The Experts below are selected from a list of 3216 Experts worldwide ranked by ideXlab platform
Mario Strazzabosco - One of the best experts on this subject based on the ideXlab platform.
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stimulation of nuclear receptor peroxisome proliferator activated receptor γ limits nf κb dependent inflammation in mouse cystic fibrosis Biliary Epithelium
Hepatology, 2015Co-Authors: R. Scirpo, Carlo Spirli, Romina Fiorotto, Ambra Villani, Mariangela Amenduni, Mario StrazzaboscoAbstract:Cystic fibrosis–associated liver disease is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing Biliary chloride and bicarbonate secretion, up-regulation of toll-like receptor 4/nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB)–dependent immune mechanisms plays a major role in the pathogenesis of cystic fibrosis–associated liver disease and may represent a therapeutic target. Nuclear receptors are transcription factors that regulate several intracellular functions. Some nuclear receptors, including peroxisome proliferator–activated receptor-γ (PPAR-γ), may counterregulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-γ stimulation in vivo in cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice exposed to dextran sodium sulfate and in vitro in primary cholangiocytes isolated from wild-type and from Cftr-knockout mice exposed to lipopolysaccharide. We found that in CFTR-defective Biliary Epithelium expression of PPAR-γ is increased but that this does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR-γ (pioglitazone and rosiglitazone) up-regulates PPAR-γ-dependent genes, while inhibiting the activation of NF-κB and the secretion of proinflammatory cytokines (lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, granulocyte colony-stimulating factor, keratinocyte chemoattractant) in response to lipopolysaccharide. PPAR-γ agonists modulate NF-κB-dependent inflammation by up-regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF-κB. Stimulation of PPAR-γ in vivo (rosiglitazone) significantly attenuates Biliary damage and inflammation in Cftr-knockout mice exposed to a dextran sodium sulfate–induced portal endotoxemia. Conclusion: These studies unravel a novel function of PPAR-γ in controlling Biliary Epithelium inflammation and suggest that impaired activation of PPAR-γ contributes to the chronic inflammatory state of CFTR-defective cholangiocytes. (Hepatology 2015;62:1551–1562)
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Stimulation of nuclear receptor peroxisome proliferator–activated receptor‐γ limits NF‐κB‐dependent inflammation in mouse cystic fibrosis Biliary Epithelium
Hepatology (Baltimore Md.), 2015Co-Authors: R. Scirpo, Carlo Spirli, Romina Fiorotto, Ambra Villani, Mariangela Amenduni, Mario StrazzaboscoAbstract:Cystic fibrosis–associated liver disease is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing Biliary chloride and bicarbonate secretion, up-regulation of toll-like receptor 4/nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB)–dependent immune mechanisms plays a major role in the pathogenesis of cystic fibrosis–associated liver disease and may represent a therapeutic target. Nuclear receptors are transcription factors that regulate several intracellular functions. Some nuclear receptors, including peroxisome proliferator–activated receptor-γ (PPAR-γ), may counterregulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-γ stimulation in vivo in cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice exposed to dextran sodium sulfate and in vitro in primary cholangiocytes isolated from wild-type and from Cftr-knockout mice exposed to lipopolysaccharide. We found that in CFTR-defective Biliary Epithelium expression of PPAR-γ is increased but that this does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR-γ (pioglitazone and rosiglitazone) up-regulates PPAR-γ-dependent genes, while inhibiting the activation of NF-κB and the secretion of proinflammatory cytokines (lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, granulocyte colony-stimulating factor, keratinocyte chemoattractant) in response to lipopolysaccharide. PPAR-γ agonists modulate NF-κB-dependent inflammation by up-regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF-κB. Stimulation of PPAR-γ in vivo (rosiglitazone) significantly attenuates Biliary damage and inflammation in Cftr-knockout mice exposed to a dextran sodium sulfate–induced portal endotoxemia. Conclusion: These studies unravel a novel function of PPAR-γ in controlling Biliary Epithelium inflammation and suggest that impaired activation of PPAR-γ contributes to the chronic inflammatory state of CFTR-defective cholangiocytes. (Hepatology 2015;62:1551–1562)
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Vascular biology of the Biliary Epithelium.
