Regulation and deregulation of cholangiocyte proliferation
2000; Elsevier BV; Volume: 33; Issue: 2 Linguagem: Inglês
10.1016/s0168-8278(00)80377-3
ISSN1600-0641
AutoresDomenico Alvaro, Alessandro Gigliozzi, A.F. Attili,
Tópico(s)Liver physiology and pathology
ResumoCholangiocytes are the epithelial cells which line the intrahepatic biliary tree, a network of interconnecting ducts of increasing diameter from the duct of Hering to the extrahepatic bile ducts (1.Roberts SK Ludwig J Larusso NF The pathobiology of biliary epithelia.Gastroenterology. 1997; 112: 269-279Abstract Full Text PDF PubMed Scopus (112) Google Scholar, 2.Strazzabosco M New insights into cholangiocyte physiology.J Hepatol. 1997; 27: 945-952Abstract Full Text PDF PubMed Scopus (39) Google Scholar, 3.Kanno N LeSage G Glaser S Alvaro D Alpini G Functional heterogeneity of the intrahepatic biliary epithelium.Hepatology. 2000; 31: 555-561Crossref PubMed Scopus (111) Google Scholar, 4.Boyer JL Vanishing Bile Duct Syndrome - from bench to bed side.in: Alvaro D Benedetti A Strazzabosco M Vanishing Bile Duct Syndrome. Kluwer Academic Publishers, London1997: 240-246Google Scholar, 5.Alvaro D Biliary epithelium: a new chapter in cell biology.It J Gastroenterol Hepatol. 1999; 31: 78-83PubMed Google Scholar, 6.Alpini G Lenzi R Sarkozi L Tavoloni N Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (289) Google Scholar). Cholangiocytes determine the final bile composition through a series of secretory and absorptive processes regulated by a number of hormones and neuropeptides (2.Strazzabosco M New insights into cholangiocyte physiology.J Hepatol. 1997; 27: 945-952Abstract Full Text PDF PubMed Scopus (39) Google Scholar, 3.Kanno N LeSage G Glaser S Alvaro D Alpini G Functional heterogeneity of the intrahepatic biliary epithelium.Hepatology. 2000; 31: 555-561Crossref PubMed Scopus (111) Google Scholar, 4.Boyer JL Vanishing Bile Duct Syndrome - from bench to bed side.in: Alvaro D Benedetti A Strazzabosco M Vanishing Bile Duct Syndrome. Kluwer Academic Publishers, London1997: 240-246Google Scholar, 5.Alvaro D Biliary epithelium: a new chapter in cell biology.It J Gastroenterol Hepatol. 1999; 31: 78-83PubMed Google Scholar). The intrahepatic bile ducts are the target of damage in a group of chronic cholestatic liver diseases recently classified as Vanishing Bile Duct Syndromes (4.Boyer JL Vanishing Bile Duct Syndrome - from bench to bed side.in: Alvaro D Benedetti A Strazzabosco M Vanishing Bile Duct Syndrome. Kluwer Academic Publishers, London1997: 240-246Google Scholar, 7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar). These diseases are characterized by the progressive disappearance of intrahepatic bile ducts, which leads to a severe ductopenic condition in the terminal stages (7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar). The residual bile ducts tend to proliferate as a compensatory mechanism (8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar). Thus, the course of these diseases is characterized by a balance between damage (loss) of bile ducts and compensatory proliferation of the residual ducts. The terminal decompensated stages are characterized by the inefficacy of proliferation to balance for the loss of intrahepatic bile ducts. Therefore, a therapeutic strategy designed to support efficacious cholangiocyte proliferation could delay progression to ductopenia. This represents a challenge for the future.The aim of this review is to focus on current knowledge of the regulation and dysregulation of cholangiocyte proliferation.Cholangiocyte ProliferationA peculiar property of cholangiocytes is the capacity to proliferate, as evidenced in specific experimental conditions as well as in different human pathological conditions (1.Roberts SK Ludwig J Larusso NF The pathobiology of biliary epithelia.Gastroenterology. 1997; 112: 269-279Abstract Full Text PDF PubMed Scopus (112) Google Scholar, 2.Strazzabosco M New insights into cholangiocyte physiology.J Hepatol. 