflammatory cells and in endothelial cells in the rat liver following CCl4-administration and in vitro after treatment with TNFalpha.  Immunol Lett. 2000;  74 153-164
• 4 Sewnath M E, Van Der P T, Van Noorden C J. et al . Endogenous interferon gamma protects against cholestatic liver injury in mice.  Hepatology. 2002;  36 1466-1477
• 5 Arii S, Imamura M. Physiological role of sinusoidal endothelial cells and Kupffer cells and their implication in the pathogenesis of liver injury.  J Hepatobiliary Pancreat Surg. 2000;  7 40-48
• 6 Bhunchet E, Wake K. Role of mesenchymal cell populations in porcine serum-induced rat liver fibrosis.  Hepatology. 1992;  16 1452-1473
• 7 Salmi M, Adams D, Jalkanen S. Cell adhesion and migration. IV. Lymphocyte trafficking in the intestine and liver.  Am J Physiol. 1998;  274 G1-G6
• 8 Baldus S E, Zirbes T K, Weidner I C. et al . Comparative quantitative analysis of macrophage populations defined by CD68 and carbohydrate antigens in normal and pathologically altered human liver tissue.  Anal Cell Pathol. 1998;  16 141-150
• 9 Sun Z, Wada T, Maemura K. et al . Hepatic allograft-derived Kupffer cells regulate T cell response in rats.  Liver Transpl. 2003;  9 489-497
• 10 Canbay A, Higuchi H, Bronk S F. et al . Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis.  Gastroenterology. 2002;  123 1323-1330
• 11 Wisse E, Luo D, Vermijlen D. et al . On the function of pit cells, the liver-specific natural killer cells.  Semin Liver Dis. 1997;  17 265-286
• 12 Bioulac-Sage P, Kuiper J, Van Berkel T J. et al . Lymphocyte and macrophage populations in the liver.  Hepatogastroenterology. 1996;  43 4-14
• 13 Vanderkerken K, Bouwens L, Van Rooijen N. et al . The role of Kupffer cells in the differentiation process of hepatic natural killer cells.  Hepatology. 1995;  22 283-290
• 14 Li X, Klintman D, Liu Q. et al . Critical role of CXC chemokines in endotoxemic liver injury in mice.  J Leukoc Biol. 2004;  75 443-452
• 15 Schumann J, Wolf D, Pahl A. et al . Importance of Kupffer cells for T-cell-dependent liver injury in mice.  Am J Pathol. 2000;  157 1671-1683
• 16 Bertolino P, McCaughan G W, Bowen D G. Role of primary intrahepatic T-cell activation in the “liver tolerance effect”.  Immunol Cell Biol. 2002;  80 84-92
• 17 Muhlen K A, Schumann J, Wittke F. et al . NK cells, but not NKT cells, are involved in Pseudomonas aeruginosa exotoxin A-induced hepatotoxicity in mice.  J Immunol. 2004;  172 3034-3041
• 18 Crispe I N, Dao T, Klugewitz K. et al . The liver as a site of T-cell apoptosis: graveyard, or killing field?.  Immunol Rev. 2000;  174 47-62
• 19 Safadi R, Ohta M, Alvarez C E. et al . Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes.  Gastroenterology. 2004;  127 870-882
• 20 Smith C I, Cooksley W G, Powell L W. Cell-mediated immunity to liver antigen in toxic liver injury. II. Role in pathogenesis of liver damage.  Clin Exp Immunol. 1980;  39 618-625
• 21 Warnatz H, Scheiffarth F, Schmeissner R. Studies on the cytotoxic effect of in vivo and in vitro immunized lymphocytes on liver target cells.  Clin Exp Immunol. 1975;  21 250-258
• 22 Finotto S, Siebler J, Hausding M. et al . Severe hepatic injury in interleukin 18 (IL-18) transgenic mice: a key role for IL-18 in regulating hepatocyte apoptosis in vivo.  Gut. 2004;  53 392-400
• 23 Ramadori G, Moebius U, Dienes H P. et al . Lymphocytes from hepatic inflammatory infiltrate kill rat hepatocytes in primary culture. Comparison with peripheral blood lymphocytes.  Virchows Arch B Cell Pathol Incl Mol Pathol. 1990;  59 263-270
• 24 Novobrantseva T I, Majeau G R, Amatucci A. et al . Attenuated liver fibrosis in the absence of B cells.  J Clin Invest. 2005;  115 3072-3082
• 25 Xue H, McCauley R L, Zhang W. Elevated interleukin-6 expression in keloid fibroblasts.  J Surg Res. 2000;  89 74-77
• 26 Choi I, Kang H S, Yang Y. et al . IL-6 induces hepatic inflammation and collagen synthesis in vivo.  Clin Exp Immunol. 1994;  95 530-535
• 27 Natsume M, Tsuji H, Harada A. et al . Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice.  J Leukoc Biol. 1999;  66 601-608
