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      The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and SOX17

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          Abstract

          Biliary atresia, the most common indication for pediatric liver transplantation, is a fibrotic disease of unknown etiology affecting the extrahepatic bile ducts of newborns. The recently described toxin biliatresone causes lumen obstruction in mouse cholangiocyte spheroids and represents a new model of biliary atresia. The goal of this study was to determine the cellular changes caused by biliatresone in mammalian cells that ultimately lead to biliary atresia and extrahepatic fibrosis. We treated mouse cholangiocytes in three‐dimensional (3D) spheroid culture and neonatal extrahepatic duct explants with biliatresone and compounds that regulate glutathione (GSH). We examined the effects of biliatresone on SOX17 levels and determined the effects of Sox17 knockdown on cholangiocytes in 3D culture. We found that biliatresone caused disruption of cholangiocyte apical polarity and loss of monolayer integrity. Spheroids treated with biliatresone had increased permeability as shown by rhodamine efflux within 5 hours compared with untreated spheroids, which retained rhodamine for longer than 12 hours. Neonatal bile duct explants treated with the toxin showed lumen obstruction with increased subepithelial staining for α‐smooth muscle actin and collagen, consistent with fibrosis. Biliatresone caused a rapid and transient decrease in GSH, which was both necessary and sufficient to mediate its effects in cholangiocyte spheroid and bile duct explant systems. It also caused a significant decrease in cholangiocyte levels of SOX17, and Sox17 knockdown in cholangiocyte spheroids mimicked the effects of biliatresone. Conclusion: Biliatresone decreases GSH and SOX17 in mouse cholangiocytes. In 3D cell systems, this leads to cholangiocyte monolayer damage and increased permeability; in extrahepatic bile duct explants, it leads to disruption of the extrahepatic biliary tree and subepithelial fibrosis. This mechanism may be important in understanding human biliary atresia. (H epatology 2016;64:880‐893)

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          Most cited references38

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          Sox17 regulates organ lineage segregation of ventral foregut progenitor cells.

          The ventral pancreas, biliary system, and liver arise from the posterior ventral foregut, but the cell-intrinsic pathway by which these organ lineages are separated is not known. Here we show that the extrahepatobiliary system shares a common origin with the ventral pancreas and not the liver, as previously thought. These pancreatobiliary progenitor cells coexpress the transcription factors PDX1 and SOX17 at E8.5 and their segregation into a PDX1+ ventral pancreas and a SOX17+ biliary primordium is Sox17-dependent. Deletion of Sox17 at E8.5 results in the loss of biliary structures and ectopic pancreatic tissue in the liver bud and common duct, while Sox17 overexpression suppresses pancreas development and promotes ectopic biliary-like tissue throughout the PDX1+ domain. Restricting SOX17+ biliary progenitor cells to the ventral region of the gut requires the notch effector Hes1. Our results highlight the role of Sox17 and Hes1 in patterning and morphogenetic segregation of ventral foregut lineages.
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            Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease?

            The primary function of the bronchial epithelium is to act as a defensive barrier aiding the maintenance of normal airway function. Bronchial epithelial cells (BEC) form the interface between the external environment and the internal milieu, making it a major target of inhaled insults. However, BEC can also serve as effectors to initiate and orchestrate immune and inflammatory responses by releasing chemokines and cytokines, which recruit and activate inflammatory cells. They also produce excess reactive oxygen species as a result of an oxidant/antioxidant imbalance that contributes to chronic pulmonary inflammation and lung tissue damage. Accumulated mucus from hyperplastic BEC obstructs the lumen of small airways, whereas impaired cell repair, squamous metaplasia and increased extracellular matrix deposition underlying the epithelium is associated with airway remodelling particularly fibrosis and thickening of the airway wall. These alterations in small airway structure lead to airflow limitation, which is critical in the clinical diagnosis of chronic obstructive pulmonary disease (COPD). In this review, we discuss the abnormal function of BEC within a disturbed immune homeostatic environment consisting of ongoing inflammation, oxidative stress and small airway obstruction. We provide an overview of recent insights into the function of the bronchial epithelium in the pathogenesis of COPD and how this may provide novel therapeutic approaches for a number of chronic lung diseases.
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              Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2.