Journal of Gastroenterology and Hepatology, 2013Co-Authors: Carola M. Morell, Luca Fabris, Mario StrazzaboscoAbstract:Cholangiocytes are involved in a variety of processes essential for liver pathophysiology. To meet their demanding metabolic and functional needs, bile ducts are nourished by an own arterial supply, the periBiliary plexus. This capillary network originates from the hepatic artery and is strictly arranged around the intrahepatic bile ducts. Biliary and vascular structures are linked by a close anatomic and functional association necessary for liver development, normal organ physiology and liver repair. This strong association is finely regulated by a range of angiogenic signals, enabling the crosstalk between cholangiocytes and the different vascular cell types. This review will briefly illustrate the “vascular” properties of cholangiocytes, their underlying molecular mechanisms and the relevant pathophysiological settings.
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Vascular biology of the Biliary Epithelium.
Journal of gastroenterology and hepatology, 2013Co-Authors: Carola M. Morell, Luca Fabris, Mario StrazzaboscoAbstract:Cholangiocytes are involved in a variety of processes essential for liver pathophysiology. To meet their demanding metabolic and functional needs, bile ducts are nourished by their own arterial supply, the periBiliary plexus. This capillary network originates from the hepatic artery and is strictly arranged around the intrahepatic bile ducts. Biliary and vascular structures are linked by a close anatomic and functional association necessary for liver development, normal organ physiology, and liver repair. This strong association is finely regulated by a range of angiogenic signals, enabling the cross talk between cholangiocytes and the different vascular cell types. This review will briefly illustrate the "vascular" properties of cholangiocytes, their underlying molecular mechanisms and the relevant pathophysiological settings.
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loss of cftr affects Biliary Epithelium innate immunity and causes tlr4 nf κb mediated inflammatory response in mice
Gastroenterology, 2011Co-Authors: Romina Fiorotto, Mario Strazzabosco, Carlo Spirli, R. Scirpo, Michael Trauner, Luca Fabris, Rafaz HoqueAbstract:Background & Aims Loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) in the Biliary Epithelium reduces bile flow and alkalinization in patients with cystic fibrosis (CF). Liver damage is believed to result from ductal cholestasis, but only 30% of patients with CF develop liver defects, indicating that another factor is involved. We studied the effects of CFTR deficiency on Toll-like receptor 4 (TLR4)-mediated responses of the Biliary Epithelium to endotoxins. Methods Dextran sodium sulfate (DSS) was used to induce colitis in C57BL/6J- Cftr tm1Unc (Cftr-KO) mice and their wild-type littermates. Ductular reaction and portal inflammation were quantified by keratin-19 and CD45 immunolabeling. Cholangiocytes isolated from wild-type and Cftr-KO mice were challenged with lipopolysaccharide (LPS); cytokine secretion was quantified. Activation of nuclear factor κB (NF-κB), phosphorylation of TLR4, and activity of Src were determined. HEK-293 that expressed the secreted alkaline phosphatase reporter and human TLR4 were transfected with CFTR complementary DNAs. Results DSS-induced colitis caused Biliary damage and portal inflammation only in Cftr-KO mice. Biliary damage and inflammation were not attenuated by restoring Biliary secretion with 24-nor - ursodeoxycholic acid but were significantly reduced by oral neomycin and polymyxin B, indicating a pathogenetic role of gut-derived bacterial products. Cftr-KO cholangiocytes incubated with LPS secreted significantly higher levels of cytokines regulated by TLR4 and NF-κB. LPS-mediated activation of NF-κB was blocked by the TLR4 inhibitor TAK-242. TLR4 phosphorylation by Src was significantly increased in Cftr-KO cholangiocytes. Expression of wild-type CFTR in the HEK293 cells stimulated with LPS reduced activation of NF-κB. Conclusions CFTR deficiency alters the innate immunity of the Biliary Epithelium and reduces its tolerance to endotoxin, resulting in an Src-dependent inflammatory response mediated by TLR4 and NF-κB. These findings might be used to develop therapies for CF-associated cholangiopathy.
Gianfranco Alpini - One of the best experts on this subject based on the ideXlab platform.
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Dual Role of Bile Acids on the Biliary Epithelium: Friend or Foe?