1997; 27: 945-952Abstract Full Text PDF PubMed Scopus (39) Google Scholar, 3.Kanno N LeSage G Glaser S Alvaro D Alpini G Functional heterogeneity of the intrahepatic biliary epithelium.Hepatology. 2000; 31: 555-561Crossref PubMed Scopus (111) Google Scholar, 4.Boyer JL Vanishing Bile Duct Syndrome - from bench to bed side.in: Alvaro D Benedetti A Strazzabosco M Vanishing Bile Duct Syndrome. Kluwer Academic Publishers, London1997: 240-246Google Scholar, 5.Alvaro D Biliary epithelium: a new chapter in cell biology.It J Gastroenterol Hepatol. 1999; 31: 78-83PubMed Google Scholar, 6.Alpini G Lenzi R Sarkozi L Tavoloni N Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (289) Google Scholar, 7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. 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Neoplastic proliferation leads to cholangiocarcinoma, which is one of the worst malignancies (13.Celli A Que FG Dysregulation of apoptosis in the cholangiopathies and cholangiocarcinoma.Semin Liver Dis. 1998; 2: 177-185Crossref Scopus (59) Google Scholar).Cholangiocyte proliferation is usually classified as type I ("typical"), type II("atypical") and type III (oval cell) proliferation. Type I or "typical" cholangiocyte proliferation is a hyperplastic reaction resulting in an increased number of intrahepatic bile ducts, which, however, remain confined to portal spaces (7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar). The proliferating cholangiocytes form a well-differentiated three-dimensional network of tubular structures with a well-defined lumen (7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar). In the rat, "typical" cholangiocyte proliferation is observed after bile duct ligation (BDL) (6.Alpini G Lenzi R Sarkozi L Tavoloni N Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (289) Google Scholar), 70% hepatectomy (14.LeSage G Glaser S Gubba S Robertson WE Phinizy JL Lasater J et al.Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal bile secretion.Gastroenterology. 1996; 111: 1633-1644Abstract Full Text PDF PubMed Scopus (123) Google Scholar), chronic α-naphthylisothiocyanate feeding (15.Goldfarb S Singer EJ Popper H Experimental cholangitis due to a-naphthylisothiocyanate (ANIT).Am J Path. 1962; 40: 585-598Google Scholar), chronic L-proline treatment (16.Vacanti JP Folkman J Bile duct enlargement by infusion of L-proline: potential significance in biliary atresia.J Pediatr Surg. 1979; 14: 814-818Abstract Full Text PDF PubMed Scopus (18) Google Scholar), prolonged oral administration of lithocholate (LCA), chenodeoxycholate and taurocholate (TCA) (17.Palmer RH Ruban Z Production of bile duct hyperplasia and gallstones by lithocholic acid.J Clin Invest. 1966; 45: 1255-1267Crossref PubMed Scopus (90) Google Scholar, 18.Alpini G Glaser S Ueno Y Phinizy JL Rodgers R Francis H et al.Bile acid feeding induces cholangiocyte proliferation and secretion: evidence for bile acid-regulated ductal secretion.Gastroenterology. 1999; 116: 179-186Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). In humans, a "typical" proliferation may be observed in acute severe obstructive cholestasis (19.James L Lygidakis NJ van Eyken P Tanka AK Bosch KS Ramaekers FC et al.Application of keratin immunocytochemistry and sirius red staining in evaluation of intrahepatic changes with acute extrahepatic cholestasis due to hepatic duct carcinoma.Hepato-Gastroenterology. 1989; 36: 151-155PubMed Google Scholar) as well as in the early phases of chronic cholestatic liver diseases (7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar). It is quite accepted that the "typical" ductal proliferation results from the elongation of pre-existing bile ducts located within portal areas. This conclusion arises from a number of observations: i) in the BDL rat proliferating ducts retain immunohistochemical, ultrastructural and functional characteristics of their normal counterparts and appear, morphologically, as elongation of pre-existing ducts (6.Alpini G Lenzi R Sarkozi L Tavoloni N Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (289) Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar); ii) thymidine labeling studies were consistent with a proliferation of pre-existing ducts (20.Slott PA Liu MH Tavoloni N Origin, pattern, and mechanism of bile duct proliferation following biliary obstruction in the rat.Gastroenterology. 