Basics of pathogenesis of liver fibrosis
Keywords:
Liver fibrosis, extracellular matrix, stellate cells, metalloproteinasesAbstract
Liver fibrosis is a complicated biochemical process in which damaged regions of the liver tissue are encapsulated by an extracellular matrix with scar formation. It develops in all patients with chronic liver injury at variable rates depending in part upon the cause of liver disease and in part upon the host factors. This process occurs earliest in regions where injury is most severe, particularly in chronic inflammatory liver diseases due to alcohol or viral infection. The development of fibrosis usually requires several months to years of ongoing injury. The exact point in which fibrosis becomes irreversible is unknown however, increasing evidence suggests that even advanced stages of fibrosis may be reversible. An understanding of the molecular mechanisms involved in fibrogenesis process has a number of clinical implications. One of the most important is development of therapeutic interventions designed to impede or reverse hepatic fibrosis. This review discusses the current mechanisms underlying liver fibrosis.
Downloads
References
Iredale IP. Models of liver fibrosis; exploring the dynamic nature of inflammation and repair in a solid organ. J. Clin. Invest. 2007;117:539-548.
Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: A critical appraisal. Hepatology 2003; 37:493- 503.
Poynard T, Mathurin P, Lai CL, Guyader D, Poupon R, Tainturier MH i wsp. A comparison of fibrosis progression in chronic liver diseases. J. Hepatol. 2003;38:257-65.
Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL i wsp. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124:105-17.
Dufour JF, DeLellis R, Kaplan MM. Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann. Intern. Med. 1997;127:981–985.
Falize L, Guillygomarc'h A, Perrin M, Laine F, Guyader D, Brissot P i wsp. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: A study of 36 cases. Hepatology. 2006; 44:472-7.
Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin. Liver Dis. 2001;21:351-72.
Rojkind, M, Giambrone, MA, Biempica L. Collagen types in normal and cirrhotic liver. Gastroenterology 1979;76:710-9.
Gressner AM. The cell biology of liver fibrogenesis - an imbalance of proliferation, growth arrest and apoptosis of myofibroblasts. Cell Tissue Res. 1998;292:447-52.
McGuire RF, Bissell DM, Boyles J, Roll FJ. Role of extracellular matrix in regulating fenestrations of sinusoidal endothelial cells isolated from normal rat liver. Hepatology 1992; 15:989-97.
Lee JS, Semela D, Iredale J, Shah VH. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?. Hepatology 2007;45:817-25.
Dev A, Patel K, Conrad A, Blatt LM, McHutchison JG. Relationship of smoking and fibrosis in patients with chronic hepatitis C. Clin. Gastroenterol. Hepatol. 2006;4:797-801.
Kitazawa E, Igarashi T, Kawaguchi N, Matsushima H, Kawashima Y, Hankins RW i wsp. Differences in anti-LKM-1 autoantibody immunoreactivity to CYP2D6 antigenic sites between hepatitis C virus-negative and -positive patients. J Autoimmun. 2001;17:243-9.
Melton AC, Soon RK Jr, Park JG, Martinez L, Dehart GW, Yee HF Jr. Focal adhesion disassembly is an essential early event in hepatic stellate cell chemotaxis. Am. J. Physiol. Gastrointest. Liver. Physiol. 2007;293:1272-80.
Yang C, Zeisberg M, Mosterman B, Sudhakar A, Yerramalla U, Holthaus K i wsp. Liver fibrosis: Insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors. Gastroenterology 2003;124:147-59.
Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology 2008;47:1394-4000.
Kinnman N, Housset C. Peribiliary myofibroblasts in biliary type liver fibrosis. Front Biosci 2002; 7:496-503.
Kruglov EA, Jain D, Dranoff JA. Isolation of primary rat liver fibroblasts. J. Investig. Med. 2002;50:179-84.
Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D i wsp. American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology 2010 ;51:2193-213.
Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA i wsp. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004;126:955-63.
Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 2001;21:311-35.
Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A i wsp. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998;115:421-32.
Bachem MG, Schunemann M, Ramadani M, Siech M, Beger H, Buck A i wsp. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005;128:907-21.
Enzan H, Himeno H, Iwamura S, Onishi S, Saibara T, Yamamoto Y i wsp. Alpha-smooth muscle actin-positive perisinusoidal stromal cells in human hepatocellular carcinoma. Hepatology 1994;19:895-903.
Enzan H, Himeno H, Iwamura S, Saibara T,Onishi S, Yamamoto Y i wsp. Sequential changes in human Ito cells and their relation to postnecrotic liver fibrosis in massive and submassive hepatic necrosis. Virchows Arch. 1995; 426:95-101.
Schmitt-Graff A, Kruger S, Bochard F, Gabbiani G, Denk H. Modulation of alpha smooth muscle actin and desmin expression in perisinusoidal cells of normal and diseased human livers. Am. J.Pathol. 1991;138:1233-42.
