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Yasuni Nakanuma - One of the best experts on this subject based on the ideXlab platform.
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matrix proteins of basement membrane of Intrahepatic Bile Ducts are degraded in congenital hepatic fibrosis and caroli s disease
The Journal of Pathology, 2009Co-Authors: Mitsue Yasoshima, Yasunori Sato, Shinichi Furubo, Kazuo Kizawa, Takahiro Sanzen, Satoru Ozaki, Kenichi Harada, Yasuni NakanumaAbstract:Congenital hepatic fibrosis (CHF) and Caroli's disease are though to result from ductal plate malformation, and the basal laminar components play important roles in biliary differentiation during development. To clarify the involvement of basal laminar components in the ductal plate malformation, this study examined the immunohistochemical expression of laminin and type IV collagen in the livers of CHF and Caroli's disease. Using the polycystic kidney (PCK) rat, an animal model of Caroli's disease with CHF, in vivo and in vitro experiments were also performed. Immunostaining showed that basement membrane expression of laminin and type IV collagen around Intrahepatic Bile Ducts was degraded in CHF, Caroli's disease, and the PCK rats. The degradation of laminin and type IV collagen around Bile Ducts was also observed in foci of cholangiocarcinoma in situ of Caroli's disease. In vitro, PCK cholangiocytes were found to overexpress plasminogen and a serine proteinase, the tissue-type plasminogen activator (tPA). When PCK cholangiocytes were cultured in Matrigel, the amounts of laminin and collagen in the gel were significantly reduced, and addition of alpha2-antiplasmin in the culture medium inhibited the degradation of laminin and collagen in Matrigel. These results suggest that biliary overexpression of plasminogen and tPA leads to the generation of excessive amounts of plasmin, and subsequent plasmin-dependent lysis of the extracellular matrix molecules may contribute to the biliary dysgenesis in CHF and Caroli's disease, including progressive cystic dilatation of the Intrahepatic Bile Ducts in Caroli's disease. In addition, it is suggested that once cholangiocarcinoma in situ develops in the biliary epithelium of CHF and Caroli's disease, it tends to transform into invasive carcinoma, due to instability of the basement membrane of the Bile Ducts.
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biliary sludge and microcalculi in Intrahepatic Bile Ducts morphologic and x ray microanalytical observations in 18 among 1 179 consecutively autopsied livers
Pathology International, 2008Co-Authors: Tadashi Terada, Yasuni Nakanuma, Katsuhiko Saito, Naoko KonoAbstract:To clarify the morphology and pathogenesis of Intrahepatic calculi in the incipient stage, we examined biliary sludge and microcalculi in Intrahepatic Bile Ducts by morphologic and X-ray microanalytical methods in 18 (1.5%) among 1,179 autopsied livers. The hepatobiliary conditions of these 18 livers were intra and extrahepatic biliary obstruction in 14 cases, hepatic fibrosis in three cases, and cirrhosis with hepatocellular carcinoma in the remaining one. Grossly, brown pigmented microcalculi were observed floating in biliary sludge. Microscopically, the biliary sludge was composed of mucin, fibrinous materials, desquamated epithelial cells and a few bilirubin granules. The microcalculi were embedded in the sludge and consisted of mucin and precipitates of bilirubin with a granular, lamellar or amorphous appearance. Bacterial colonies were recognized in both the sludge and microcalculi in all but three cases. Intrahepatic Bile Ducts harboring sludge and microcalculi showed a minimal to moderate degree of glandular proliferation with mucin production. X-ray microanalysis disclosed that the sludge contained little calcium ion, whereas microcalculi were calcium rich. These findings suggest that biliary obstruction, bacterial infection and mucin hypersecretion play an important role in the formation of Intrahepatic biliary sludge and microcalculi, and that sludge is causally related to the formation of Intrahepatic microcalculi. Intrahepatic microcalculi and biliary sludge may represent a pathogenetic sequence in the early stage of calcium bilirubinate hepatoiithiasis. Acta Pathol Jpn 40: 894–901, 1990.
