Hostname: page-component-745bb68f8f-mzp66 Total loading time: 0 Render date: 2025-01-26T23:08:52.910Z Has data issue: false hasContentIssue false
  • English
  • Français

Cholangiocyte proliferation and liver fibrosis

Published online by Cambridge University Press:  25 February 2009

Shannon S. Glaser ,
Eugenio Gaudio ,
Tim Miller ,
Domenico Alvaro  and
Gianfranco Alpini
Shannon S. Glaser*
Affiliation:
Department of Medicine, Scott and White and Texas A&M Health Science Center, Temple, TX 76504, USA.
Eugenio Gaudio
Affiliation:
Department of Anatomy, Sapienza University of Rome, Via Alfonso Borelli 50, 00161 Rome, Italy.
Tim Miller
Affiliation:
Department of Medicine, Scott and White and Texas A&M Health Science Center, Temple, TX 76504, USA.
Domenico Alvaro
Affiliation:
Division of Gastroenterology, Sapienza University of Rome, Polo Pontino, Via R. Rossellini 51, 00137 Rome, Italy.
Gianfranco Alpini
Affiliation:
Department of Medicine, Scott and White and Texas A&M Health Science Center, Temple, TX 76504, USA.
*
*Corresponding author: Medical Research Building Room 316B, Scott and White and Texas A&M Health Science Center, 702 SW HK Dodgen Loop, Temple, TX 76504, USA. Tel: +1 254 742 7058; Fax: +1 254 724 5944; E-mail: sglaser@tamu.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

Cholangiocyte proliferation is triggered during extrahepatic bile duct obstruction induced by bile duct ligation, which is a common in vivo model used for the study of cholangiocyte proliferation and liver fibrosis. The proliferative response of cholangiocytes during cholestasis is regulated by the complex interaction of several factors, including gastrointestinal hormones, neuroendocrine hormones and autocrine or paracrine signalling mechanisms. Activation of biliary proliferation (ductular reaction) is thought to have a key role in the initiation and progression of liver fibrosis. The first part of this review provides an overview of the primary functions of cholangiocytes in terms of secretin-stimulated bicarbonate secretion – a functional index of cholangiocyte growth. In the second section, we explore the important regulators, both inhibitory and stimulatory, that regulate the cholangiocyte proliferative response during cholestasis. We discuss the role of proliferating cholangiocytes in the induction of fibrosis either directly via epithelial mesenchymal transition or indirectly via the activation of other liver cell types. The possibility of targeting cholangiocyte proliferation as potential therapy for reducing and/or preventing liver fibrosis, and future avenues for research into how cholangiocytes participate in the process of liver fibrogenesis are described.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 11 , July 2009 , e7
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Alpini, G., Prall, R.T. and LaRusso, N.F. (2001) The pathobiology of biliary epithelia. In The Liver; Biology & Pathobiology, 4E. (Arias, I. M. et al. , eds.), pp. 421-435, Lippincott Williams & WilkinsGoogle Scholar
2Racanelli, V. and Rehermann, B. (2006) The liver as an immunological organ. Hepatology 43, S54-62CrossRefGoogle ScholarPubMed
3Nathanson, M.H. and Boyer, J.L. (1991) Mechanisms and regulation of bile secretion. Hepatology 14, 551-566CrossRefGoogle ScholarPubMed
4Alpini, G. et al. (1988) Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules. Journal of Clinical Investigation 81, 569-578CrossRefGoogle ScholarPubMed
5Alvaro, D. et al. (1997) Role and mechanisms of action of acetylcholine in the regulation of rat cholangiocyte secretory functions. Journal of Clinical Investigation 100, 1349-1362Google Scholar
6Alvaro, D. et al. (1993) Effect of secretion on intracellular pH regulation in isolated rat bile duct epithelial cells. Journal of Clinical Investigation 92, 1314-1325CrossRefGoogle ScholarPubMed
