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

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@article{7083285340aa41cabdeb03865214961d,
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",
abstract = "Objective: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD), wherein aberrant trafficking of mucosal T-cells from the gut is proposed to drive liver injury. Integral to this process is the ectoenzyme vascular adhesion protein (VAP)-1, which through its amine oxidase activity up-regulates mucosal addressin cell adhesion molecule (MAdCAM)-1 expression on hepatic endothelial vasculature, promoting recruitment of gut-tropic (7+) lymphocytes to the liver. Design: We examined VAP-1 expression in PSC patients, correlated levels with clinical characteristics, and determined the functional consequences of enzyme activation through varying substrate provision. Results: The intrahepatic enzyme activity of VAP-1 was elevated in PSC vs. immune-mediated disease controls and non-diseased liver (p<0.001), and adhesion of gut-tropic 7+ lymphocytes to hepatic endothelial cells under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). The natural substrate with highest VAP-1 efficiency (enzymatic rate) and efficacy (ability to induce functional MAdCAM-1 expression) was cysteamine – an amine known to be secreted by gut bacteria and colonic epithelium, capable of inducing colitis in mice. Elevated sVAP-1 levels predicted significantly worse transplant-free survival in PSC patients, independently (hazard ratio [HR]: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis. Conclusion: VAP-1 expression is heightened in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and levels of the circulating form predict clinical outcome. ",
keywords = "VAP-1, Primary sclerosing cholangitis, Lymphocytes",
author = "Palak Trivedi and Joseph Tickle and Mette Vesterhus and Peter Eddowes and Tony Bruns and Jani Vainio and Richard Parker and David Smith and Evaggelia Liaskou and Thorbjornsen, {Liv Wenche} and Gideon Hirschfield and Kaisa Auvinen and Stefan Hubscher and Marko Salmi and David Adams and Christopher Weston",
year = "2017",
month = apr,
day = "20",
doi = "10.1136/gutjnl-2016-312354",
language = "English",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",

}

RIS

TY - JOUR

T1 - 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

AU - Trivedi, Palak

AU - Tickle, Joseph

AU - Vesterhus, Mette

AU - Eddowes, Peter

AU - Bruns, Tony

AU - Vainio, Jani

AU - Parker, Richard

AU - Smith, David

AU - Liaskou, Evaggelia

AU - Thorbjornsen, Liv Wenche

AU - Hirschfield, Gideon

AU - Auvinen, Kaisa

AU - Hubscher, Stefan

AU - Salmi, Marko

AU - Adams, David

AU - Weston, Christopher

PY - 2017/4/20

Y1 - 2017/4/20

N2 - Objective: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD), wherein aberrant trafficking of mucosal T-cells from the gut is proposed to drive liver injury. Integral to this process is the ectoenzyme vascular adhesion protein (VAP)-1, which through its amine oxidase activity up-regulates mucosal addressin cell adhesion molecule (MAdCAM)-1 expression on hepatic endothelial vasculature, promoting recruitment of gut-tropic (7+) lymphocytes to the liver. Design: We examined VAP-1 expression in PSC patients, correlated levels with clinical characteristics, and determined the functional consequences of enzyme activation through varying substrate provision. Results: The intrahepatic enzyme activity of VAP-1 was elevated in PSC vs. immune-mediated disease controls and non-diseased liver (p<0.001), and adhesion of gut-tropic 7+ lymphocytes to hepatic endothelial cells under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). The natural substrate with highest VAP-1 efficiency (enzymatic rate) and efficacy (ability to induce functional MAdCAM-1 expression) was cysteamine – an amine known to be secreted by gut bacteria and colonic epithelium, capable of inducing colitis in mice. Elevated sVAP-1 levels predicted significantly worse transplant-free survival in PSC patients, independently (hazard ratio [HR]: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis. Conclusion: VAP-1 expression is heightened in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and levels of the circulating form predict clinical outcome.

AB - Objective: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD), wherein aberrant trafficking of mucosal T-cells from the gut is proposed to drive liver injury. Integral to this process is the ectoenzyme vascular adhesion protein (VAP)-1, which through its amine oxidase activity up-regulates mucosal addressin cell adhesion molecule (MAdCAM)-1 expression on hepatic endothelial vasculature, promoting recruitment of gut-tropic (7+) lymphocytes to the liver. Design: We examined VAP-1 expression in PSC patients, correlated levels with clinical characteristics, and determined the functional consequences of enzyme activation through varying substrate provision. Results: The intrahepatic enzyme activity of VAP-1 was elevated in PSC vs. immune-mediated disease controls and non-diseased liver (p<0.001), and adhesion of gut-tropic 7+ lymphocytes to hepatic endothelial cells under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). The natural substrate with highest VAP-1 efficiency (enzymatic rate) and efficacy (ability to induce functional MAdCAM-1 expression) was cysteamine – an amine known to be secreted by gut bacteria and colonic epithelium, capable of inducing colitis in mice. Elevated sVAP-1 levels predicted significantly worse transplant-free survival in PSC patients, independently (hazard ratio [HR]: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis. Conclusion: VAP-1 expression is heightened in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and levels of the circulating form predict clinical outcome.

KW - VAP-1

KW - Primary sclerosing cholangitis

KW - Lymphocytes

U2 - 10.1136/gutjnl-2016-312354

DO - 10.1136/gutjnl-2016-312354

M3 - Article

JO - Gut

JF - Gut

SN - 0017-5749

ER -