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glandular elements around the Intrahepatic Bile Ducts in man their morphology and distribution in normal livers
Liver, 2008Co-Authors: M Tadashi D Terada, Yasuni Nakanuma, Goroku OhtaAbstract:ABSTRACT— The morphology and distribution of the glandular elements around the Intrahepatic Bile Ducts, hitherto poorly described, were examined in autopsied human livers with the aid of postmortem cholangiographs. The glands could be divided into intramural and extramural. The former were small in number, scattered within the Bile duct walls, and were simple tubular mucous glands. The latter were more abundant, located in the periductal connective tissue, and were branched tubuloalveolar seromucous glands. Serial section observations revealed that neither gland communicated with the hepatic parenchyma, and the extramural glands drained into the large Bile duct lumina via the conduits. The mucous cells of both glands contained neutral, carboxylated and sulfated glycoproteins. The extramural glands were distributed from the hepatic to the segment Ducts in almost all livers, and were also discerned around the area Ducts in two-fifths of the livers. The glands seemed to decrease in number as the Bile Ducts became more branched.
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characterization of biliary intra epithelial lymphocytes at different anatomical levels of Intrahepatic Bile Ducts under normal and pathological conditions numbers of cd4 cd28 intra epithelial lymphocytes are increased in primary biliary cirrhosis
Pathology International, 2006Co-Authors: Kumiko Isse, Kenichi Harada, Yasunori Sato, Yasuni NakanumaAbstract:Distribution of intra-epithelial lymphocytes along Intrahepatic biliary tree (bIEL), and their density and phenotype were examined in normal and diseased livers, particularly in primary biliary cirrhosis (PBC). Immunohistochemically, bIEL were examined in 28 normal livers, 13 cases of chronic viral hepatitis (CVH), 13 cases of PBC, five cases of primary sclerosing cholangitis (PSC), seven cases of extrahepatic biliary obstruction (EBO), and 16 hepatolithiatic livers. In normal livers, bIEL were relatively dense at large and septal Bile Ducts compared to interlobular Ducts. Most of them were positive for CD3 and CD8, while a few were positive for CD4, CD20 and CD57. In CVH, PSC and EBO, neither distribution, phenotype nor density of bIEL differed from normal liver. In hepatolithiasis, numbers of CD8(+)bIEL were increased in stone-containing Ducts. In PBC, numbers of CD4(+)CD28(-)bIEL, which are reportedly responsible for target tissue destruction in autoimmune diseases, were markedly increased in damaged interlobular Ducts. In conclusion, CD3(+)CD8(+)bIEL may be involved in immune homeostasis of Intrahepatic Bile Ducts in normal livers and in CVH, PSC and EBO. Altered distribution and phenotypes of bIEL in PBC and hepatolithiasis may reflect their participation in biliary lesions. Increased CD4(+)CD28(-)bIEL in damaged Bile Ducts of PBC may be related to immune-mediated biliary damage.
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generation of monoclonal antibodies to murine Bile duct epithelial cells identification of annexin v as a new marker of small Intrahepatic Bile Ducts
Hepatology, 1999Co-Authors: Yasuni Nakanuma, Eric M Gershwin, Kazuyoshi Katayanagi, Judith A Van De Water, Thomas P Kenny, Aftab A Ansari, Ross L CoppelAbstract:Biliary epithelial cells (BECs) are distributed along the length of both the extrahepatic and Intrahepatic biliary tree, but have distinctly different phenotypes and functions according to their anatomical location. It has been reasoned that the distinct appearance of pathogenic lesions in different biliary diseases may be associated with the expression of distinct proteins. These data prompted us to immunize rats with cultured murine BECs with the objective of determining if there are unique antigens on BECs. Of the 45 monoclonal antibodies (mAbs) produced, 12 mAbs (MBEC 1-12) were selected for detailed study based on their classification into three major groups. These groups included four antibodies (MBEC 1-4) that reacted in a staining pattern typical of mucin. A second group of mAbs, MBECs 5 to 8, reacted strongly along the biliary tract and by immunoblot analysis, reacted with several bands ranging from 44 kd to 64 kd. These antibodies were considered as markers of pan BECs and their staining pattern proved similar to that of a control polyclonal pan-cytokeratin. The final group of mAbs, MBECs 9 to 12, recognized a 36-kd antigen using lysates of murine BECs. These antibodies also predominantly stained small peripheral Bile Ducts. The reactive antigen was purified by immunoprecipitation and microsequenced; the peptides sequenced showed 100% homology with murine annexin V. The identification of annexin V with predominantly Intrahepatic Bile Ducts, is of significant interest because of the multiple roles of annexin V, including that of membrane cytoskeletal interactions during transport and apoptosis.