7Glaser, S. et al. (2006) Heterogeneity of the intrahepatic biliary epithelium. World Journal of Gastroenterology 12, 3523-3536Google Scholar
8Glaser, S. et al. (1997) Gastrin inhibits secretin-induced ductal secretion by interaction with specific receptors on rat cholangiocytes. American Journal of Physiology Gastrointestinal and Liver Physiology 273, G1061-1070CrossRefGoogle ScholarPubMed
9Kanno, N. et al. (2001) Regulation of cholangiocyte bicarbonate secretion. American Journal of Physiology – Gastrointestinal and Liver Physiology 281, G612-625CrossRefGoogle ScholarPubMed
10Tietz, P.S. et al. (1995) Somatostatin inhibits secretin-induced ductal hypercholeresis and exocytosis by cholangiocytes. American Journal of Physiology – Gastrointestinal and Liver Physiology 269, G110-118CrossRefGoogle ScholarPubMed
11Ulrich, C.D. 2nd, Holtmann, M. and Miller, L.J. (1998) Secretin and vasoactive intestinal peptide receptors, members of a unique family of G protein-coupled receptors. Gastroenterology 114, 382-397Google Scholar
12Farouk, M. et al. (1993) Secretin receptors in a new preparation of plasma membranes from intrahepatic biliary epithelium. Journal of Surgical Research 54, 1-6CrossRefGoogle Scholar
13Alpini, G. et al. (1994) Upregulation of secretin receptor gene expression in rat cholangiocytes after bile duct ligation. American Journal of Physiology – Gastrointestinal and Liver Physiology 266, G922-928CrossRefGoogle ScholarPubMed
14Alvaro, D., Mennone, A. and Boyer, J.L. (1997) Role of kinases and phosphatases in the regulation of fluid secretion and Cl−/HCO3− exchange in cholangiocytes American Journal of Physiology – Gastrointestinal and Liver Physiology 273, G303-313CrossRefGoogle ScholarPubMed
15McGill, J.M. et al. (1994) Secretin activates Cl− channels in bile duct epithelial cells through a cAMP-dependent mechanism. American Journal of Physiology – Gastrointestinal and Liver Physiology 266, G731-736CrossRefGoogle ScholarPubMed
16Martinez-Anso, E. et al. (1994) Immunohistochemical detection of chloride/bicarbonate anion exchangers in human liver. Hepatology 19, 1400-1406Google Scholar
17Holz, G.G. et al. (2006) Cell physiology of cAMP sensor Epac. Journal of Physiology 577, 5-15CrossRefGoogle ScholarPubMed
18Masyuk, A.I. et al. (2008) Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors. American Journal of Physiology – Gastrointestinal and Liver Physiology 295, G725-734CrossRefGoogle ScholarPubMed
19LeSage, G. et al. (1996) Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion. Gastroenterology 111, 1633-1644CrossRefGoogle ScholarPubMed
20Alpini, G. et al. (1999) Bile acid feeding induces cholangiocyte proliferation and secretion, evidence for bile acid-regulated ductal secretion. Gastroenterology 116, 179-186CrossRefGoogle ScholarPubMed
21Alpini, G. et al. (1997) gamma-Interferon inhibits secretin-induced choleresis and cholangiocyte proliferation in a murine model of cirrhosis. Journal of Hepatology 27, 371-380Google Scholar
22Alpini, G. et al. (1998) Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation. American Journal of Physiology – Gastrointestinal and Liver Physiology 274, G767-775CrossRefGoogle ScholarPubMed
23Francis, H. et al. (2004) cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathway. Journal of Hepatology 41, 528-537CrossRefGoogle Scholar
24Glaser, S. et al. (2000) Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/Gastrin receptors via D-myo-inositol 1,4,5-triphosphate-, Ca(2+)-, and protein kinase C alpha-dependent mechanisms. Hepatology 32, 17-25Google Scholar
25LeSage, G. et al. (1999) Acute carbon tetrachloride feeding selectively damages large, but not small, cholangiocytes from normal rat liver. Hepatology 29, 307-319CrossRefGoogle Scholar
26LeSage, G. et al. (1999) Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver. American Journal of Physiology – Gastrointestinal and Liver Physiology 276, G1289-1301Google Scholar