International journal of molecular sciences, 2019Co-Authors: Leonardo Baiocchi, Shannon Glaser, Heather Francis, Fanyin Meng, Tianhao Zhou, Suthat Liangpunsakul, Ilaria Lenci, Francesco Santopaolo, Lindsey Kennedy, Gianfranco AlpiniAbstract:Bile acids are a family of amphipathic compounds predominantly known for their role in solubilizing and absorbing hydrophobic compounds (including liposoluble vitamins) in the intestine. Bile acids also are key signaling molecules and inflammatory agents that activate transcriptional factors and cell signaling pathways that regulate lipid, glucose, and energy metabolism in various human disorders, including chronic liver diseases. However, in the last decade increased awareness has been founded on the physiological and chemical heterogeneity of this category of compounds and their possible beneficial or injurious effects on the Biliary tree. In this review, we provide an update on the current understanding of the molecular mechanism involving bile acid and Biliary Epithelium. The last achievements of the research in this field are summarized, focusing on the molecular aspects and the elements with relevance regarding human liver diseases.
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Role of lactoferrin and its receptors on Biliary Epithelium.
Biometals : an international journal on the role of metal ions in biology biochemistry and medicine, 2018Co-Authors: Romina Mancinelli, Gianfranco Alpini, Antonio Franchitto, Guido Carpino, Francesca Olivero, Diletta Overi, Luigi Rosa, Maria Stefania Lepanto, Antimo Cutone, Paolo OnoriAbstract:Human lactoferrin is an iron-binding glycoprotein present at high concentrations in breast milk and colostrum. It is produced by many exocrine glands and widely distributed in a variety of body fluids. This protein has antimicrobial, immunomodulatory, antioxidant, and anticancer properties. Two important hLf receptors have been identified: LDL receptor related protein (LRP1), a low specificity receptor, and intelectin-1 (ITLN1), a high specificity receptor. No data are present on the role of hLf on the Biliary Epithelium. Our aims have been to evaluate the expression of Lf and its receptors in human and murine cholangiocytes and its effect on proliferation. Immunohistochemistry and immunofluorescence (IF) were conducted on human healthy and primary Biliary cholangitis (PBC) liver samples as well as on liver samples obtained from normal and bile duct ligated (BDL) mice to evaluate the expression of Lf, LRP1 and ITLN1. Cell proliferation in vitro studies were performed on human cholangiocyte cell lines via 3-(4,5-dimetiltiazol-2-il)-2,5-diphenyltetrazolium assay as well as IF to evaluate proliferating cell nuclear antigen (PCNA) expression. Our results show that mouse and human cholangiocytes express Lf, LRP1 and ITLN1, at higher extent in cholangiocytes from BDL and PBC samples. Furthermore, the in vitro addition of bovine Lf (bLf) has a proliferative effect on human cholangiocyte cell line. The results support a proliferative role of hLf on the Biliary Epithelium; this pro-proliferative effect of hLf and bLf on cholangiocytes could be particularly relevant in human cholangiopathies such as PBC, characterized by cholangiocyte death and ductopenia.
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Anatomy and Physiology of the Biliary Epithelium
Comprehensive Toxicology, 2018Co-Authors: C.m. Hall, Shannon Glaser, Gianfranco AlpiniAbstract:The Biliary Epithelium of the liver is a system of interconnecting ducts that transport bile out of the liver to the duodenum. The bile ducts are lined by epithelial cells (cholangiocytes) which actively modify bile by secreting or absorbing solutes and water using transporters, exchangers, channels, and receptors, and by processes such as endocytosis, exocytosis, and pinocytosis. Gastrointestinal hormones, neurotransmitters, growth factors, bile acids, osmosensors, and mechanoreceptors regulate cholangiocyte function through multiple, complex pathways and mechanisms. Cholangiocyte pathophysiology is studied in vivo using bile duct cannulated animals and cholestatic models of primary Biliary cirrhosis and primary sclerosing cholangitis and in vitro using freshly isolated intrahepatic and extrahepatic cholangiocytes, cholangiocyte monolayers, cell lines, and isolated intrahepatic bile duct units. Cholangiocytes express phase I and II enzymes as well as cholangiocyte-specific proteins. Additionally, receptors and transport proteins are differentially expressed by cholangiocytes of different sizes lining small and large ducts, respectively.
