All Title Author
Keywords Abstract

Cholangiopathy with Respect to Biliary Innate Immunity

DOI: 10.1155/2012/793569

Full-Text   Cite this paper   Add to My Lib


Biliary innate immunity is involved in the pathogenesis of cholangiopathies in cases of biliary disease. Cholangiocytes possess Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and play a pivotal role in the innate immune response. Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. Moreover, in primary biliary cirrhosis (PBC) and biliary atresia, biliary innate immunity is closely associated with the dysregulation of the periductal cytokine milieu and the induction of biliary apoptosis and epithelial-mesenchymal transition (EMT), forming in disease-specific cholangiopathy. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems. 1. Introduction Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and hepatolithiasis in adults and biliary atresia and choledochal cyst in infants are biliary diseases in which different anatomical levels of the biliary tree are specifically affected and characterized by cholangiopathy. The biliary tree, consisting of cholangiocytes, is a system of connecting ducts that drain the bile secreted by hepatocytes into the duodenum. Cholangiocytes provide the first line of defense in the biliary system against luminal microbes originating from the intestines via portal blood and duodenum [1]. In general, although human bile is normally sterile, it can contain bacterial components such as lipopolysaccharide (LPS), lipoteichoic acid, and bacterial DNA fragments, known as pathogen-associated molecular patterns (PAMPs) [2–5], and cultivable bacteria are detectable in bile of patients with biliary diseases [1, 6–8]. Enteric bacteria, in particular, may be responsible for the chronic proliferative cholangitis associated with hepatolithiasis [1, 6]. These findings indicate that cholangiocytes are exposed to bacterial PAMPs under physiological as well as pathological conditions. Innate immunity was initially thought to be limited to immunocompetent cells such as dendritic cells and macrophages, but epithelial cells also possess TLRs and proper innate immune systems reflecting the specific micro-environment and function of each epithelial cell type. Recent studies concerning biliary innate immunity indicate that cholangiocytes express a variety of pathogen-recognition receptors such as Toll-like receptors (TLRs) [9, 10]. Infectious agents have been implicated in the


[1]  J. Y. Sung, J. W. Costerton, and E. A. Shaffer, “Defense system in the biliary tract against bacterial infection,” Digestive Diseases and Sciences, vol. 37, no. 5, pp. 689–696, 1992.
[2]  K. Harada, S. Ohira, K. Isse et al., “Lipopolysaccharide activates nuclear factor-kappaB through Toll-like receptors and related molecules in cultured biliary epithelial cells,” Laboratory Investigation, vol. 83, no. 11, pp. 1657–1667, 2003.
[3]  K. Hiramatsu, K. Harada, K. Tsuneyama et al., “Amplification and sequence analysis of partial bacterial 16S ribosomal RNA gene in gallbladder bile from patients with primary biliary cirrhosis,” Journal of Hepatology, vol. 33, no. 1, pp. 9–18, 2000.
[4]  T. Osnes, O. Sandstad, V. Skar, and M. Osnes, “Lipopolysaccharides and beta-glucuronidase activity in choledochal bile in relation to choledocholithiasis,” Digestion, vol. 58, no. 5, pp. 437–443, 1997.
[5]  K. Sasatomi, K. Noguchi, S. Sakisaka, M. Sata, and K. Tanikawa, “Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis,” Journal of Hepatology, vol. 29, no. 3, pp. 409–416, 1998.
[6]  S. M. Sheen-Chen, W. J. Chen, H. L. Eng et al., “Bacteriology and antimicrobial choice in hepatolithiasis,” American Journal of Infection Control, vol. 28, no. 4, pp. 298–301, 2000.
[7]  K. Harada, S. Ozaki, N. Kono et al., “Frequent molecular identification of Campylobacter but not Helicobacter genus in bile and biliary epithelium in hepatolithiasis,” Journal of Pathology, vol. 193, no. 2, pp. 218–223, 2001.
[8]  H. O. Nilsson, J. Taneera, M. Castedal, E. Glatz, R. Olsson, and T. Wadstr?m, “Identification of Helicobacter pylori and other Helicobacter species by PCR, hybridization, and partial DNA sequencing in human liver samples from patients with primary sclerosing cholangitis or primary biliary cirrhosis,” Journal of Clinical Microbiology, vol. 38, no. 3, pp. 1072–1076, 2000.