• 28 Bansal M B, Kovalovich K, Gupta R. et al . Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression.  J Hepatol. 2005;  42 548-556
• 29 Bot A. Immunoglobulin deficient mice generated by gene targeting as models for studying the immune response.  Int Rev Immunol. 1996;  13 327-340
• 30 Zhou X, Tan F K, Milewicz D M. et al . Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-beta pathway to recapitulate the “scleroderma phenotype”.  J Immunol. 2005;  175 4555-4560
• 31 Neubauer K, Knittel T, Armbrust T. et al . Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver injury.  Gastroenterology. 1995;  108 1124-1135
• 32 Romero-Gomez M, Montes-Cano M A, Otero-Fernandez M A. et al . SLC11A1 promoter gene polymorphisms and fibrosis progression in chronic hepatitis C.  Gut. 2004;  53 446-450
• 33 Bataller R, North K E, Brenner D A. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal.  Hepatology. 2003;  37 493-503
• 34 Ramadori G, Saile B. Portal tract fibrogenesis in the liver.  Lab Invest. 2004;  84 153-159
• 35 Reeves H L, Friedman S L. Activation of hepatic stellate cells - a key issue in liver fibrosis.  Front Biosci. 2002;  7 d808-d826
• 36 Marra F, Romanelli R G, Giannini C. et al . Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells.  Hepatology. 1999;  29 140-148
• 37 Kinnman N, Hultcrantz R, Barbu V. et al . PDGF-mediated chemoattraction of hepatic stellate cells by bile duct segments in cholestatic liver injury.  Laboratory Investigation. 2000;  80 697-707
• 38 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 1205-1221
• 39 Lorena D, Darby I A, Reinhardt D P. et al . 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;  84 203-212
• 40 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;  34 514-522
• 41 Friedman S L. Stellate cells: A moving target in hepatic fibrogenesis.  Hepatology. 2004;  40 1041-1043
• 42 Magness S T, Bataller R, Yang L. et al . A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations.  Hepatology. 2004;  40 1151-1159
• 43 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;  112 387-401
• 44 Dudas J, Saile B, El Armouche H. et al . Endoreplication and polyploidy in primary culture of rat hepatic stellate cells.  Cell Tissue Res. 2003;  313 301-311
• 45 Saile B, Knittel T, Matthes N. et al . CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair.  Am J Pathol. 1997;  151 1265-1272
• 46 Saile B, Matthes N, Knittel T. et al . Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells.  Hepatology. 1999;  30 196-202
• 47 Saile B, Matthes N, Neubauer K. et al . Rat liver myofibroblasts and hepatic stellate cells differ in CD95-mediated apoptosis and response to TNF-alpha.  Am J Physiol Gastrointest Liver Physiol. 2002;  283 G435-G444
• 48 Saile B, DiRocco P, Dudas J. et al . IGF-I induces DNA synthesis and apoptosis in rat liver hepatic stellate cells (HSC) but DNA synthesis and proliferation in rat liver myofibroblasts (rMF).  Lab Invest. 2004;  84 1037-1049
• 49 Kinnman N, Goria O, Wendum D. et al . Hepatic stellate cell proliferation is an early platelet-derived growth factor-mediated cellular event in rat cholestatic liver injury.  Lab Invest. 2001;  81 1709-1716
• 50 Kinnman N, Francoz C, Barbu V. et al . The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis.  Lab Invest. 2003;  83 163-173
• 51 Tuchweber B, Desmouliere A, Bochaton-Piallat M L. et al . Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the rat.  Lab Invest. 1996;  74 265-278
• 52 Kinnman N, Housset C. Peribiliary myofibroblasts in biliary type liver fibrosis.  Front Biosci. 2002;  7 d496-d503
• 53 Desmouliere A, Darby I, Costa A M. et al . Extracellular matrix deposition, lysyl oxidase expression, and myofibroblastic differentiation during the initial stages of cholestatic fibrosis in the rat.  Lab Invest. 1997;  76 765-778
• 54 Slott P A, Liu M H, Tavoloni N. Origin, pattern, and mechanism of bile duct proliferation following biliary obstruction in the rat.  Gastroenterology. 1990;  99 466-477