Herbst H, Frey A, Heinrichs O, Milani S, Bechstein WO, Neuhaus P i wsp. Heterogeneity of liver cells expressing procollagen types I and IV in vivo. Histochem Cell Biol. 1997;107:399-409.
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;86:1641-8.
Roskams T, Moshage H, De Vos R, Guido D, Yap P, Desmet V. Heparan sulfate proteoglycan expression in normal human liver. Hepatology 1995;21:950-8.
Ruoslahti E, Engvall E. Integrins and vascular extracellular matrix assembly. J. Clin. Invest. 1997;99:1149-52.
Carloni V, Defranco RM, Caligiuri A, Gentilini A, Sciammetta SC, Baldi E i wsp. Cell adhesion regulates platelet-derived growth factor-induced MAP kinase and PI-3 kinase activation in stellate cells. Hepatology 2002;36:582-91.
Carloni V, Pinzani M, Giusti S, Romanelli RG, Parola M, Bellomo G i wsp. Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on ras in human hepatic stellate cells. Hepatology 2000;31:131-40.
Couvelard A, Scoazec JY, Feldmann G. Expression of cell-cell and cell-matrix adhesion proteins by sinusoidal endothelial cells in the normal and cirrhotic human liver. Am. J. Pathol. 1993;143:738-52.
Matsumoto S, Yamamoto K, Nagano T, Okamoto R, Ibuki N, Tagashira M i wsp. Immunohistochemical study on phenotypical changes of hepatocytes in liver disease with reference to extracellular matrix composition. Liver 1999;19:32-8.
Ismair MG, Stieger B, Cattori V, Hagenbuch B, Fried M, Meier PJ i wsp. Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides oatp4 and oatp8 of rat and human liver. Gastroenterology 2001;121:1185-90.
Racine-Samson L, Rockey DC, Bissell DM. The role of alpha1beta1 integrin in wound contraction. A quantitative analysis of liver myofibroblasts in vivo and in primary culture. J. Biol. Chem. 1997;272:30911-7.
Adams DH, Burra P, Hubscher SG, Elias E, Newman W. Endothelial activation and circulating vascular adhesion molecules in alcoholic liver disease. Hepatology 1994;19:588-94.
Adams DH, Hubscher SG, Fisher NC, Williams A, Robinson M. Expression of E-selectin and E-selectin ligands in human liver inflammation. Hepatology 1996;24:533-8.
Nakanuma Y, Yasoshima M, Tsuneyama K, Harada, K. Histopathology of primary biliary cirrhosis with emphasis on expression of adhesion molecules. Semin. Liver Dis. 1997;17:35- 47.
Vlodavsky I, Miao HQ, Medalion B, Danagher P, Ron D. Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor. Cancer Metastasis Rev. 1996;15:177-86.
Schuppan D, Schmid M, Somasundaram R, Ackermann R, Ruehl M, Nakamura T i wsp. Collagens in the liver extracellular matrix bind hepatocyte growth factor. Gastroenterology 1998;114:139-52.
Breitkopf K, Godoy P, Ciuclan L, Singer MV, Dooley S. TGF-beta/Smad signaling in the injured liver. Z. Gastroenterol. 2006; 44:57-66.
Inagaki Y, Okazaki I. Emerging insights into transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut 2007;56:284-92.
Liu C, Gaca MD, Swenson ES, Vellucci VF; Reiss M; Wells RG. Smads 2 and 3 are differentially activated by transforming growth factor-beta (TGF-beta ) in quiescent and activated hepatic stellate cells. Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent. J. Biol. Chem. 2003;278:11721-8.
Uemura M, Swenson ES, Gaca MD, Giordano FJ, Reiss M, Wells RG. Smad2 and Smad3 play different roles in rat hepatic stellate cell function and alpha-smooth muscle actin organization. Mol. Biol. Cell 2005;16:4214-24.
Wiercinska E, Wickert L, Denecke B, Said HM, Hamzavi J, Gressner AM i wsp. Id1 is a critical mediator in TGF-beta-induced transdifferentiation of rat hepatic stellate cells. Hepatology 2006;43:1032-41.
Czaja AJ. Autoimmune hepatitis. Str. 337-348. [w]:Mayo Clinic. Gastroenterology and Hepatology Board Review. Second Edition. S.C. Hauser Ed. Mayo Clinic Scientific Press, Taylor & Francis Group. New York 2006.
Arthur MJ, Stanley A, Iredale JP, Rafferty JA, Hembry RM, Friedman SL. Secretion of 72 kDa type IV collagenase/gelatinase by cultured human lipocytes. Analysis of gene expression, protein synthesis and proteinase activity. Biochem. J. 1992;287:701-7.
Milani S, Herbst H, Schuppan D, Grappone C, Pellegrini G, Pinzani M i wsp. Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am. J. Patrol. 1994;144:528-37.
Vyas SK, Leyland H, Gentry J, Arthur MJ. Rat hepatic lipocytes synthesize and secrete transin (stromelysin) in early primary culture. Gastroenterology 1995;109:889-98.