[9]  B. Lemaitre, E. Nicolas, L. Michaut, J. M. Reichhart, and J. A. Hoffmann, “The dorsoventral regulatory gene cassette spatzle/Toll/Cactus controls the potent antifungal response in Drosophila adults,” Cell, vol. 86, no. 6, pp. 973–983, 1996.
[10]  S. Akira and K. Takeda, “Toll-like receptor signalling,” Nature Reviews Immunology, vol. 4, no. 7, pp. 499–511, 2004.
[11]  L. Xu, Z. Shen, L. Guo et al., “Does a betaretrovirus infection trigger primary biliary cirrhosis?” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 14, pp. 8454–8459, 2003.
[12]  K. L. Tyler, R. J. Sokol, S. M. Oberhaus et al., “Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts,” Hepatology, vol. 27, no. 6, pp. 1475–1482, 1998.
[13]  I. Nilsson, I. Kornilovs'ka, S. Lindgren, A. Ljungh, and T. Wadstr?m, “Increased prevalence of seropositivity for non-gastric Helicobacter species in patients with autoimmune liver disease,” Journal of Medical Microbiology, vol. 52, no. 11, pp. 949–953, 2003.
[14]  J. G. Fox, F. E. Dewhirst, Z. Shen et al., “Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis,” Gastroenterology, vol. 114, no. 4, pp. 755–763, 1998.
[15]  K. Tsuneyama, K. Harada, N. Kono et al., “Scavenger cells with Gram-positive bacterial lipoteichoic acid infiltrate around the damaged interlobular bile ducts of primary biliary cirrhosis,” Journal of Hepatology, vol. 35, no. 2, pp. 156–163, 2001.
[16]  K. V. Anderson, “Toll signaling pathways in the innate immune response,” Current Opinion in Immunology, vol. 12, no. 1, pp. 13–19, 2000.
[17]  K. Takeda and S. Akira, “Toll-like receptors in innate immunity,” International Immunology, vol. 17, no. 1, pp. 1–14, 2005.
[18]  J. Viala, P. Sansonetti, and D. J. Philpott, “Nods and ‘intracellular’ innate immunity,” Comptes Rendus, vol. 327, no. 6, pp. 551–555, 2004.
[19]  X. M. Chen, S. P. O'Hara, J. B. Nelson et al., “Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum via activation of NF-κB,” Journal of Immunology, vol. 175, no. 11, pp. 7447–7456, 2005.
[20]  K. Harada, K. Isse, and Y. Nakanuma, “Interferon γ accelerates NF-κB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction,” Journal of Clinical Pathology, vol. 59, no. 2, pp. 184–190, 2006.
[21]  T. Yokoyama, A. Komori, M. Nakamura et al., “Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-κB and -MAPK signaling pathways,” Liver International, vol. 26, no. 4, pp. 467–476, 2006.
[22]  K. Harada, K. Ohba, S. Ozaki et al., “Peptide antibiotic human beta-defensin-1 and -2 contribute to antimicrobial defense of the intrahepatic biliary tree,” Hepatology, vol. 40, no. 4, pp. 925–932, 2004.
[23]  K. Harada, Y. Sato, K. Itatsu et al., “Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia,” Hepatology, vol. 46, no. 4, pp. 1146–1154, 2007.
[24]  Y. Takii, M. Nakamura, M. Ito et al., “Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis,” Laboratory Investigation, vol. 85, no. 7, pp. 908–920, 2005.
[25]  A. P. Wang, K. Migita, M. Ito et al., “Hepatic expression of toll-like receptor 4 in primary biliary cirrhosis,” Journal of Autoimmunity, vol. 25, no. 1, pp. 85–91, 2005.
[26]  J. B. Nelson, S. P. O'hara, A. J. Small et al., “Cryptosporidium parvum infects human cholangiocytes via sphingolipid-enriched membrane microdomains,” Cellular Microbiology, vol. 8, no. 12, pp. 1932–1945, 2006.