1990; 99: 466-477Abstract Full Text PDF PubMed Google Scholar, 21.Grisham JW A morphological study of deoxyribonucleic acid synthesis and cell proliferation, in regenerating rat liver: autoradiography with thymidine-H3.Cancer Res. 1962; 22: 842-849PubMed Google Scholar); iii) in humans with extrahepatic biliary obstruction of recent onset, proliferating parenchymal and bile duct cells express their respective normal cytokine profile (19.James L Lygidakis NJ van Eyken P Tanka AK Bosch KS Ramaekers FC et al.Application of keratin immunocytochemistry and sirius red staining in evaluation of intrahepatic changes with acute extrahepatic cholestasis due to hepatic duct carcinoma.Hepato-Gastroenterology. 1989; 36: 151-155PubMed Google Scholar). However, in young rats submitted to BDL, proliferating ductular cells show characteristics of progenitor cells given the expression of full length α-fetoprotein and stem cell factor, c-kit, thus indicating that, in "typical" proliferation as well, the participation of a stem cell compartment cannot be completely ruled out (22.Omori M Evarts RP Omori N Hu Z Marsden ER Thorgeirsson SS Expression of α-feto-protein and stem cell factor/c-kit system in BDL young rats.Hepatology. 1997; 25: 1115-1122Crossref PubMed Scopus (75) Google Scholar).Type II or "atypical" ductular proliferation occurs in rodents in association with oval cell proliferation after chronic administration of chemicals such as D-galactosamine (23.Kuhlmann WD Wurster K Correlation of histology and alpha 1-fetoprotein resurgence in rat liver regeneration after experimental injury by galactosamine.Virchows Arch A Pathol Anat Histol. 1980; 387: 47-57Crossref PubMed Scopus (35) Google Scholar) and carbon tetrachloride (CCl4) (24.LeSage GD Benedetti A Glaser S Marucci L Tretjak Z Caligiuri A et al.Acute carbon tetrachloride feeding selectively damages large, but not small, cholangiocytes from normal rat liver.Hepatology. 1999; 29: 307-319Crossref PubMed Scopus (99) Google Scholar). In humans, it occurs after massive hepatic necrosis, in alcoholic liver diseases, long-standing extrahepatic biliary obstruction, focal nodular hyperplasia and chronic cholestatic liver diseases [(i.e. primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)] (7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar, 25.Desmet VJ Current problems in diagnosis of biliary disease and-cholestasis.Semin Liv Dis. 1986; 6: 233-245Crossref PubMed Scopus (38) Google Scholar, 26.Fausto N Webber EM Liver regeneration.in: Arias IM Boyer JL Fausto N Jakoby WB Schachter D Shafritz DA The Liver: Biology and Pathobiology. 3rd ed. Raven Press, Ltd, New York1994: 1059-1084Google Scholar, 27.Nagore N Howe S Boxer L Scheuer PJ Liver cell rosettes: structural differences in cholestasis and hepatitis.Liver. 1989; 9: 43-51Crossref PubMed Scopus (32) Google Scholar). The process is characterized by an irregular proliferation of intrahepatic bile ducts which are not confined to portal areas but spread into periportal and parenchymal regions as wedge-shaped extensions creating an irregular portal-parenchymal interface("biliary piecemeal necrosis"). These proliferating ductular structures are arranged in a three-dimensional network of tortuous and irregular conduits that do not possess a well-defined lumen and are associated with edema and neutrophil infiltration (7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar, 25.Desmet VJ Current problems in diagnosis of biliary disease and-cholestasis.Semin Liv Dis. 1986; 6: 233-245Crossref PubMed Scopus (38) Google Scholar, 26.Fausto N Webber EM Liver regeneration.in: Arias IM Boyer JL Fausto N Jakoby WB Schachter D Shafritz DA The Liver: Biology and Pathobiology. 