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Lactoferrin regulate Biliary Epithelium growth and the activation of hepatic progenitor cell niche
Italian journal of anatomy and embryology, 2015Co-Authors: Anastasia Renzi, Julie Venter, Gianfranco Alpini, Guido Carpino, Diletta Overi, Piera Valenti, Eugenio GaudioAbstract:Lactoferin (Lf) is an iron-binding glycoprotein belonging to the transferrin family and it is present at high levels in breast milk and colostrum. This protein has many known functions and it is a potential antibacterial, antiviral, immunostimulatory, antioxidant, and cancer preventive agent.It has been seen that a 105 kDa Lf receptor (LfR) specifically mediates the effects of Lf in several different cell types (1). In human cholangiopathies, cholangiocytes are able to proliferate and replace the cell loss restoring the integrity of damaged Biliary Epithelium. However, when cholangiocyte proliferation is severely impaired, the activation of facultative hepatic progenitor cells (HPCs) takes place (2). The aims of our study have been i) to investigate the expression of Lf and LfR in cholangiocytes and in HPCs both in rats and in humans; and ii) to evaluate the in vitro effects of bLf on cholangiocyte proliferation and on HPC activation. Liver specimens have been obtained from normal (N=5) and bile duct ligated (BDL) (N=5) rats; from normal patients (N=5) and from patients with primary Biliary cirrhosis (PBC, N=5); Specimens were processed for histology, immunohistochemistry and immunofluorescence. Moreover for the in vitro study small and large cholangioytes from mouse, human non malignant cholangiocytes (H69), and HPCs treated or not with lactoferrin were used. Our results showed that: i) cholangiocytes and hepatic progenitor cells express lactoferrin and its receptor, ii) cholangiocytes and HPC proliferation is enhanced by lactoferrin; iii) the treatment with lactoferrin determine the commitment of HPCs towards cholangiocyte fate; this commitment is characterized by HPC morphological and phenotypical changes. Our current findings suggest that modulation of lactoferrin may be an important therapeutic tool for managing the proliferation of cholangiocyte and the activation of progenitor cell compartment in Biliary disorders.
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Histamine regulation of Biliary proliferation
Journal of hepatology, 2012Co-Authors: Heather Francis, Eugenio Gaudio, Fanyin Meng, Gianfranco AlpiniAbstract:Cholangiocytes, which line the Biliary Epithelium, are hormone-responsive and responsible for the modification of canalicular bile before reaching the duodenum. Cholangiocytes are the target cells in cholangiopathies such as primary Biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) that are characterized by cholangiocyte proliferation/loss [1]. The Biliary Epithelium is morphologically and functionally heterogeneous and is lined by small ( 15 lm in diameter) cholangiocytes lining small and large bile ducts, respectively [2]. Cholangiocyte responses are regulated by both Ca2+- and cAMP-dependent signaling [2–5].
Yasuni Nakanuma - One of the best experts on this subject based on the ideXlab platform.
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Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat Biliary Epithelium in vivo and in culture
Laboratory investigation; a journal of technical methods and pathology, 2007Co-Authors: Hiroko Ikeda, Motoko Sasaki, Kenichi Harada, Akira Ishikawa, Yasunori Sato, Yoh Zen, Hideaki Kazumori, Yasuni NakanumaAbstract:Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat Biliary Epithelium in vivo and in culture
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aberrant expression of trefoil factor family 1 in Biliary Epithelium in hepatolithiasis and cholangiocarcinoma
Laboratory Investigation, 2003Co-Authors: Motoko Sasaki, Koichi Tsuneyama, Yasuni NakanumaAbstract:Aberrant Expression of Trefoil Factor Family 1 in Biliary Epithelium in Hepatolithiasis and Cholangiocarcinoma
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Aberrant expression of trefoil factor family 1 in Biliary Epithelium in hepatolithiasis and cholangiocarcinoma.