[27]  M. W. Hornef, B. H. Normark, A. Vandewalle, and S. Normark, “Intracellular recognition of lipopolysaccharide by Toll-like receptor 4 in intestinal epithelial cells,” Journal of Experimental Medicine, vol. 198, no. 8, pp. 1225–1235, 2003.
[28]  D. Foell, H. Wittkowski, and J. Roth, “Mechanisms of disease: a ‘DAMP’ view of inflammatory arthritis,” Nature Clinical Practice Rheumatology, vol. 3, no. 7, pp. 382–390, 2007.
[29]  K. Saito and Y. Nakanuma, “Lactoferrin and lysozyme in the intrahepatic bile duct of normal livers and hepatolithiasis. An immunohistochemical study,” Journal of Hepatology, vol. 15, no. 1-2, pp. 147–153, 1992.
[30]  R. Bals, X. Wang, Z. Wu et al., “Human β-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung,” Journal of Clinical Investigation, vol. 102, no. 5, pp. 874–880, 1998.
[31]  H. Sugiura and Y. Nakanuma, “Secretory component and immunoglobulins in the intrahepatic biliary tree and peribiliary gland in normal livers and hepatolithiasis,” Gastroenterologia Japonica, vol. 24, no. 3, pp. 308–314, 1989.
[32]  K. Harada, S. Shimoda, Y. Sato, K. Isse, H. Ikeda, and Y. Nakanuma, “Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis,” Clinical and Experimental Immunology, vol. 157, no. 2, pp. 261–270, 2009.
[33]  K. Isse, K. Harada, and Y. Nakanuma, “IL-8 expression by biliary epithelial cells is associated with neutrophilic infiltration and reactive bile ductules,” Liver International, vol. 27, no. 5, pp. 672–680, 2007.
[34]  K. Isse, K. Harada, Y. Zen et al., “Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts,” Hepatology, vol. 41, no. 3, pp. 506–516, 2005.
[35]  S. Sawada, K. Harada, K. Isse et al., “Involvement of Escherichia coli in pathogenesis of xanthogranulomatous cholecystitis with scavenger receptor class A and CXCL16-CXCR6 interaction,” Pathology International, vol. 57, no. 10, pp. 652–663, 2007.
[36]  C. M. Morland, J. Fear, G. McNab, R. Joplin, and D. H. Adams, “Promotion of leukocyte transendothelial cell migration by chemokines derived from human biliary epithelial cells in vitro,” Proceedings of the Association of American Physicians, vol. 109, no. 4, pp. 372–382, 1997.
[37]  S. Shimoda, K. Harada, H. Niiro et al., “CX3CL1 (fractalkine): a signpost for biliary inflammation in primary biliary cirrhosis,” Hepatology, vol. 51, no. 2, pp. 567–575, 2010.
[38]  K. Matsumoto, H. Fujii, G. Michalopoulos, J. J. Fung, and A. J. Demetris, “Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro,” Hepatology, vol. 20, no. 2, pp. 376–382, 1994.
[39]  J. H. Lefkowitch, “Bile ductular cholestasis: an ominous histopathologic sign related to sepsis and ‘cholangitis lenta’,” Human Pathology, vol. 13, no. 1, pp. 19–24, 1982.
[40]  S. Reynoso-Paz, R. L. Coppel, I. R. Mackay, N. M. Bass, A. A. Ansari, and M. E. Gershwin, “The immunobiology of bile and biliary epithelium,” Hepatology, vol. 30, no. 2, pp. 351–357, 1999.
[41]  H. Y. Hsu, M. H. Chang, Y. H. Ni, and S. F. Huang, “Cytomegalovirus infection and proinflammatory cytokine activation modulate the surface immune determinant expression and immunogenicity of cultured murine extrahepatic bile duct epithelial cells,” Clinical and Experimental Immunology, vol. 126, no. 1, pp. 84–91, 2001.
[42]  M. Scholz, J. Cinatl, R. A. Blaheta, B. Kornhuber, B. H. Markus, and H. W. Doerr, “Expression of human leukocyte antigens class I and class II on cultured biliary epithelial cells after cytomegalovirus infection,” Tissue Antigens, vol. 49, no. 6, pp. 640–643, 1997.