27LeSage, G. et al. (2001) Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis. American Journal of Physiology – Gastrointestinal and Liver Physiology 281, G182-190CrossRefGoogle ScholarPubMed
28Alvaro, D. et al. (2007) Proliferating cholangiocytes, a neuroendocrine compartment in the diseased liver. Gastroenterology 132, 415-431Google Scholar
29Marzioni, M. et al. (2007) Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis. Gastroenterology 133, 244-255CrossRefGoogle ScholarPubMed
30Gigliozzi, A. et al. (2004) Nerve growth factor modulates the proliferative capacity of the intrahepatic biliary epithelium in experimental cholestasis. Gastroenterology 127, 1198-1209CrossRefGoogle ScholarPubMed
31Gaudio, E. et al. (2006) Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism. Gastroenterology 130, 1270-1282CrossRefGoogle ScholarPubMed
32Marzioni, M. et al. (2008) Control of cholangiocyte adaptive responses by visceral hormones and neuropeptides. Clinical Reviews in Allergy and Immunology, Jun 11 [Epub ahead of print]Google Scholar
33Roskams, T. et al. (1990) Neuroendocrine features of reactive bile ductules in cholestatic liver disease. American Journal of Pathology 137, 1019-1025Google Scholar
34Desmet, V., Roskams, T. and Van Eyken, P. (1995) Ductular reaction in the liver. Pathology, Research and Practice 191, 513-524CrossRefGoogle ScholarPubMed
35Ebrahimkhani, M.R., Elsharkawy, A.M. and Mann, D.A. (2008) Wound healing and local neuroendocrine regulation in the injured liver. Expert Reviews in Molecular Medicine 10, e11Google Scholar
36Lazaridis, K.N., Strazzabosco, M. and LaRusso, N.F. (2004) The cholangiopathies, disorders of biliary epithelia. Gastroenterology 127, 1565-1577CrossRefGoogle ScholarPubMed
37Glaser, S. et al. (2003) Gastrin reverses established cholangiocyte proliferation and enhanced secretin-stimulated ductal secretion of BDL rats by activation of apoptosis through increased expression of Ca2+- dependent PKC isoforms. Liver International 23, 78-88CrossRefGoogle ScholarPubMed
38Tracy, T.F. Jr. et al. (1993) Somatostatin analogue (octreotide) inhibits bile duct epithelial cell proliferation and fibrosis after extrahepatic biliary obstruction. American Journal of Pathology 143, 1574-1578Google ScholarPubMed
39Masyuk, T.V. et al. (2007) Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3',5'-cyclic monophosphate. Gastroenterology 132, 1104-1116Google Scholar
40Drucker, D.J. (2003) Glucagon-like peptides, regulators of cell proliferation, differentiation, and apoptosis. Molecular Endocrinology 17, 161-171CrossRefGoogle ScholarPubMed
41Bulotta, A. et al. (2002) Cultured pancreatic ductal cells undergo cell cycle re-distribution and beta-cell-like differentiation in response to glucagon-like peptide-1. Journal of Molecular Endocrinology 29, 347-360CrossRefGoogle ScholarPubMed
42Alpini, G. et al. (1997) Bile acids stimulate proliferative and secretory events in large but not small cholangiocytes. American Journal of Physiology – Gastrointestinal and Liver Physiology 273, G518-529Google Scholar
43Alpini, G. et al. (1997) Functional expression of the apical Na+-dependent bile acid transporter in large but not small rat cholangiocytes. Gastroenterology 113, 1734-1740Google Scholar
44Lazaridis, K.N. et al. (1997) Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter. Journal of Clinical Investigation 100, 2714-2721Google Scholar
45Alpini, G. et al. (2001) Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes. Hepatology 34, 868-876Google Scholar
46Alpini, G. et al. (2002) Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha. Hepatology 35, 1041-1052Google Scholar
47Alpini, G. et al. (2005) Secretin activation of the apical Na+-dependent bile acid transporter is associated with cholehepatic shunting in rats. Hepatology 41, 1037-1045CrossRefGoogle ScholarPubMed