Tsan-shium Liu - One of the best experts on this subject based on the ideXlab platform.
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expression of transforming growth factor betas and their signaling receptors in stone containing Intrahepatic Bile Ducts and cholangiocarcinoma
World Journal of Surgery, 2003Co-Authors: King-teh Lee, Tsan-shium LiuAbstract:Transforming growth factor betas (TGF-βs) are multifunctional polypeptides that either inhibit or stimulate cell proliferation. They mediate their functions through their signaling receptors. Clinically, hepatolithiasis has been regarded as a risk factor for cholangiocarcinoma. The aim of this study was to examine the expression of TGF-βs and their receptors in stone-containing Intrahepatic Bile Ducts (IHD) and cholangiocarcinoma and try to predict whether hepatolithiasis has a predisposition to development of cholangiocarcinoma. Twenty-eight surgically resected specimens of stone-containing IHD and 15 specimens of cholangiocarcinoma were subjects for this study. Immunohistochemical analysis was done on three TGF-βs and their signaling receptors to check their expression in non-neoplastic and neoplastic Bile Ducts. No immunoreactivity of TGF-β1 was found in any specimens. The overexpression of TGF-β2 and TGF-β3 was found in both hepatolithiasis (93%–100%) and cholangiocarcinoma (80%) at levels significantly higher than those of normal controls (10%–20%) (p < 0.001). The immunoreactivity of type I receptor (TβRI) and type II receptor (TβRII) also showed increased expression in stone-containing IHD, whereas TβRII was absent in cholangiocarcinoma. We conclude that the overexpression of TGF-β2 and TGF-β3 and the absence of TβRII in cholangiocarcinoma could lead to enhanced tumor cell proliferation. At the same time, the overexpression of TGF-βs and their receptors in stone-containing IHD could suggest a close relationship between hepatolithiasis and cholangiocarcinoma.
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Altered mucin gene expression in stone-containing Intrahepatic Bile Ducts and cholangiocarcinomas.
Digestive diseases and sciences, 2001Co-Authors: King-teh Lee, Tsan-shium LiuAbstract:Neoplastic transformation of epithelial cells is commonly associated with alterations in the synthesis and structures of mucin. Mucin protein epitopes and mRNA levels were frequently altered in adenocarcinomas compared to corresponding normal tissues. Clinically, hepatolithiasis has been regarded as a risk factor for cholangiocarcinoma. The aims of this study were to determine the possible alteration of mucin gene expression in stone-containing Intrahepatic Bile Ducts and cholangiocarcinomas and to try to predict whether or not hepatolithiasis has a predisposition to development of cholangiocarcinoma. In situ hybridization with DIG-tailed oligonucleotides was performed on sections of paraffin-embedded tissues of stone-containing Intrahepatic Bile Ducts, cholangiocarcinomas, and normal controls to identify the expression of MUC2, MUC3, MUC4, MUC5B, and MUC5AC in nonneoplastic and neoplastic biliary epithelium. The findings showed that (1) while multiple diverse mucin genes were expressed in the biliary epithelium, MUC3 and MUC5B mRNA were the main mucin genes expressed in the biliary epithelium of stone-containing Intrahepatic Bile Ducts and normal controls; (2) absent or decreased expression of MUC2, MUC3, and MUC5B of mRNA was found in cholangiocarcinomas in contrast to nonneoplastic biliary epithelium; and (3) increased expression of MUC4 and MU5AC of mRNA was found in cholangiocarcinomas and the biliary epithelium, especially for dysplastic cells of stone-containing Intrahepatic Bile Ducts compared with normal controls. In this study, using in situ hybridization we demonstrated that neoplastic transformation of the biliary epithelium is accompained by alterations in mucin gene expression, the altered mucin gene expression in dysplastic cells of stone-containing Intrahepatic Bile Ducts may reflect a higher potential for malignant transformation in these cells, and it could be a precursor of cholangiocarcinoma in the presence of hepatolithiasis.