Laboratory investigation; a journal of technical methods and pathology, 2003Co-Authors: Motoko Sasaki, Koichi Tsuneyama, Yasuni NakanumaAbstract:Stepwise progression of intrahepatic cholangiocarcinoma (ICC) has been proposed in hepatolithiasis. We examined the participation of trefoil factor family 1 (TFF1), which is critical for mucosal protection and tumor suppression in the stomach, in the development and progression of ICC. We used 16 livers of ICC with hepatolithiasis, 11 of Biliary epithelial dysplasia with hepatolithiasis, 16 of hepatolithiasis without dysplasia or carcinoma, 18 of ICC without hepatolithiasis, and 39 control livers. TFF1 expression in the Biliary Epithelium was increased in hepatolithiasis compared with control livers (p < 0.01). In Biliary epithelial dysplasia and noninvasive ICC with hepatolithiasis, TFF1 was extensively expressed and MUC5AC gastric mucin was usually colocalized with TFF1. However, TFF1 expression was significantly decreased in invasive ICC despite preserved expression of MUC5AC. A total of four missense mutations were detected: three in two noninvasive ICC with hepatolithiasis (28.6%) and one in invasive ICC (11%). Loss of heterozygosity of the TFF1 gene was not detectable. The decreased expression of TFF1 in invasive ICC may be explained by the methylation of the TFF1 promoter region. Up-regulation of TFF1 coupled with MUC5AC in Biliary Epithelium in hepatolithiasis, Biliary epithelial dysplasia, and noninvasive ICC may reflect the gastric metaplasia and early neoplastic lesion. Under such conditions, decreased TFF1 expression may lead to increased cell proliferation and then to the invasive character of ICC.
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frequent molecular identification of campylobacter but not helicobacter genus in bile and Biliary Epithelium in hepatolithiasis
The Journal of Pathology, 2001Co-Authors: Kenichi Harada, Koichi Tsuneyama, Satoru Ozaki, Naoko Kono, Kazuyoshi Katayanagi, Katsushi Hiramatsu, Yasuni NakanumaAbstract:Bacterial infection of the Biliary tree and bile stasis may be causally related to hepatolithiasis, but which bacterial species are involved and their roles in the pathogenesis of hepatolithiasis have not been ascertained. Recently, the Helicobacter genus was detected in human bile and Biliary mucosal samples by molecular techniques, and its association with several Biliary diseases has been suggested. The Campylobacter genus, which is closely related to the Helicobacter genus, has also recently been identified as causative of human gastrointestinal diseases. This study attempted to elucidate whether Helicobacter and/or Campylobacter bacteria are present in bile samples and Biliary mucosal specimens from hepatolithiasis patients and whether they are involved in the pathogenesis of hepatolithiasis. The 16S rRNA gene of the Helicobacter and of the Campylobacter genus was examined by polymerase chain reaction in DNA samples extracted from bile and/or microdissected Biliary Epithelium from 69 patients with hepatolithiasis and control patients with choledocholithiasis, cholecystolithiasis, and normal gall bladders. The Helicobacter genus was detected in 1 of 8 (13%) Biliary epithelial samples in hepatolithiasis and 1 of 10 (10%) bile samples in choledocholithiasis. The Campylobacter genus was detected in 3 of 14 (21%) bile samples and 5 of 8 (63%) epithelial samples in hepatolithiasis, and in 2 of 15 (13%) bile samples and 1 of 8 (13%) epithelial samples in cholecystolithiasis. The detection rate for Campylobacter in Biliary Epithelium of hepatolithiasis was significantly higher than in the bile or Biliary Epithelium of control groups (p<0.05). By a phylogenetic analysis based on nucleotide sequences, the Campylobacter genuses detected in hepatolithiasis were clustered with C. rectus or C. showae. The frequent detection of the Campylobacter 16S rRNA gene in bile, and especially in Biliary Epithelium of hepatolithiasis, suggests a pathogenetic relationship with Campylobacter infection. Copyright © 2000 John Wiley & Sons, Ltd.
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Frequent molecular identification of Campylobacter but not Helicobacter genus in bile and Biliary Epithelium in hepatolithiasis
The Journal of pathology, 2001Co-Authors: Kenichi Harada, Koichi Tsuneyama, Satoru Ozaki, Naoko Kono, Kazuyoshi Katayanagi, Katsushi Hiramatsu, Yasuni NakanumaAbstract:Bacterial infection of the Biliary tree and bile stasis may be causally related to hepatolithiasis, but which bacterial species are involved and their roles in the pathogenesis of hepatolithiasis have not been ascertained. Recently, the Helicobacter genus was detected in human bile and Biliary mucosal samples by molecular techniques, and its association with several Biliary diseases has been suggested. The Campylobacter genus, which is closely related to the Helicobacter genus, has also recently been identified as causative of human gastrointestinal diseases. This study attempted to elucidate whether Helicobacter and/or Campylobacter bacteria are present in bile samples and Biliary mucosal specimens from hepatolithiasis patients and whether they are involved in the pathogenesis of hepatolithiasis. The 16S rRNA gene of the Helicobacter and of the Campylobacter genus was examined by polymerase chain reaction in DNA samples extracted from bile and/or microdissected Biliary Epithelium from 69 patients with hepatolithiasis and control patients with choledocholithiasis, cholecystolithiasis, and normal gall bladders. The Helicobacter genus was detected in 1 of 8 (13%) Biliary epithelial samples in hepatolithiasis and 1 of 10 (10%) bile samples in choledocholithiasis. The Campylobacter genus was detected in 3 of 14 (21%) bile samples and 5 of 8 (63%) epithelial samples in hepatolithiasis, and in 2 of 15 (13%) bile samples and 1 of 8 (13%) epithelial samples in cholecystolithiasis. The detection rate for Campylobacter in Biliary Epithelium of hepatolithiasis was significantly higher than in the bile or Biliary Epithelium of control groups (p
Shannon Glaser - One of the best experts on this subject based on the ideXlab platform.