3rd ed. Raven Press, Ltd, New York1994: 1059-1084Google Scholar, 27.Nagore N Howe S Boxer L Scheuer PJ Liver cell rosettes: structural differences in cholestasis and hepatitis.Liver. 1989; 9: 43-51Crossref PubMed Scopus (32) Google Scholar). This implies that the neoformed bile ducts are often functionally inefficient, andthe lack of anatomic contact with the canalicular spaces and peribiliary plexus around them further supports this concept. At variance with "typical" proliferation, in "atypical" proliferation, transitional or intermediate cells with phenotypical characteristics of both hepatocytes and cholangiocytes have been documented (28.Wegmann R Corcos V Caroli J Histoenzymologie des ductules biliaires chez l'embryon humain normal et au cours des cirrhoses humaines.Arch Mal Appar Dig. 1967; 54: 215-228Google Scholar). This favors the view that this type II hyperplasia originates from ductular metaplasia or transformation of hepatic liver cell cords (i.e., retrodifferentiation of hepatocytes into cholangiocytes) and not from replication of pre-existing cholangiocytes (9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar, 25.Desmet VJ Current problems in diagnosis of biliary disease and-cholestasis.Semin Liv Dis. 1986; 6: 233-245Crossref PubMed Scopus (38) Google Scholar, 26.Fausto N Webber EM Liver regeneration.in: Arias IM Boyer JL Fausto N Jakoby WB Schachter D Shafritz DA The Liver: Biology and Pathobiology. 3rd ed. Raven Press, Ltd, New York1994: 1059-1084Google Scholar, 27.Nagore N Howe S Boxer L Scheuer PJ Liver cell rosettes: structural differences in cholestasis and hepatitis.Liver. 1989; 9: 43-51Crossref PubMed Scopus (32) Google Scholar). Three-dimensional reconstruction studies support this concept (29.Yamada S Howe s Scheuer PJ Three-dimensional reconstruction of biliary pathways in primary biliary cirrhosis: a computer-assisted study.J Pathol. 1987; 152: 317-323Crossref PubMed Scopus (36) Google Scholar). As demonstrated by Hillan et al. (30.Hillan KJ Burt AD George WD Macsween RN Grifiths MR Bradley JA Intrasplenic hepatocytes transplantation in rats with exprerimental liver injury: morphological and morphometric studies.J Pathol. 1989; 159: 67-73Crossref PubMed Scopus (30) Google Scholar), when hepatocytes are transplanted into the spleen of BDL rats, but not normal rats, they can give rise to bile duct structures, suggesting that a pattern of hormones/growth factors during BDL may trigger the ductal metaplasia of hepatocytes. The alternative hypothesis that the "atypical" proliferation may arise from a stem cell compartment has also been considered (31.Scarpelli DG Multipotent developmental capacity of cells in the adult animal.Lab Invest. 1985; 52: 331-333PubMed Google Scholar). Independently of their origin, proliferating cholangiocytes, especially in the "atypical" proliferation, acquire phenotypical features of a neuroendocrine epithelium: 1) expression of neuroendocrine markers (chromogranin A, glycolipid A2-B4, S-100 protein, neural cell adhesion molecule) and acquisition of neuroendocrine granules (8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 32.Roskams T Van den Oord JJ De Vos R Desmet VJ Neuroendocrine features or reactive bile ductules in cholestatic liver disease.Am J Pathol. 1990; 137: 1019-1025PubMed Google Scholar); 2) expression of parathyroid hormonerelated peptide (PTHrP), which is encoded by a growth factor regulated "early response" gene and which is involved in the growth and differentiation of the cell (33.Roskams T Campos RV Drucker DJ Desmet V Reactive human bile ductules express parathyroid hormone-related peptide.Histopathology. 