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Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner

OBJECTIVE: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to examine the expr...

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Autores principales: Trivedi, Palak J, Tickle, Joseph, Vesterhus, Mette Nåmdal, Eddowes, Peter J, Bruns, Tony, Vainio, Jani, Parker, Richard, Smith, David, Liaskou, Evaggelia, Thorbjørnsen, Liv Wenche, Hirschfield, Gideon M, Auvinen, Kaisa, Hubscher, Stefan G, Salmi, Marko, Adams, David H, Weston, Chris J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969351/
https://www.ncbi.nlm.nih.gov/pubmed/28428344
http://dx.doi.org/10.1136/gutjnl-2016-312354
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author Trivedi, Palak J
Tickle, Joseph
Vesterhus, Mette Nåmdal
Eddowes, Peter J
Bruns, Tony
Vainio, Jani
Parker, Richard
Smith, David
Liaskou, Evaggelia
Thorbjørnsen, Liv Wenche
Hirschfield, Gideon M
Auvinen, Kaisa
Hubscher, Stefan G
Salmi, Marko
Adams, David H
Weston, Chris J
author_facet Trivedi, Palak J
Tickle, Joseph
Vesterhus, Mette Nåmdal
Eddowes, Peter J
Bruns, Tony
Vainio, Jani
Parker, Richard
Smith, David
Liaskou, Evaggelia
Thorbjørnsen, Liv Wenche
Hirschfield, Gideon M
Auvinen, Kaisa
Hubscher, Stefan G
Salmi, Marko
Adams, David H
Weston, Chris J
author_sort Trivedi, Palak J
collection PubMed
description OBJECTIVE: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to examine the expression, function and enzymatic activation of the ectoenzyme VAP-1 in patients with PSC. DESIGN: We examined VAP-1 expression in patients with PSC, correlated levels with clinical characteristics and determined the functional consequences of enzyme activation by specific enzyme substrates on hepatic endothelium. RESULTS: The intrahepatic enzyme activity of VAP-1 was elevated in PSC versus immune-mediated disease controls and non-diseased liver (p<0.001). The adhesion of gut-tropic α4β7(+)lymphocytes to hepatic endothelial cells in vitro under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). Of a number of natural VAP-1 substrates tested, cysteamine—which can be secreted by inflamed colonic epithelium and gut bacteria—was the most efficient (yielded the highest enzymatic rate) and efficacious in its ability to induce expression of functional mucosal addressin cell adhesion molecule-1 on hepatic endothelium. In a prospectively evaluated patient cohort with PSC, elevated serum soluble (s)VAP-1 levels predicted poorer transplant-free survival for patients, independently (HR: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis. CONCLUSIONS: VAP-1 expression is increased in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and elevated levels of its circulating form predict clinical outcome in patients.
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spelling pubmed-59693512018-06-01 Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner Trivedi, Palak J Tickle, Joseph Vesterhus, Mette Nåmdal Eddowes, Peter J Bruns, Tony Vainio, Jani Parker, Richard Smith, David Liaskou, Evaggelia Thorbjørnsen, Liv Wenche Hirschfield, Gideon M Auvinen, Kaisa Hubscher, Stefan G Salmi, Marko Adams, David H Weston, Chris J Gut Hepatology OBJECTIVE: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to examine the expression, function and enzymatic activation of the ectoenzyme VAP-1 in patients with PSC. DESIGN: We examined VAP-1 expression in patients with PSC, correlated levels with clinical characteristics and determined the functional consequences of enzyme activation by specific enzyme substrates on hepatic endothelium. RESULTS: The intrahepatic enzyme activity of VAP-1 was elevated in PSC versus immune-mediated disease controls and non-diseased liver (p<0.001). The adhesion of gut-tropic α4β7(+)lymphocytes to hepatic endothelial cells in vitro under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). Of a number of natural VAP-1 substrates tested, cysteamine—which can be secreted by inflamed colonic epithelium and gut bacteria—was the most efficient (yielded the highest enzymatic rate) and efficacious in its ability to induce expression of functional mucosal addressin cell adhesion molecule-1 on hepatic endothelium. In a prospectively evaluated patient cohort with PSC, elevated serum soluble (s)VAP-1 levels predicted poorer transplant-free survival for patients, independently (HR: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis. CONCLUSIONS: VAP-1 expression is increased in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and elevated levels of its circulating form predict clinical outcome in patients. BMJ Publishing Group 2018-06 2017-04-20 /pmc/articles/PMC5969351/ /pubmed/28428344 http://dx.doi.org/10.1136/gutjnl-2016-312354 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
spellingShingle Hepatology
Trivedi, Palak J
Tickle, Joseph
Vesterhus, Mette Nåmdal
Eddowes, Peter J
Bruns, Tony
Vainio, Jani
Parker, Richard
Smith, David
Liaskou, Evaggelia
Thorbjørnsen, Liv Wenche
Hirschfield, Gideon M
Auvinen, Kaisa
Hubscher, Stefan G
Salmi, Marko
Adams, David H
Weston, Chris J
Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
title Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
title_full Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
title_fullStr Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
title_full_unstemmed Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
title_short Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
title_sort vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
topic Hepatology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969351/
https://www.ncbi.nlm.nih.gov/pubmed/28428344
http://dx.doi.org/10.1136/gutjnl-2016-312354
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