Theret N, Musso O, L'Helgoualc'h A, Clement B. Activation of matrix metalloproteinase-2 from hepatic stellate cells requires interactions with hepatocytes. Am. J. Pathol. 1997;150:51-8.
Theret N, Lehti K, Musso O, Clement B. MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells. Hepatology 1999;30:462-8.
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;110:821-31.
Benyon RC, Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. Semin. Liver. Dis. 2001;21:373-84.
Herbst H, Wege T, Milani S, Pellegrini G, Orzechowski HD, Bechstein WO i wsp. Tissue inhibitor of metalloproteinase-1 and -2 RNA expression in rat and human liver fibrosis. Am. J. Pathol. 1997;150:1647-59.
Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S i wsp. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J. Clin. Invest. 1998;102:538-49.
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;26:1213-9.
Friedman, SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J. Biol. Chem. 2000;275:2247-50.
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;127:2037-48.
Bachem MG, Melchior R, Gressner AM. The role of thrombocytes in liver fibrogenesis: effects of platelet lysate and thrombocyte-derived growth factors on the mitogenic activity and glycosaminoglycan synthesis of cultured rat liver fat storing cells. J. Clin. Chem. Clin. Biochem. 1989;27:555-65.
Fischer R, Cariers A, Reinehr R, Haussinger D. Caspase 9-dependent killing of hepatic stellate cells by activated Kupffer cells. Gastroenterology 2002;123:845-61.
Canbay A, Higuchi H, Bronk SF, Taniai M, Sebo TJ, Gores GJ . Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis. Gastroenterology 2002; 123:1323-30.
Watanabe A, Hashmi A, Gomes DA, Town T, Badou A, Flavell RA i wsp. Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology 2007;46:1509-18.
Pinzani M. PDGF and signal transduction in hepatic stellate cells. Front. Biosci. 2002;7:1720-6.
Wong L, Yamasaki G, Johnson RJ, Friedman SL. Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture. J. Clin. Invest. 1994;94:1563-9.
Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC i wsp. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc. Natl. Acad. Sci. U S A 2005;102:3389-94.
Marra F, Grandaliano G, Valente AJ, Abboud HE. Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology 1995;22:780-7.
Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ i wsp. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 2003;52:1347-54.
Steiling H, Muhlbauer M, Bataille F, Schölmerich J, Werner S, Hellerbrand C. Activated hepatic stellate cells express keratinocyte growth factor in chronic liver disease. Am. J. Pathol. 2004;165:1233-41.
Maher JJ. Interactions between hepatic stellate cells and the immune system. Semin. Liver Dis. 2001;21:417-26.
Marra F, DeFranco R, Grappone C, Parola M, Milani S, Leonarduzzi G i wsp. Expression of monocyte chemotactic protein-1 precedes monocyte recruitment in a rat model of acute liver injury, and is modulated by vitamin E. J. Investig. Med. 1999;47:66-75.
Bonacchi A, Romagnani P, Romanelli RG, Efsen E, Annunziato F, Lasagni L i wsp. 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;276:9945-54.
George J, Wang SS, Sevcsik AM, Sanicola M, Cate RL, Koteliansky VE i wsp. Transforming growth factor-beta initiates wound repair in rat liver through induction of the EIIIA-fibronectin splice isoform. Am. J. Pathol. 2000;156:115-24.
Gressner AM. The cell biology of liver fibrogenesis - an imbalance of proliferation, growth arrest and apoptosis of myofibroblasts. Cell Tissue Res. 1998;292:447-52.
Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J i wsp. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J. Clin. Invest. 2003;112:1383-94.
Rockey DC. Hepatic blood flow regulation by stellate cells in normal and injured liver. Semin. Liver Dis. 2001;21:337-49.
Bonacchi A, Petrai I, Defranco RM, Lazzeri E, Annunziato F, Efsen E i wsp. The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology 2003;125:1060-76.
Schwabe, RF, Bataller, R, Brenner, DA. Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am. J. Physiol. Gastrointest. Liver Physiol. 2003; 285:G949-58.
Brun P, Castagliuolo I, Pinzani M, Palu G, Martines D. Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am. J. Physiol. Gastrointest. Liver. Physiol. 2005;289:G571-8.
Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 2003;37:1043-55.
Vinas O, Bataller R, Sancho-Bru P, Gines P, Berenguer C, Enrich C i wsp. Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology 2003;38:919-29.
Safadi R, Ohta M, Alvarez CE, Fiel MI, Bansal M, Mehal WZ i wsp. Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes. Gastroenterology 2004;127:870-82.
Kordes C, Sawitza I, Muller-Marbach A, Ale-Agha N, Keitel V, Klonowski-Stumpe H i wsp. CD133+ hepatic stellate cells are progenitor cells. Biochem. Biophys. Res. Commun. 2007; 352:410-7.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2012 Medical Journal of the Rzeszow University and the National Medicines Institute, Warsaw
This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.