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Dual Role of Bile Acids on the Biliary Epithelium: Friend or Foe?
International journal of molecular sciences, 2019Co-Authors: Leonardo Baiocchi, Shannon Glaser, Heather Francis, Fanyin Meng, Tianhao Zhou, Suthat Liangpunsakul, Ilaria Lenci, Francesco Santopaolo, Lindsey Kennedy, Gianfranco AlpiniAbstract:Bile acids are a family of amphipathic compounds predominantly known for their role in solubilizing and absorbing hydrophobic compounds (including liposoluble vitamins) in the intestine. Bile acids also are key signaling molecules and inflammatory agents that activate transcriptional factors and cell signaling pathways that regulate lipid, glucose, and energy metabolism in various human disorders, including chronic liver diseases. However, in the last decade increased awareness has been founded on the physiological and chemical heterogeneity of this category of compounds and their possible beneficial or injurious effects on the Biliary tree. In this review, we provide an update on the current understanding of the molecular mechanism involving bile acid and Biliary Epithelium. The last achievements of the research in this field are summarized, focusing on the molecular aspects and the elements with relevance regarding human liver diseases.
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Anatomy and Physiology of the Biliary Epithelium
Comprehensive Toxicology, 2018Co-Authors: C.m. Hall, Shannon Glaser, Gianfranco AlpiniAbstract:The Biliary Epithelium of the liver is a system of interconnecting ducts that transport bile out of the liver to the duodenum. The bile ducts are lined by epithelial cells (cholangiocytes) which actively modify bile by secreting or absorbing solutes and water using transporters, exchangers, channels, and receptors, and by processes such as endocytosis, exocytosis, and pinocytosis. Gastrointestinal hormones, neurotransmitters, growth factors, bile acids, osmosensors, and mechanoreceptors regulate cholangiocyte function through multiple, complex pathways and mechanisms. Cholangiocyte pathophysiology is studied in vivo using bile duct cannulated animals and cholestatic models of primary Biliary cirrhosis and primary sclerosing cholangitis and in vitro using freshly isolated intrahepatic and extrahepatic cholangiocytes, cholangiocyte monolayers, cell lines, and isolated intrahepatic bile duct units. Cholangiocytes express phase I and II enzymes as well as cholangiocyte-specific proteins. Additionally, receptors and transport proteins are differentially expressed by cholangiocytes of different sizes lining small and large ducts, respectively.
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vasopressin regulates the growth of the Biliary Epithelium in polycystic liver disease
Laboratory Investigation, 2016Co-Authors: Romina Mancinelli, Shannon Glaser, Julie Venter, Antonio Franchitto, Antonella Vetuschi, Roberta SferraAbstract:The neurohypophysial hormone arginine vasopressin (AVP) acts by three distinct receptor subtypes: V1a, V1b, and V2. In the liver, AVP is involved in ureogenesis, glycogenolysis, neoglucogenesis and regeneration. No data exist about the presence of AVP in the Biliary Epithelium. Cholangiocytes are the target cells in a number of animal models of cholestasis, including bile duct ligation (BDL), and in several human pathologies, such as polycystic liver disease characterized by the presence of cysts that bud from the Biliary Epithelium. In vivo, liver fragments from normal and BDL mice and rats as well as liver samples from normal and ADPKD patients were collected to evaluate: (i) intrahepatic bile duct mass by immunohistochemistry for cytokeratin-19; and (ii) expression of V1a, V1b and V2 by immunohistochemistry, immunofluorescence and real-time PCR. In vitro, small and large mouse cholangiocytes, H69 (non-malignant human cholangiocytes) and LCDE (human cholangiocytes from the cystic Epithelium) were stimulated with vasopressin in the absence/presence of AVP antagonists such as OPC-31260 and Tolvaptan, before assessing cellular growth by MTT assay and cAMP levels. Cholangiocytes express V2 receptor that was upregulated following BDL and in ADPKD liver samples. Administration of AVP increased proliferation and cAMP levels of small cholangiocytes and LCDE cells. We found no effect in the proliferation of large mouse cholangiocytes and H69 cells. Increases were blocked by preincubation with the AVP antagonists. These results showed that AVP and its receptors may be important in the modulation of the proliferation rate of the Biliary Epithelium.