[43]  P. Sheth, N. D. Santos, A. Seth, N. F. LaRusso, and R. K. Rao, “Lipopolysaccharide disrupts tight junctions in cholangiocyte monolayers by a c-Src-, TLR4-, and LBP-dependent mechanism,” American Journal of Physiology, vol. 293, no. 1, pp. G308–G318, 2007.
[44]  X. M. Chen, B. Q. Huang, P. L. Splinter et al., “Cryptosporidium parvum invasion of biliary epithelia requires host cell tyrosine phosphorylation of cortactin via c-Src,” Gastroenterology, vol. 125, no. 1, pp. 216–228, 2003.
[45]  M. T. Abreu, E. T. Arnold, L. S. Thomas et al., “TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells,” Journal of Biological Chemistry, vol. 277, no. 23, pp. 20431–20437, 2002.
[46]  T. Matsumura, A. Ito, T. Takii, H. Hayashi, and K. Onozaki, “Endotoxin and cytokine regulation of toll-like receptor (TLR) 2 and TLR4 gene expression in murine liver and hepatocytes,” Journal of Interferon and Cytokine Research, vol. 20, no. 10, pp. 915–921, 2000.
[47]  M. T. Abreu, P. Vora, E. Faure, L. S. Thomas, E. T. Arnold, and M. Arditi, “Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide,” Journal of Immunology, vol. 167, no. 3, pp. 1609–1616, 2001.
[48]  K. Harada, J. van de Water, P. S. C. Leung et al., “In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset,” Hepatology, vol. 25, no. 4, pp. 791–796, 1997.
[49]  A. Karrar, U. Broomé, T. S?dergren et al., “Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis,” Gastroenterology, vol. 132, no. 4, pp. 1504–1514, 2007.
[50]  X. M. Chen, P. L. Splinter, S. P. O'Hara, and N. F. LaRusso, “A cellular micro-RNA, let-7i, regulates toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection,” Journal of Biological Chemistry, vol. 282, no. 39, pp. 28929–28938, 2007.
[51]  G. Hu, R. Zhou, J. Liu et al., “MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge,” Journal of Immunology, vol. 183, no. 3, pp. 1617–1624, 2009.
[52]  J. M. Otte, E. Cario, and D. K. Podolsky, “Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells,” Gastroenterology, vol. 126, no. 4, pp. 1054–1070, 2004.
[53]  N. Hyakushima, H. Mitsuzawa, C. Nishitani et al., “Interaction of soluble form of recombinant extracellular TLR4 domain with MD-2 enables lipopolysaccharide binding and attenuates TLR4-mediated signaling,” Journal of Immunology, vol. 173, no. 11, pp. 6949–6954, 2004.
[54]  D. Wald, J. Qin, Z. Zhao et al., “SIGIRR, a negative regulator of Toll-like receptor—interleukin 1 receptor signaling,” Nature Immunology, vol. 4, no. 9, pp. 920–927, 2003.
[55]  K. Kobayashi, L. D. Hernandez, J. E. Galán, C. A. Janeway, R. Medzhitov, and R. A. Flavell, “IRAK-M is a negative regulator of Toll-like receptor signaling,” Cell, vol. 110, no. 2, pp. 191–202, 2002.
[56]  S. Janssens, K. Burns, E. Vercammen, J. Tschopp, and R. Beyaert, “MyD88S, a splice variant of MyD88, differentially modulates NF-κB- and AP-1-dependent gene expression,” FEBS Letters, vol. 548, no. 1–3, pp. 103–107, 2003.
[57]  G. Zhang and S. Ghosh, “Negative regulation of toll-like receptor-mediated signaling by Tollip,” Journal of Biological Chemistry, vol. 277, no. 9, pp. 7059–7065, 2002.
[58]  M. Carty, R. Goodbody, M. Schr?der, J. Stack, P. N. Moynagh, and A. G. Bowie, “The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling,” Nature Immunology, vol. 7, no. 10, pp. 1074–1081, 2006.
[59]  K. Harada, K. Isse, Y. Sato, S. Ozaki, and Y. Nakanuma, “Endotoxin tolerance in human intrahepatic biliary epithelial cells is induced by upregulation of IRAK-M,” Liver International, vol. 26, no. 8, pp. 935–942, 2006.