• 55 Sedlaczek N, Jia J D, Bauer M. et al . Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis.  Am J Pathol. 2001;  158 1239-1244
• 56 Bhunchet E, Wake K. Role of mesenchymal cell populations in porcine serum-induced rat liver fibrosis.  Hepatology. 1992;  16 1452-1473
• 57 Andrade Z A, Guerret S, Fernandes A L. Myofibroblasts in schistosomal portal fibrosis of man.  Mem Inst Oswaldo Cruz. 1999;  94 87-93
• 58 Desmouliere A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior.  Int J Dev Biol. 2004;  48 509-517
• 59 Jahoda C A, Reynolds A J. Hair follicle dermal sheath cells: unsung participants in wound healing.  The Lancet. 2001;  358 1445-1448
• 60 Forbes S J, Russo F P, Rey V. et al . A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis.  Gastroenterology. 2004;  126 955-963
• 61 Abe R, Donnelly S C, Peng T. et al . Peripheral blood fibrocytes: Differentiation pathway and migration to wound sites.  J Immunol. 2001;  166 7556-7562
• 62 Russo F P, Alison M R, Bigger B W. et al . The bone marrow functionally contributes to liver fibrosis.  Gastroenterology. 2006;  130 1807-1821
• 63 Quan T E, Cowper S, Wu S P. et al . Circulating fibrocytes: collagen-secreting cells of the peripheral blood.  Int J Biochem Cell Biol. 2004;  36 598-606
• 64 Kisseleva T, Uchinami H, Feirt N. et al . Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis.  J Hepatol. 2006;  45 429-438
• 65 Czaja M J, Flanders K C, Biempica L. et al . Expression of tumor necrosis factor-alpha and transforming growth factor-beta 1 in acute liver injury.  Growth Factors. 1989;  1 219-226
• 66 Nakatsukasa H, Nagy P, Evarts R P. et al . 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 1833-1843
• 67 Bissell D M, Wang S S, Jarnagin W R. et al . Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation.  J Clin Invest. 1995;  96 447-455
• 68 Davis B H. Transforming growth factor beta responsiveness is modulated by the extracellular collagen matrix during hepatic Ito cell culture.  J Cell Physiol. 1988;  136 547-553
• 69 Czaja M J, Weiner F R, Flanders K C. et al . In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis.  J Cell Biol. 1989;  108 2477-2482
• 70 Pinzani M, Gesualdo L, Sabbah G M. et al . 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. 1989;  84 1786-1793
• 71 Gressner A M. Hepatic fibrogenesis: the puzzle of interacting cells, fibrogenic cytokines, regulatory loops, and extracellular matrix molecules.  Z Gastroenterol. 1992;  30 (Suppl 1) 5-16
• 72 Dooley S, Hamzavi J, Breitkopf K. et al . Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats.  Gastroenterology. 2003;  125 178-191
• 73 Pinzani M, Marra F, Carloni V. Signal transduction in hepatic stellate cells.  Liver. 1998;  18 2-13
• 74 Schonherr E, Hausser H J. Extracellular matrix and cytokines: a functional unit.  Dev Immunol. 2000;  7 89-101
• 75 Schuppan D, Ruehl M, Somasundaram R. et al . Matrix as a modulator of hepatic fibrogenesis.  Semin Liver Dis. 2001;  21 351-372
• 76 Friedman S L. The virtuosity of hepatic stellate cells.  Gastroenterology. 1999;  117 1244-1246
• 77 Gaca M D, Zhou X, Issa R. et al . Basement membrane-like matrix inhibits proliferation and collagen synthesis by activated rat hepatic stellate cells: evidence for matrix-dependent deactivation of stellate cells.  Matrix Biol. 2003;  22 229-239
• 78 Sohara N, Znoyko I, Levy M T. et al . Reversal of activation of human myofibroblast-like cells by culture on a basement membrane-like substrate.  J Hepatol. 2002;  37 214-221
• 79 Ramadori G, Saile B. Mesenchymal cells in the liver - one cell type or two?.  Liver. 2002;  22 283-294
• 80 Kim W H, Matsumoto K, Bessho K. et al . Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis.  Am J Pathol. 2005;  166 1017-1028
• 81 Sancho-Bru P, Bataller R, Gasull X. et al . Genomic and functional characterization of stellate cells isolated from human cirrhotic livers.  J Hepatol. 2005;  43 272-282
• 82 Inside Lab Invest.  Lab Invest. 2004;  84 149-150