Eric M Gershwin - One of the best experts on this subject based on the ideXlab platform.
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generation of monoclonal antibodies to murine Bile duct epithelial cells identification of annexin v as a new marker of small Intrahepatic Bile Ducts
Hepatology, 1999Co-Authors: Yasuni Nakanuma, Eric M Gershwin, Kazuyoshi Katayanagi, Judith A Van De Water, Thomas P Kenny, Aftab A Ansari, Ross L CoppelAbstract:Biliary epithelial cells (BECs) are distributed along the length of both the extrahepatic and Intrahepatic biliary tree, but have distinctly different phenotypes and functions according to their anatomical location. It has been reasoned that the distinct appearance of pathogenic lesions in different biliary diseases may be associated with the expression of distinct proteins. These data prompted us to immunize rats with cultured murine BECs with the objective of determining if there are unique antigens on BECs. Of the 45 monoclonal antibodies (mAbs) produced, 12 mAbs (MBEC 1-12) were selected for detailed study based on their classification into three major groups. These groups included four antibodies (MBEC 1-4) that reacted in a staining pattern typical of mucin. A second group of mAbs, MBECs 5 to 8, reacted strongly along the biliary tract and by immunoblot analysis, reacted with several bands ranging from 44 kd to 64 kd. These antibodies were considered as markers of pan BECs and their staining pattern proved similar to that of a control polyclonal pan-cytokeratin. The final group of mAbs, MBECs 9 to 12, recognized a 36-kd antigen using lysates of murine BECs. These antibodies also predominantly stained small peripheral Bile Ducts. The reactive antigen was purified by immunoprecipitation and microsequenced; the peptides sequenced showed 100% homology with murine annexin V. The identification of annexin V with predominantly Intrahepatic Bile Ducts, is of significant interest because of the multiple roles of annexin V, including that of membrane cytoskeletal interactions during transport and apoptosis.
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expression of co stimulatory factor b7 2 on the Intrahepatic Bile Ducts in primary biliary cirrhosis and primary sclerosing cholangitis an immunohistochemical study
The Journal of Pathology, 1998Co-Authors: Koichi Tsuneyama, Mitsue Yasoshima, Kenichi Harada, Kyosuke Kaji, Eric M Gershwin, Yasuni NakanumaAbstract:Co-stimulatory factors B7-1 (CD80) and B7-2 (CD86) and their ligands, including CD28, are important for the efficient presentation and persistence of an antigen-specific immune reaction. Hitherto, there has been a paucity of data on the roles of such co-stimulatory factors in immune-mediated biliary diseases. In this investigation, the hepatic immunohistochemical expression of B7-1 and B7-2 has been studied, with emphasis on Intrahepatic biliary epithelia, using wedge biopsies from 22 patients with primary biliary cirrhosis (PBC), seven with primary sclerosing cholagitis (PSC), and, as controls, eight cases of extrahepatic biliary obstruction, eight of chronic viral hepatitis C, and three histologically normal livers. In 10/22 (45 per cent) patients with PBC and 3/7 (43 per cent) patients with PSC, B7-2, but not B7-1, was expressed on the epithelial cells of small Intrahepatic Bile Ducts and Bile ductules. This expression was manifest as diffuse but variable cytoplasmic staining. Such B7-2-positive Bile Ducts were not seen in controls. Positive staining was found only in the early stage of PBC and PSC. In PBC and PSC, almost all lymphocytes in the portal tracts, including those around the damaged Bile Ducts, were positive for CD28, a ligand of B7-2. These results suggest that B7-2 expression on biliary epithelial cells is involved in antigen presentation and perhaps in Bile duct destruction in PSC and PBC.
