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
Hirschfield GM; Liaskou E; Thorbjørnsen LW; Auvinen K; Adams DH; Smith D; Tickle J; Bruns T; Trivedi PJ; Weston CJ; Vainio J; Salmi M; Eddowes PJ; Vesterhus MN; Parker R; Hubscher SG
https://urn.fi/URN:NBN:fi-fe2021042718125
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]