1993; 23: 11-19Crossref PubMed Scopus (48) Google Scholar); 3) increased expression of and response to endothelin (34.Caligiuri A Glaser S Rodgers R Phinizy JL Robertson W Papa E et al.Endothelin 1 inhibits secretin-stimulated ductal secretion by interacting with ETA receptors on large cholangiocytes.Am J Physiol. 1998; 275: G835-G846PubMed Google Scholar); 4) enhanced response to hormones/neuropeptides such as secretin, somatostatin and acetylcholine (1.Roberts SK Ludwig J Larusso NF The pathobiology of biliary epithelia.Gastroenterology. 1997; 112: 269-279Abstract Full Text PDF PubMed Scopus (112) Google Scholar, 2.Strazzabosco M New insights into cholangiocyte physiology.J Hepatol. 1997; 27: 945-952Abstract Full Text PDF PubMed Scopus (39) Google Scholar, 3.Kanno N LeSage G Glaser S Alvaro D Alpini G Functional heterogeneity of the intrahepatic biliary epithelium.Hepatology. 2000; 31: 555-561Crossref PubMed Scopus (111) Google Scholar, 4.Boyer JL Vanishing Bile Duct Syndrome - from bench to bed side.in: Alvaro D Benedetti A Strazzabosco M Vanishing Bile Duct Syndrome. Kluwer Academic Publishers, London1997: 240-246Google Scholar, 5.Alvaro D Biliary epithelium: a new chapter in cell biology.It J Gastroenterol Hepatol. 1999; 31: 78-83PubMed Google Scholar, 6.Alpini G Lenzi R Sarkozi L Tavoloni N Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (289) Google Scholar).Type III ductular hyperplasia, also called "oval cell" proliferation, occurs in the early stages of carcinogenesis in rat liver (35.Petropoulos CJ Yaswen P Panzica M Fausto N Cell lineages in liver carcinogenesis: possible clues from studies of the distribution of alpha-fetoprotein RNA sequences in cell populations isolated from normal, regenerating, and preneoplastic rat livers.Cancer Res. 1985; 43: 5762-5768Google Scholar, 36.Sirica AE Cihla HP Isolation and partial characterizations of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats.Cancer Res. 1984; 44: 3454-3466PubMed Google Scholar, 37.Farber E Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetyl-aminofluorene, and 3′-methyl-4-dimethyl-aminoazobenzene.CancerRes. 1956; 16: 142-148Google Scholar, 38.Farber E The sequential analysis of cancer induction with chemicals.Acta Pathol Japonica. 1981; 31: 1-11PubMed Google Scholar) and is caused by a number of chemicals including ethionine and 2-acetyl-aminofluorene. This type of proliferation induces the formation of disorganized tubular structures with a poorly defined duct lumen which randomly spread into hepatic lobules, creating a distorted hepatic architecture (7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar). Oval cells represent a subpopulation of nonparenchymal cells which are heterogeneous with regard to proteins and cell surface markers and which are unable to form recognizable ductular structures. Oval cells express phenotypes of parenchymal or neoplastic cells (i.e., α-fetoprotein, albumin, and G-6-PO4) (7.Desmet V Roskams T Van Eyken P Histopathology of vanishing bile duct diseases.Adv Clin Pathol. 1998; 2: 87-99PubMed Google Scholar, 8.Desmet V Roskams T Van Eyken P Ductular reaction in the liver.Path Res Pract. 1995; 191: 513-524Crossref PubMed Scopus (168) Google Scholar, 9.Desmet V Roskams T Van Eyken P Pathology of the biliary tree in cholestasis: ductular reaction.in: Manns MP Boyer JL Jansen PLM Reichen J Cholestatic Liver Diseases. Kluwer Academic Publishers, London1998: 143-154Google Scholar, 35.Petropoulos CJ Yaswen P Panzica M Fausto N Cell lineages in liver carcinogenesis: possible clues from studies of the distribution of alpha-fetoprotein RNA sequences in cell populations isolated from normal, regenerating, and preneoplastic rat livers.Cancer Res. 1985; 43: 5762-5768Google Scholar, 36.Sirica AE Cihla HP Isolation and partial characterizations of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats.Cancer Res. 1984; 44: 3454-3466PubMed Google Scholar, 37.Farber E Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetyl-aminofluorene, and 3′-methyl-4-dimethyl-aminoazobenzene.CancerRes. 