              Biliary atresia (BA) is characterized by the progressive fibrosclerosing obliteration of the extrahepatic biliary system during the first few weeks of life. Despite early diagnosis and prompt surgical intervention, the disease progresses to cirrhosis in many patients. The current theory for the pathogenesis of BA proposes that during the perinatal period, a still unknown exogenous factor meets the innate immune system of a genetically predisposed individual and induces an uncontrollable and potentially self-limiting immune response, which becomes manifest in liver fibrosis and atresia of the extrahepatic bile ducts. Genetic factors that could account for the disease, let alone for its high incidence in Chinese, are to be investigated. To identify BA susceptibility loci, we carried out a genome-wide association study (GWAS) using the Affymetrix 5.0 and 500 K marker sets. We genotyped nearly 500 000 single-nucleotide polymorphisms (SNPs) in 200 Chinese BA patients and 481 ethnically matched control subjects. The 10 most BA-associated SNPs from the GWAS were genotyped in an independent set of 124 BA and 90 control subjects. The strongest overall association was found for rs17095355 on 10q24, downstream XPNPEP1, a gene involved in the metabolism of inflammatory mediators. Allelic chi-square test P-value for the meta-analysis of the GWAS and replication results was 6.94 x 10(-9). The identification of putative BA susceptibility loci not only opens new fields of investigation into the mechanisms underlying BA but may also provide new clues for the development of preventive and curative strategies.
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                Author and article information

                Journal
                Hepatology
                Hepatology
                10.1002/(ISSN)1527-3350
                HEP
                Hepatology (Baltimore, Md.)
                John Wiley and Sons Inc. (Hoboken )
                0270-9139
                1527-3350
                20 May 2016
                September 2016
                : 64
                : 3 ( doiID: 10.1002/hep.v64.3 )
                : 880-893
                Affiliations
                [ 1 ] Division of Gastroenterology, Hepatology and Nutrition The Children's Hospital of Philadelphia Philadelphia PA
                [ 2 ] Division of Gastroenterology, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia PA
                [ 3 ] Department of Pediatrics Yonsei University College of Medicine, Severance Children's Hospital Seoul South Korea
                [ 4 ] Department of Biological Sciences University of the Sciences Philadelphia PA
                [ 5 ] Department of Economic Development, Jobs, Transport and Resources Government of Victoria Victoria Australia
                Author notes
                [*] [* ]ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:

                Rebecca G. Wells, M.D.

                University of Pennsylvania School of Medicine

                905 BRB II/III

                421 Curie Boulevard

                Philadelphia, PA 19104

                E‐mail: rgwells@ 123456mail.med.upenn.edu

                Tel: 215‐573‐1860

                Fax: 215‐573‐2024

                Article
                HEP28599
                10.1002/hep.28599
                4992464
                27081925
                6123bbd9-a24d-4963-9fa0-53078ef8832b
                © 2016 The Authors. H epatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 17 January 2016
                : 19 March 2016
                : 12 April 2016
                Page count
                Pages: 14
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases
                Award ID: R01 DK092111 (to M.P., J.R.P., and R.G.W.)
                Award ID: 5T32 HD043021‐10
                Award ID: 1T32 DK101371‐01 (to O.W.‐Z.)
                Funded by: AASLD Advanced Hepatology and Liver Transplant Fellowship grant (to O.W.‐Z.)
                Funded by: Fred and Suzanne Biesecker Pediatric Liver Center (to M.P. and R.G.W.)
                Categories
                Biliary Atresia
                Etiology
                Regulatory Pathways
                Autoimmune, Cholestatic and Biliary Disease
                Autoimmune, Cholestatic and Biliary Disease
                Custom metadata
                2.0
                hep28599
                September 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:05.08.2019

                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

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