[60]  K. Harada, Y. Sato, K. Isse, H. Ikeda, and Y. Nakanuma, “Induction of innate immune response and absence of subsequent tolerance to dsRNA in biliary epithelial cells relate to the pathogenesis of biliary atresia,” Liver International, vol. 28, no. 5, pp. 614–621, 2008.
[61]  Y. Nakanuma and G. Ohta, “Histometric and serial section observations of the intrahepatic bile ducts in primary biliary cirrhosis,” Gastroenterology, vol. 76, no. 6, pp. 1326–1332, 1979.
[62]  A. Parikh-Patel, E. B. Gold, H. Worman, K. E. Krivy, and M. E. Gershwin, “Risk factors for primary biliary cirrhosis in a cohort of patients from the United States,” Hepatology, vol. 33, no. 1, pp. 16–21, 2001.
[63]  K. Harada, K. Tsuneyama, Y. Sudo, S. Masuda, and Y. Nakanuma, “Molecular identification of bacterial 16S ribosomal RNA gene in liver tissue of primary biliary cirrhosis: is Propionibacterium acnes involved in granuloma formation?” Hepatology, vol. 33, no. 3, pp. 530–536, 2001.
[64]  S. Shimoda, M. Nakamura, H. Ishibashi, K. Hayashida, and Y. Niho, “HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases,” Journal of Experimental Medicine, vol. 181, no. 5, pp. 1835–1845, 1995.
[65]  C. Selmi, D. L. Balkwill, P. Invernizzi et al., “Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium,” Hepatology, vol. 38, no. 5, pp. 1250–1257, 2003.
[66]  S. Shimoda, F. Ishikawa, T. Kamihira et al., “Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory,” Gastroenterology, vol. 131, no. 2, pp. 606–618, 2006.
[67]  S. Shimoda, M. Nakamura, H. Shigematsu et al., “Mimicry peptides of human PDC-E2 163-176 peptide, the immunodominant T- cell epitope of primary biliary cirrhosis,” Hepatology, vol. 31, no. 6, pp. 1212–1216, 2000.
[68]  S. Shimoda, M. Nakamura, H. Ishibashi et al., “Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis,” Gastroenterology, vol. 124, no. 7, pp. 1915–1925, 2003.
[69]  A. Lleo, C. L. Bowlus, G. X. Yang et al., “Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis,” Hepatology, vol. 52, no. 3, pp. 987–996, 2010.
[70]  T. K. Mao, Z. X. Lian, C. Selmi et al., “Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis,” Hepatology, vol. 42, no. 4, pp. 802–808, 2005.
[71]  S. Shimoda, K. Harada, H. Niiro et al., “Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis,” Hepatology, vol. 53, no. 4, pp. 1270–1281, 2011.
[72]  M. Yasoshima, N. Kono, H. Sugawara, K. Katayanagi, K. Harada, and Y. Nakanuma, “Increased expression of interleukin-6 and tumor necrosis factor-α in pathologic biliary epithelial cells: in situ and culture study,” Laboratory Investigation, vol. 78, no. 1, pp. 89–100, 1998.
[73]  K. Harada, K. Isse, T. Kamihira, S. Shimoda, and Y. Nakanuma, “Th1 cytokine-induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis,” Hepatology, vol. 41, no. 6, pp. 1329–1338, 2005.
[74]  T. Nakajima, Y. Kamijo, N. Tanaka et al., “Peroxisome proliferator-activated receptor α protects against alcohol-induced liver damage,” Hepatology, vol. 40, no. 4, pp. 972–980, 2004.
[75]  P. R. Mangan, L. E. Harrington, D. B. O'Quinn et al., “Transforming growth factor-β induces development of the T H17 lineage,” Nature, vol. 441, no. 7090, pp. 231–234, 2006.
[76]  E. V. Acosta-Rodriguez, G. Napolitani, A. Lanzavecchia, and F. Sallusto, “Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells,” Nature Immunology, vol. 8, no. 9, pp. 942–949, 2007.
[77]  R. Y. Z. Lan, T. L. Salunga, K. Tsuneyama et al., “Hepatic IL-17 responses in human and murine primary biliary cirrhosis,” Journal of Autoimmunity, vol. 32, no. 1, pp. 43–51, 2009.