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Recent advances in the morphological and functional heterogeneity of the Biliary Epithelium.
Experimental biology and medicine (Maywood N.J.), 2013Co-Authors: Yuyan Han, Domenico Alvaro, Shannon Glaser, Heather Francis, Marco Marzioni, Julie Venter, Fanyin Meng, Kelly Mcdaniel, Guido Carpino, Paolo OnoriAbstract:This review focuses on the recent advances related to the heterogeneity of different-sized bile ducts with regard to the morphological and phenotypical characteristics, and the differential secretory, apoptotic and proliferative responses of small and large cholangiocytes to gastrointestinal hormones/peptides, neuropeptides and toxins. We describe several in vivo and in vitro models used for evaluating Biliary heterogeneity. Subsequently, we discuss the heterogeneous proliferative and apoptotic responses of small and large cholangiocytes to liver injury and the mechanisms regulating the differentiation of small into large (more differentiated) cholangiocytes. Following a discussion on the heterogeneity of stem/progenitor cells in the Biliary Epithelium, we outline the heterogeneity of bile ducts in human cholangiopathies. After a summary section, we discuss the future perspectives that will further advance the field of the functional heterogeneity of the Biliary Epithelium.
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Morphological and functional heterogeneity of the mouse intrahepatic Biliary Epithelium
Laboratory investigation; a journal of technical methods and pathology, 2009Co-Authors: Shannon Glaser, Heather Francis, Julie Venter, Eugenio Gaudio, Arundhati Rao, Lisa M. Pierce, Paolo Onori, Antonio Franchitto, David E. Dostal, Sharon DemorrowAbstract:Rat and human Biliary Epithelium is morphologically and functionally heterogeneous. As no information exists on the heterogeneity of the murine intrahepatic Biliary Epithelium, and with increased usage of transgenic mouse models to study liver disease pathogenesis, we sought to evaluate the morphological, secretory, and proliferative phenotypes of small and large bile ducts and purified cholangiocytes in normal and cholestatic mouse models. For morphometry, normal and bile duct ligation (BDL) mouse livers (C57/BL6) were dissected into blocks of 2–4 μm2, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Sizes of bile ducts and cholangiocytes were evaluated by using SigmaScan to measure the diameters of bile ducts and cholangiocytes. In small and large normal and BDL cholangiocytes, we evaluated the expression of cholangiocyte-specific markers, keratin-19 (KRT19), secretin receptor (SR), cystic fibrosis transmembrane conductance regulator (CFTR), and chloride bicarbonate anion exchanger 2 (Cl−/HCO3− AE2) by immunofluorescence and western blot; and intracellular cyclic adenosine 3′,5′-monophosphate (cAMP) levels and chloride efflux in response to secretin (100 nM). To evaluate cholangiocyte proliferative responses after BDL, small and large cholangiocytes were isolated from BDL mice. The proliferation status was determined by analysis of the cell cycle by fluorescence-activated cell sorting, and bile duct mass was determined by the number of KRT19-positive bile ducts in liver sections. In situ morphometry established that the Biliary Epithelium of mice is morphologically heterogeneous, with smaller cholangiocytes lining smaller bile ducts and larger cholangiocytes lining larger ducts. Both small and large cholangiocytes express KRT19 and only large cholangiocytes from normal and BDL mice express SR, CFTR, and Cl−/HCO3− exchanger and respond to secretin with increased cAMP levels and chloride efflux. Following BDL, only large mouse cholangiocytes proliferate. We conclude that similar to rats, mouse intrahepatic Biliary Epithelium is morphologically and functionally heterogeneous. The mouse is therefore a suitable model for defining the heterogeneity of the Biliary tree.