King-teh Lee - One of the best experts on this subject based on the ideXlab platform.
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expression of transforming growth factor betas and their signaling receptors in stone containing Intrahepatic Bile Ducts and cholangiocarcinoma
World Journal of Surgery, 2003Co-Authors: King-teh Lee, Tsan-shium LiuAbstract:Transforming growth factor betas (TGF-βs) are multifunctional polypeptides that either inhibit or stimulate cell proliferation. They mediate their functions through their signaling receptors. Clinically, hepatolithiasis has been regarded as a risk factor for cholangiocarcinoma. The aim of this study was to examine the expression of TGF-βs and their receptors in stone-containing Intrahepatic Bile Ducts (IHD) and cholangiocarcinoma and try to predict whether hepatolithiasis has a predisposition to development of cholangiocarcinoma. Twenty-eight surgically resected specimens of stone-containing IHD and 15 specimens of cholangiocarcinoma were subjects for this study. Immunohistochemical analysis was done on three TGF-βs and their signaling receptors to check their expression in non-neoplastic and neoplastic Bile Ducts. No immunoreactivity of TGF-β1 was found in any specimens. The overexpression of TGF-β2 and TGF-β3 was found in both hepatolithiasis (93%–100%) and cholangiocarcinoma (80%) at levels significantly higher than those of normal controls (10%–20%) (p < 0.001). The immunoreactivity of type I receptor (TβRI) and type II receptor (TβRII) also showed increased expression in stone-containing IHD, whereas TβRII was absent in cholangiocarcinoma. We conclude that the overexpression of TGF-β2 and TGF-β3 and the absence of TβRII in cholangiocarcinoma could lead to enhanced tumor cell proliferation. At the same time, the overexpression of TGF-βs and their receptors in stone-containing IHD could suggest a close relationship between hepatolithiasis and cholangiocarcinoma.
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Altered mucin gene expression in stone-containing Intrahepatic Bile Ducts and cholangiocarcinomas.
Digestive diseases and sciences, 2001Co-Authors: King-teh Lee, Tsan-shium LiuAbstract:Neoplastic transformation of epithelial cells is commonly associated with alterations in the synthesis and structures of mucin. Mucin protein epitopes and mRNA levels were frequently altered in adenocarcinomas compared to corresponding normal tissues. Clinically, hepatolithiasis has been regarded as a risk factor for cholangiocarcinoma. The aims of this study were to determine the possible alteration of mucin gene expression in stone-containing Intrahepatic Bile Ducts and cholangiocarcinomas and to try to predict whether or not hepatolithiasis has a predisposition to development of cholangiocarcinoma. In situ hybridization with DIG-tailed oligonucleotides was performed on sections of paraffin-embedded tissues of stone-containing Intrahepatic Bile Ducts, cholangiocarcinomas, and normal controls to identify the expression of MUC2, MUC3, MUC4, MUC5B, and MUC5AC in nonneoplastic and neoplastic biliary epithelium. The findings showed that (1) while multiple diverse mucin genes were expressed in the biliary epithelium, MUC3 and MUC5B mRNA were the main mucin genes expressed in the biliary epithelium of stone-containing Intrahepatic Bile Ducts and normal controls; (2) absent or decreased expression of MUC2, MUC3, and MUC5B of mRNA was found in cholangiocarcinomas in contrast to nonneoplastic biliary epithelium; and (3) increased expression of MUC4 and MU5AC of mRNA was found in cholangiocarcinomas and the biliary epithelium, especially for dysplastic cells of stone-containing Intrahepatic Bile Ducts compared with normal controls. In this study, using in situ hybridization we demonstrated that neoplastic transformation of the biliary epithelium is accompained by alterations in mucin gene expression, the altered mucin gene expression in dysplastic cells of stone-containing Intrahepatic Bile Ducts may reflect a higher potential for malignant transformation in these cells, and it could be a precursor of cholangiocarcinoma in the presence of hepatolithiasis.