48Lazaridis, K.N. et al. (2000) Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties. Proceedings of the National Academy of Sciences of the United States of America 97, 11092-11097CrossRefGoogle Scholar
49Gaudio, E. et al. (1996) Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis, a morphological study. Gastroenterology 111, 1118-1124CrossRefGoogle ScholarPubMed
50Sartelet, H. et al. (2004) Expression of vascular endothelial growth factor (VEGF) and its receptors (VEGF-R1 [Flt-1] and VEGF-R2 [KDR/Flk-1]) in tumorlets and in neuroendocrine cell hyperplasia of the lung. Human Pathology 35, 1210-1217CrossRefGoogle ScholarPubMed
51Gaudio, E. et al. (2006) Administration of r-VEGF-A prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats. American Journal of Physiology – Gastrointestinal and Liver Physiology 291, G307-317Google Scholar
52Fabris, L. et al. (2006) Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases. Hepatology 43, 1001-1012Google Scholar
53Amura, C.R. et al. (2007) VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice. American Journal of Physiology – Cell Physiology 293, C419-428CrossRefGoogle ScholarPubMed
54Luo, B. et al. (2005) Cholangiocyte endothelin 1 and transforming growth factor beta1 production in rat experimental hepatopulmonary syndrome. Gastroenterology 129, 682-695Google Scholar
55LeSage, G. et al. (1999) Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats. Gastroenterology 117, 191-199Google Scholar
56Iwai, M. and Shimazu, T. (1992) Alteration in sympathetic nerve activity during liver regeneration in rats after partial hepatectomy. Journal of the Autonomic Nervous System 41, 209-214Google Scholar
57Glaser, S. et al. (2006) Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt. American Journal of Physiology – Gastrointestinal and Liver Physiology 290, G813-826Google Scholar
58Marzioni, M. et al. (2007) Cytoprotective effects of taurocholic acid feeding on the biliary tree after adrenergic denervation of the liver. Liver International 27, 558-568Google Scholar
59Marzioni, M. et al. (2005) Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin. Gastroenterology 128, 121-137CrossRefGoogle ScholarPubMed
60Swain, M.G. and Maric, M. (1997) Improvement in cholestasis-associated fatigue with a serotonin receptor agonist using a novel rat model of fatigue assessment. Hepatology 25, 291-294Google Scholar
61Jones, E.A. and Bergasa, N.V. (1999) The pathogenesis and treatment of pruritus and fatigue in patients with PBC. European Journal of Gastroenterology and Hepatology 11, 623-631Google Scholar
62Hou, Y.F. et al. (2006) Modulation of expression and function of Toll-like receptor 3 in A549 and H292 cells by histamine. Molecular Immunology 43, 1982-1992CrossRefGoogle ScholarPubMed
63Jancso, G. et al. (2000) Inhibitory neurogenic modulation of histamine-induced cutaneous plasma extravasation in the pigeon. Regulatory Peptides 95, 75-80CrossRefGoogle ScholarPubMed
64Parsons, M.E. and Ganellin, C.R. (2006) Histamine and its receptors. British Journal of Pharmacology 147 Suppl 1, S127-135CrossRefGoogle ScholarPubMed
65Francis, H. et al. (2007) H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway. Laboratory Investigation 87, 473-487Google Scholar
66Francis, H. et al. (2008) Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway. American Journal of Physiology – Cell Physiology 295, C499-513Google Scholar
67Glaser, S. et al. (2007) Knockout of alpha-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice. Laboratory Investigation 87, 914-926Google Scholar
68Tippins, J.R. (1986) CGRP, a novel neuropeptide from the calcitonin gene is the most potent vasodilator known. Journal of Hypertension. Supplement. 4, S102-105Google Scholar
69Brain, S.D. et al. (1985) Calcitonin gene-related peptide is a potent vasodilator. Nature 313, 54-56Google Scholar