Motoko Sasaki - One of the best experts on this subject based on the ideXlab platform.
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Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat Biliary Epithelium in vivo and in culture
Laboratory investigation; a journal of technical methods and pathology, 2007Co-Authors: Hiroko Ikeda, Motoko Sasaki, Kenichi Harada, Akira Ishikawa, Yasunori Sato, Yoh Zen, Hideaki Kazumori, Yasuni NakanumaAbstract:Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat Biliary Epithelium in vivo and in culture
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aberrant expression of trefoil factor family 1 in Biliary Epithelium in hepatolithiasis and cholangiocarcinoma
Laboratory Investigation, 2003Co-Authors: Motoko Sasaki, Koichi Tsuneyama, Yasuni NakanumaAbstract:Aberrant Expression of Trefoil Factor Family 1 in Biliary Epithelium in Hepatolithiasis and Cholangiocarcinoma
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Aberrant expression of trefoil factor family 1 in Biliary Epithelium in hepatolithiasis and cholangiocarcinoma.
Laboratory investigation; a journal of technical methods and pathology, 2003Co-Authors: Motoko Sasaki, Koichi Tsuneyama, Yasuni NakanumaAbstract:Stepwise progression of intrahepatic cholangiocarcinoma (ICC) has been proposed in hepatolithiasis. We examined the participation of trefoil factor family 1 (TFF1), which is critical for mucosal protection and tumor suppression in the stomach, in the development and progression of ICC. We used 16 livers of ICC with hepatolithiasis, 11 of Biliary epithelial dysplasia with hepatolithiasis, 16 of hepatolithiasis without dysplasia or carcinoma, 18 of ICC without hepatolithiasis, and 39 control livers. TFF1 expression in the Biliary Epithelium was increased in hepatolithiasis compared with control livers (p < 0.01). In Biliary epithelial dysplasia and noninvasive ICC with hepatolithiasis, TFF1 was extensively expressed and MUC5AC gastric mucin was usually colocalized with TFF1. However, TFF1 expression was significantly decreased in invasive ICC despite preserved expression of MUC5AC. A total of four missense mutations were detected: three in two noninvasive ICC with hepatolithiasis (28.6%) and one in invasive ICC (11%). Loss of heterozygosity of the TFF1 gene was not detectable. The decreased expression of TFF1 in invasive ICC may be explained by the methylation of the TFF1 promoter region. Up-regulation of TFF1 coupled with MUC5AC in Biliary Epithelium in hepatolithiasis, Biliary epithelial dysplasia, and noninvasive ICC may reflect the gastric metaplasia and early neoplastic lesion. Under such conditions, decreased TFF1 expression may lead to increased cell proliferation and then to the invasive character of ICC.
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Increased MUC6 apomucin expression is a characteristic of reactive Biliary Epithelium in chronic viral hepatitis.
The Journal of pathology, 1998Co-Authors: Motoko Sasaki, Yasuni Nakanuma, Young S. KimAbstract:The significance of bile ductular proliferation in the progression of various hepatoBiliary diseases remains unclear. Increased expression of MUC6 apomucin, a major gastric mucin, has previously been noticed in proliferating bile ductules in chronic viral hepatitis. The purpose of the present study was to characterize MUC6 apomucin and mRNA expression in 35 histologically 'normal livers', 47 livers with chronic viral hepatitis, 28 with primary Biliary cirrhosis, and seven with extrahepatic Biliary obstruction. MUC6 protein was expressed focally in cytoplasm and/or on the luminal surface of septal and interlobular bile ducts in normal and diseased livers. Bile ductules in normal livers rarely expressed MUC6 protein. The MUC6 expression intensified and spread in proliferating bile ductules and small bile ducts in chronic viral hepatitis and to a lesser degree in other diseases. In the former, the extent and degree of MUC6 expression paralleled the degree of active necroinflammation. MUC6 mRNA expression resembled MUC6 protein expression in proliferating bile ductules and intralobular small Biliary cells, suggesting increased transcription and synthesis of MUC6. In conclusion, proliferating bile ductular cells express MUC6 apomucin in diseased liver, especially in chronic viral hepatitis with active necroinflammation. This secreted mucin may act as a cytoprotective agent and represent a phenotype of reactive Biliary Epithelium in chronic viral hepatitis.