[78]  K. Harada, S. Shimoda, H. Ikeda et al., “Significance of periductal Langerhans cells and biliary epithelial cell-derived macrophage inflammatory protein-3α in the pathogenesis of primary biliary cirrhosis,” Liver International, vol. 31, no. 2, pp. 245–253, 2011.
[79]  R. Morecki, J. H. Glaser, S. Cho, et al., “Biliary atresia and reovirus type 3 infection,” New England Journal of Medicine, vol. 307, no. 8, pp. 481–484, 1982.
[80]  M. Riepenhoff-Talty, K. Schaekel, H. F. Clark et al., “Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice,” Pediatric Research, vol. 33, no. 4, pp. 394–399, 1993.
[81]  P. O. Szavay, J. Leonhardt, G. Czech-Schmidt, and C. Petersen, “The role of reovirus type 3 infection in an established murine model for biliary atresia,” European Journal of Pediatric Surgery, vol. 12, no. 4, pp. 248–250, 2002.
[82]  N. Funaki, H. Sasano, S. Shizawa et al., “Apoptosis and cell proliferation in biliary atresia,” Journal of Pathology, vol. 186, no. 4, pp. 429–433, 1998.
[83]  H. Sasaki, M. Nio, D. Iwami et al., “E-cadherin, α-catenin and β-catenin in biliary atresia: correlation with apoptosis and cell cycle,” Pathology International, vol. 51, no. 12, pp. 923–932, 2001.
[84]  K. Harada, M. Iwata, N. Kono, W. Koda, T. Shimonishi, and Y. Nakanuma, “Distribution of apoptotic cells and expression of apoptosis-related proteins along the intrahepatic biliary tree in normal and non-biliary diseased liver,” Histopathology, vol. 37, no. 4, pp. 347–354, 2000.
[85]  J. H. Chuang, M. H. Chou, C. L. Wu, and Y. Y. Du, “Implication of innate immunity in the pathogenesis of biliary atresia,” Chang Gung Medical Journal, vol. 29, no. 3, pp. 240–250, 2006.
[86]  A. N. Al-Masri, P. Flemming, B. Rodeck, M. Melter, J. Leonhardt, and C. Petersen, “Expression of the interferon-induced Mx proteins in biliary atresia,” Journal of Pediatric Surgery, vol. 41, no. 6, pp. 1139–1143, 2006.
[87]  Y. H. Huang, M. H. Chou, Y. Y. Du et al., “Expression of toll-like receptors and type 1 interferon specific protein MxA in biliary atresia,” Laboratory Investigation, vol. 87, no. 1, pp. 66–74, 2007.
[88]  Y. Nakanuma and N. Kono, “Expression of vimentin in proliferating and damaged bile ductules and interlobular bile ducts in nonneoplastic hepatobiliary diseases,” Modern Pathology, vol. 5, no. 5, pp. 550–554, 1992.
[89]  K. A. Rygiel, H. Robertson, H. L. Marshall et al., “Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease,” Laboratory Investigation, vol. 88, no. 2, pp. 112–123, 2008.
[90]  Y. Sato, K. Harada, S. Ozaki et al., “Cholangiocytes with mesenchymal features contribute to progressive hepatic fibrosis of the polycystic kidney rat,” American Journal of Pathology, vol. 171, no. 6, pp. 1859–1871, 2007.
[91]  R. Díaz, J. W. Kim, J.-J. Hui et al., “Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis,” Human Pathology, vol. 39, no. 1, pp. 102–115, 2008.
[92]  J. P. Thiery, “Epithelial-mesenchymal transitions in development and pathologies,” Current Opinion in Cell Biology, vol. 15, no. 6, pp. 740–746, 2003.
[93]  F. Valdés, A. M. álvarez, A. Locascio et al., “The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor β in fetal rat hepatocytes,” Molecular Cancer Research, vol. 1, no. 1, pp. 68–78, 2002.
[94]  K. Harada, Y. Sato, H. Ikeda et al., “Epithelial-mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia,” Journal of Pathology, vol. 217, no. 5, pp. 654–664, 2009.


comments powered by Disqus