70Wimalawansa, S.J. (1996) Calcitonin gene-related peptide and its receptors, molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocrine Reviews 17, 533-585CrossRefGoogle ScholarPubMed
71DiPette, D.J. et al. (1989) Dose-dependent systemic and regional hemodynamic effects of calcitonin gene-related peptide. American Journal of the Medical Sciences 297, 65-70Google Scholar
72Bang, R. et al. (2004) Neurokinin-1 receptor antagonists protect mice from CD95- and tumor necrosis factor-alpha-mediated apoptotic liver damage. Journal of Pharmacology and Experimental Therapeutics 308, 1174-1180Google Scholar
73Bang, R. et al. (2003) Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury. Journal of Pharmacology and Experimental Therapeutics 305, 31-39Google Scholar
74Neuhuber, W.L. and Tiegs, G. (2004) Innervation of immune cells, evidence for neuroimmunomodulation in the liver. Anatomical Record A. Discoveries in Molecular, Cellular and Evolutionary Biology 280, 884-892CrossRefGoogle Scholar
75Galtier-Dereure, F. et al. (1992) Estradiol stimulates cell growth and secretion of procathepsin D and a 120-kilodalton protein in the human ovarian cancer cell line BG-1. Journal of Clinical Endocrinology and Metabolism 75, 1497-1502Google Scholar
76Chalbos, D. et al. (1982) Estrogens stimulate cell proliferation and induce secretory proteins in a human breast cancer cell line (T47D). Journal of Clinical Endocrinology and Metabolism 55, 276-283CrossRefGoogle Scholar
77Beckmann, M.W. et al. (2001) Hormone replacement therapy after treatment of breast cancer, effects on postmenopausal symptoms, bone mineral density and recurrence rates. Oncology 60, 199-206Google Scholar
78Alvaro, D. et al. (2000) Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats. Gastroenterology 119, 1681-1691CrossRefGoogle ScholarPubMed
79Alvaro, D. et al. (2002) Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat. Hepatology 36, 297-304CrossRefGoogle ScholarPubMed
80Alvaro, D. et al. (2002) Effect of ovariectomy on the proliferative capacity of intrahepatic rat cholangiocytes. Gastroenterology 123, 336-344Google Scholar
81Svegliati-Baroni, G. et al. (2006) Estrogens maintain bile duct mass and reduce apoptosis after biliodigestive anastomosis in bile duct ligated rats. Journal of Hepatology 44, 1158-1166CrossRefGoogle ScholarPubMed
82Alvaro, D. et al. (2004) Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. Journal of Hepatology 41, 905-912CrossRefGoogle ScholarPubMed
83Invernizzi, P. et al. (2004) Tamoxifen in treatment of primary biliary cirrhosis. Hepatology 39, 1175-1176Google Scholar
84Glaser, S. et al. (2008) Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms. American Journal of Physiology – Gastrointestinal and Liver Physiology 295, G124-136CrossRefGoogle ScholarPubMed
85Alvaro, D. et al. (2005) The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis. Journal of Hepatology 43, 875-83CrossRefGoogle ScholarPubMed
86Gatto, M. et al. (2008) Insulin-like growth factor-1 isoforms in rat hepatocytes and cholangiocytes and their involvement in protection against cholestatic injury. Laboratory Investigation 88, 986-994Google Scholar
87He, Y. et al. (2008) Interaction of CD44 and Hyaluronic Acid Enhances Biliary Epithelial Proliferation in Cholestatic Livers. American Journal of Physiology – Gastrointestinal and Liver Physiology 295, G305-312CrossRefGoogle ScholarPubMed
88Bajorath, J. (2000) Molecular organization, structural features, and ligand binding characteristics of CD44, a highly variable cell surface glycoprotein with multiple functions. Proteins 39, 103-111Google Scholar
89Bartolazzi, A. et al. (1996) Glycosylation of CD44 is implicated in CD44-mediated cell adhesion to hyaluronan. Journal of Cell Biology 132, 1199-1208CrossRefGoogle ScholarPubMed