1956; 16: 142-148Google Scholar, 38.Farber E The sequential analysis of cancer induction with chemicals.Acta Pathol Japonica. 1981; 31: 1-11PubMed Google Scholar) and may differentiate into hepatocytes, bile duct epithelial cells, enterocytes and exocrine pancreatic cells (35.Petropoulos CJ Yaswen P Panzica M Fausto N Cell lineages in liver carcinogenesis: possible clues from studies of the distribution of alpha-fetoprotein RNA sequences in cell populations isolated from normal, regenerating, and preneoplastic rat livers.Cancer Res. 1985; 43: 5762-5768Google Scholar, 36.Sirica AE Cihla HP Isolation and partial characterizations of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats.Cancer Res. 1984; 44: 3454-3466PubMed Google Scholar, 37.Farber E Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetyl-aminofluorene, and 3′-methyl-4-dimethyl-aminoazobenzene.CancerRes. 1956; 16: 142-148Google Scholar, 38.Farber E The sequential analysis of cancer induction with chemicals.Acta Pathol Japonica. 1981; 31: 1-11PubMed Google Scholar).Regulation of Cholangiocyte ProliferationSeveral growth factors, hormones and neuropetides as well as bile salts (BS) are involved in the regulation of cholangiocyte proliferation (Table 1). In the BDL rat, early studies suggested that the increased pressure in the biliary tree triggers duct proliferation (6.Alpini G Lenzi R Sarkozi L Tavoloni N Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (289) Google Scholar). However, by using the model of selective ligation of lobar ducts, Polimeno et al. (39.Polimeno L Azzarone A Zeng QH Panella C Subbotin V Carr B et al.Cell proliferation and oncogene expression after bile duct ligation in the rat: evidence of a specific growth effect on bile duct cells.Hepatology. 1995; 21: 1070-1088PubMed Google Scholar) showed that proliferation also occurs in the non-ligated lobes, suggesting that humoral factors play a more important role.TABLE 1Regulation of cholangiocyte proliferationStimulationInhibitionCytokines/growth factorsIL1α, IL6, TGF-α TNF-α, EGF, HGF, IGF-1TGF-β1, TGF-β2Hormones/neuropeptidesEstrogens, ACh, PTHrPSomatostatin, gastrinBile saltsLCA, TLCA, TCAUDCA, TUDCAIL=interleukin; TGF=transforming growth factor; TNF=tumor necrosis factor; EGF=epidermal growth factor; HGF=hepatocyte growth factor; IGF=insulin-like growth factor; ACh=acetylcholine; PTHrP=parathyroid hormone-related peptide; LCA=lithocholate; TLCA=taurolithocholate; TCA=taurocholate; UDCA=ursodeoxycholate; TUDCA=tauroursodeoxycholate. Open table in a new tab Growth factors and cytokinesStudies on the role and effect of growth factors in modulating cholangiocyte proliferation have been performed in vitro by using cell cultures, or in vivo in the BDL rat, in the model of partial hepatectomy or by studying cholangiocyte proliferation after injury.Epidermal growth factor (EGF), hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF1), the interleukin-6 (IL-6)/gp-80 ligand/receptor system, IL 1α, and tumor necrosis factor α (TNFα) stimulate in vitro proliferation of cholangiocyte or cholangiocyte cell lines (40.Joplin R Hishida T Tsubouchi H Daikuhara Y Ayres R Neuberger JM et al.Human intrahepatic biliary epithelial cells proliferate in vitro in response to human hepatocyte growth factor.J Clin Invest. 1992; 90: 1284-1289Crossref PubMed Scopus (129) Google Scholar, 41.Matsumoto K Fuji H Michalopoulos G Fung JJ Demetris AJ Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factor in vitro: interleukin-6, hepatocyte growth factor factor promote DNA synthesis in vitro.Hepatology. 1994; 20: 376-382Crossref PubMed Scopus (122) Google Scholar).In the BDL model, selective and "typical" cholangiocyte proliferation is associated with the increased intrahepatic expression of EGF, IL-6, basic fibroblast growth factor, and transforming growth factor β (TGFβ) (42.Liu Z Sakamoto T Ezure T Yokomuro S Mu
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