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Lectin histochemical study of cholagiocarcinoma arising from stone-bearing Intrahepatic Bile duct
Journal of surgical oncology, 1995Co-Authors: King-teh Lee, Pai-ching SheenAbstract:With the purpose of studying changes in the expression of glycoconjugate structures in cholangiocarcinoma and the nonneoplastic epithelium of stone-bearing Intrahepatic Bile Ducts, a panel of 12 biotinylated lectins were used on formalin-fixed, paraffin-embedded tissue sections from 13 patients who had undergone surgical resection of cholangiocarcinoma and on nonneoplastic stone-bearing Intrahepatic Bile Ducts from 10 patients. Of the 13 patients with cholangiocarcinoma 10 had hepatolithiasis and 3 did not. Among the 12 lectins, only wheat germ agglutinin (WGA) stained the cholangiocarcinoma and nonneoplastic epithelium of the stone-bearing Intrahepatic Bile duct. All nonneoplastic epithelia of stone-bearing Intrahepatic Bile Ducts were stained heavily and homogenously by WGA, the GlcNAC-specific lectin. The high columnar epithelium of both intramural and extramural glands was stained in the supranuclear region, while the low columnar epithelium of serous acini was stained in the whole cytoplasm. In the well-differentiated cholangiocarcinoma, the WGA weakly stained the neoplastic cells in the supranuclear region, while it stained the luminal cytoplasmic membrane heavily. In the poorly-differentiated cholangiocarcinoma, about 50% of cancer cells were stained with WGA. The carcinoma was moderately stained in the cytoplasm. Less reactivity and a lower percentage of cells stained with lectin were found in cholangiocarcinomas when compared to nonneoplastic epithelia. This led us to conclude that there is a dramatic decrease in lectin-binding carbohydrate structures associated with cholangiocarcinoma progression. © 1995 Wiley-Liss, Inc.
Jean Rosenbaum - One of the best experts on this subject based on the ideXlab platform.
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expression of collagens type i and iv osteonectin and transforming growth factor beta 1 tgfβ1 in biliary atresia and paucity of Intrahepatic Bile Ducts during infancy
Journal of Hepatology, 1999Co-Authors: Thierry Lamireau, Brigitte Le Bail, Liliane Boussarie, Monique Fabre, Pierre Vergnes, Olivier Bernard, Frederic Gautier, Paulette Bioulacsage, Jean RosenbaumAbstract:Abstract Background/Aims: Biliary atresia and paucity of Intrahepatic Bile Ducts are the main causes of neonatal cholestasis leading to hepatic fibrosis. Fibrotic evolution is slow in paucity of Bile Ducts as compared to the rapid progression to biliary cirrhosis in biliary atresia when cholestasis persists despite hepatoportoenterostomy. Our aim was to compare the expression of collagens type I and IV,α-smooth muscle actin, osteonectin and transforming growth factor β1 in biliary atresia and paucity of Bile Ducts. Methods: Liver biopsies were obtained in 12 children with biliary atresia and in five with paucity of Bile Ducts. Collagens type I and IV, α-smooth muscle actin were detected with immunostaining. Collagens type I and IV, osteonectin and transforming growth factor β1 mRNAs were detected by in situ hybridization. Results: Expression of mRNA and proteins was roughly parallel. In ductular proliferation areas of biliary atresia: (1) the expression of collagens type I and IV and osteonectin was increased, and was localized to periductular myofibroblasts; (2) transforming growth factor β1 was expressed around biliary ductules, probably in inflammatory cells, and also in biliary cells. Osteonectin expression was also increased in the lobules. In paucity of Bile Ducts, there was no overexpression of collagens type I and IV and transforming growth factor β1, except in the only child with marked fibrosis. However, osteonectin expression was enhanced at the periphery of the lobules, even when fibrosis was mild or absent. Conclusions: These findings suggest that in biliary atresia ductular proliferation areas are the site of a marked production of extracellular matrix proteins in periductular myofibroblasts, probably secondary to transforming growth factor β1 production by inflammatory cells and by biliary cells. The weak expression of transforming growth factor β1 could explain the slow progression of fibrosis in paucity of Bile Ducts.