90Tammi, M.I., Day, A.J. and Turley, E.A. (2002) Hyaluronan and homeostasis, a balancing act. Journal of Biological Chemistry 277, 4581-4584CrossRefGoogle ScholarPubMed
91Mikami, T. et al. (2001) Significant correlations of E-cadherin, catenin, and CD44 variant form expression with carcinoma cell differentiation and prognosis of extrahepatic bile duct carcinomas. American Journal of Clinical Pathology 116, 369-376Google Scholar
92Xu, B. et al. (2002) High frequency of autoantibodies in patients with primary sclerosing cholangitis that bind biliary epithelial cells and induce expression of CD44 and production of interleukin 6. Gut 51, 120-127CrossRefGoogle ScholarPubMed
93Sedlaczek, N. et al. (2001) Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis. American Journal of Pathology 158, 1239-1244Google Scholar
94Milani, S. et al. (1990) Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis. Gastroenterology 98, 175-184Google Scholar
95Milani, S. et al. (1991) Transforming growth factors beta 1 and beta 2 are differentially expressed in fibrotic liver disease. American Journal of Pathology 139, 1221-1229Google ScholarPubMed
96Milani, S. et al. (1989) Cellular localization of laminin gene transcripts in normal and fibrotic human liver. American Journal of Pathology 134, 1175-1182Google Scholar
97Grappone, C. et al. (1999) Expression of platelet-derived growth factor in newly formed cholangiocytes during experimental biliary fibrosis in rats. Journal of Hepatology 31, 100-109Google Scholar
98Pinzani, M. et al. (1996) Inhibition by pentoxifylline of extracellular signal-regulated kinase activation by platelet-derived growth factor in hepatic stellate cells. British Journal of Pharmacology 119, 1117-1124CrossRefGoogle ScholarPubMed
99Cho, J.J. et al. (2000) An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology 118, 1169-1178Google Scholar
100Lowes, K.N. et al. (1999) Oval cell numbers in human chronic liver diseases are directly related to disease severity. American Journal of Pathology 154, 537-541CrossRefGoogle ScholarPubMed
101Davies, S.E. et al. (1991) Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology 13, 150-157CrossRefGoogle ScholarPubMed
102Ray, M.B. et al. (1993) Bile duct changes in alcoholic liver disease. The Veterans Administration Cooperative Study Group. Liver 13, 36-45CrossRefGoogle ScholarPubMed
103Clouston, A.D. et al. (2005) Fibrosis correlates with a ductular reaction in hepatitis C, roles of impaired replication, progenitor cells and steatosis. Hepatology 41, 809-818Google Scholar
104Richardson, M.M. et al. (2007) Progressive fibrosis in nonalcoholic steatohepatitis, association with altered regeneration and a ductular reaction. Gastroenterology 133, 80-90CrossRefGoogle Scholar
105Roskams, T. and Desmet, V. (1998) Ductular reaction and its diagnostic significance. Seminars in Diagnostic Pathology 15, 259-269Google Scholar
106Robertson, H. et al. (2004) Chronic renal allograft dysfunction, the role of T cell-mediated tubular epithelial to mesenchymal cell transition. Journal of the American Society of Nephrology 15, 390-397CrossRefGoogle ScholarPubMed
107Burns, W.C., Kantharidis, P. and Thomas, M.C. (2007) The role of tubular epithelial-mesenchymal transition in progressive kidney disease. Cells Tissues Organs 185, 222-231Google Scholar
108Diaz, R. et al. (2008) Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis. Human Pathology 39, 102-115Google Scholar
109Robertson, H. et al. (2007) Biliary epithelial-mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis. Hepatology 45, 977-981CrossRefGoogle ScholarPubMed
110Sicklick, J.K. et al. (2006) Evidence for epithelial-mesenchymal transitions in adult liver cells. American Journal of Physiology – Gastrointestinal and Liver Physiology 291, G575-583Google Scholar
111Rygiel, K.A. et al. (2008) Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Laboratory Investigation 88, 112-123Google Scholar