• 83 Cassiman D, Libbrecht L, Desmet V. et al . Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers.  J Hepatol. 2002;  36 200-209
• 84 Cassiman D, Roskams T. Beauty is in the eye of the beholder: emerging concepts and pitfalls in hepatic stellate cell research.  J Hepatol. 2002;  37 527-535
• 85 Geerts A. On the origin of stellate cells: mesodermal, endodermal or neuro-ectodermal?.  J Hepatol. 2004;  40 331-334
• 86 Cassiman D, Barlow A, Vander B S. et al . Hepatic stellate cells do not derive from the neural crest.  J Hepatol. 2006;  44 1098-1104
• 87 Cassiman D, Roskams T, PJ. et al . Alpha B-crystallin expression in human and rat hepatic stellate cells.  J Hepatol. 2001;  35 200-207
• 88 Dudas J van, Mansuroglu T, Saile B. et al . Comparison of Thy-1 expression in human liver cirrhosis and different models of rat liver injury.  Z Gastroenterol. 2006;  54 86
• 89 Uchio K, Tuchweber B, Manabe N. et al . Cellular retinol-binding protein-1 expression and modulation during in vivo and in vitro myofibroblastic differentiation of rat hepatic stellate cells and portal fibroblasts.  Lab Invest. 2002;  82 619-628
• 90 Lepreux S, Bioulac-Sage P, Gabbiani G. et al . Cellular retinol-binding protein-1 expression in normal and fibrotic/cirrhotic human liver: different patterns of expression in hepatic stellate cells and (myo)fibroblast subpopulations.  J Hepatol. 2004;  40 774-780
• 91 Dranoff J A, Kruglov E A, Robson S C. et al . The ecto-nucleoside triphosphate diphosphohydrolase NTPDase2/CD39L1 is expressed in a novel functional compartment within the liver.  Hepatology. 2002;  36 1135-1144
• 92 Wanless I R, Crawford J M. Cirrhosis; Surgical pathology of the GI tract, liver, biliary tract, and pancreas. Philadelphia; Saunders 2004: 863-884
• 93 Gall E A, Dobrogorski O. Hepatic alterations in obstructive jaundice.  Am J Clin Pathol. 1964;  41 126-139
• 94 Iredale J P, Benyon R C, 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;  102 538-549
• 95 Murphy F R, Issa R, Zhou X. et al . Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition. Implications for reversibility of liver fibrosis.  J Biol Chem. 2002;  277 11 069-11 076
• 96 Issa R, Zhou X, Constandinou C M. et al . Spontaneous recovery from micronodular cirrhosis: Evidence for incomplete resolution associated with matrix cross-linking.  Gastroenterology. 2004;  126 1795-1808
• 97 Birns M, Masek B, Uerbach O. The effects of experimental acute biliary obstruction and release on the rat liver. A histochemical study.  Am J Pathol. 1962;  40 95-111
• 98 Hammel P, Couvelard A, O’Toole D. et al . 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
• 99 Costa A M, Tuchweber B, Lamireau T. et al . Role of apoptosis in the remodeling of cholestatic liver injury following release of the mechanical stress.  Virchows Arch. 2003;  442 372-380
• 100 Desmet V J, Roskams T. Cirrhosis reversal: a duel between dogma and myth.  J Hepatol. 2004;  40 860-867
• 101 Pol S, Carnot F, Nalpas B. et al . Reversibility of hepatitis C virus-related cirrhosis.  Hum Pathol. 2004;  35 107-112
• 102 Wanless I R, Nakashima E, Sherman M. Regression of human cirrhosis: Morphologic features and the genesis of incomplete septal cirrhosis.  Arch Pathol & Lab Medicine. 2000;  124 1599-1607
• 103 Parsons C J, Bradford B U, Pan C Q. et al . Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats.  Hepatology. 2004;  40 1106-1115
• 104 Lotersztajn S, Julien B, Teixeira-Clerc F. et al . Hepatic fibrosis: Molecular mechanisms and drug targets.  Ann Rev Pharmacol & Toxicol. 2005;  45 605-628
• 105 Beljaars L, Meijer D K, Poelstra K. Targeting hepatic stellate cells for cell-specific treatment of liver fibrosis.  Front Biosci. 2002;  7 e214-e222
• 106 Garcia-Banuelos J, Siller-Lopez F, Miranda A. et al . Cirrhotic rat livers with extensive fibrosis can be safely transduced with clinical-grade adenoviral vectors. Evidence of cirrhosis reversion.  Gene Ther. 2002;  9 127-134
• 107 Sakaida I, Terai S, Yamamoto N. et al . Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice.  Hepatology. 2004;  40 1304-1311