112Omenetti, A. et al. (2007) Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation. Laboratory Investigation 87, 499-514CrossRefGoogle ScholarPubMed
113Kinnman, N. et al. (2003) The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Laboratory Investigation 83, 163-173CrossRefGoogle ScholarPubMed
114Kinnman, N. et al. (2001) Hepatic stellate cell proliferation is an early platelet-derived growth factor-mediated cellular event in rat cholestatic liver injury. Laboratory Investigation 81, 1709-1716Google Scholar
115Luo, B.H. and Springer, T.A. (2006) Integrin structures and conformational signaling. Current Opinion in Cell Biology 18, 579-586Google Scholar
116Patsenker, E. et al. (2008) Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 135, 660-670Google Scholar
117Popov, Y. et al. (2008) Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. Journal of Hepatology 48, 453-464CrossRefGoogle Scholar
118Marra, F. et al. (2005) Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis. World Journal of Gastroenterology 11, 4931-4938Google Scholar
119Yoshiji, H. et al. (2006) Angiotensin-II and vascular endothelial growth factor interaction plays an important role in rat liver fibrosis development. Hepatology Research 36, 124-129Google Scholar
120Yasuda, M. et al. (1999) Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats. Hepatology 29, 719-727Google Scholar
121Rasi, G. et al. (2007) Nerve growth factor involvement in liver cirrhosis and hepatocellular carcinoma. World Journal of Gastroenterology 13, 4986-4995CrossRefGoogle ScholarPubMed
122Li, T. et al. (2006) Effects of 5-hydroxytamine and its antagonists on hepatic stellate cells. Hepatobiliary and Pancreatic Diseases International 5, 96-100Google Scholar
123Ruddell, R.G. et al. (2006) A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. American Journal of Pathology 169, 861-876Google Scholar
124Marzioni, M. et al. (2003) Taurocholate prevents the loss of intrahepatic bile ducts due to vagotomy in bile duct-ligated rats. American Journal of Physiology Gastrointestinal and Liver Physiology 284, G837-852CrossRefGoogle ScholarPubMed
125Oben, J.A. et al. (2004) Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut 53, 438-445Google Scholar
126Umezu, K., Yuasa, S. and Sudoh, A. (1985) Change of hepatic histamine content during hepatic fibrosis. Biochemical Pharmacology 34, 2007-2011Google Scholar
127Schiavon, L.L. et al. (2008) Serum levels of YKL-40 and hyaluronic acid as noninvasive markers of liver fibrosis in haemodialysis patients with chronic hepatitis C virus infection. Journal of Viral Hepatitis 15, 666-674Google Scholar

Further reading, resources and contacts

The American Association for the Study of Liver Disease (AASLD) website provides guidelines on the management of various liver diseases for professionals as well as numerous patient resources and links:

Alvaro, D. et al. (2007) Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 132, 415-431CrossRefGoogle ScholarPubMed
Wallace, K., Burt, A. and Wright, M. (2008) Liver fibrosis. Biochemistry Journal 411, 1-18Google Scholar
Parola, M., Marra, F. and Pinzani, M. (2008) Myofibroblast-like cells and liver fibrogenesis: Emerging concepts in a rapidly moving scenario. Molecular Aspects of Medicine 29, 58-66Google Scholar
https://www.aasld.orgGoogle Scholar
http://www.liverfoundation.org/Google Scholar
Alvaro, D. et al. (2007) Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 132, 415-431CrossRefGoogle ScholarPubMed
Wallace, K., Burt, A. and Wright, M. (2008) Liver fibrosis. Biochemistry Journal 411, 1-18Google Scholar
Parola, M., Marra, F. and Pinzani, M. (2008) Myofibroblast-like cells and liver fibrogenesis: Emerging concepts in a rapidly moving scenario. Molecular Aspects of Medicine 29, 58-66Google Scholar
https://www.aasld.orgGoogle Scholar
http://www.liverfoundation.org/Google Scholar