An exploration of Vascular Adhesion Protein (VAP)-1 expression in Primary Sclerosing Cholangitis (PSC)

Trivedi, Palak Jitendrakumar (2016). An exploration of Vascular Adhesion Protein (VAP)-1 expression in Primary Sclerosing Cholangitis (PSC). University of Birmingham. Ph.D.

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Abstract

Primary sclerosing cholangitis (PSC) is an immune-mediated cholangiopathy and extra-intestinal manifestation of inflammatory bowel disease (IBD). It is hypothesised that long-lived, α4β7\(^+\) CCR9\(^+\) effector memory T-cells generated within the intestine drive hepatobiliary injury in PSC, being recruited to the liver via hepatic endothelial expression of mucosal addressin cell adhesion molecule (MAdCAM)-1 and CCL25.
Previous studies (mainly murine) claim CCL25 expression and CCR9\(^+\) T-cells as confined to small bowel under homeostatic and inflammatory conditions, whereas PSC is typified by colonic disease. However, I was able to illustrate that in man, a significant proportion of tissue-infiltrating T-cells do express CCR9 in colitis relative to low numbers in the absence of colonic inflammation. Moreover, CCL25 expression is not only apparent in colonic IBD but also correlates with inflammatory indices.
Vascular adhesion protein (VAP)-1 is a potent amine oxidase capable of augmenting expression of other hepatic endothelial adhesion molecules through an enzyme-dependent process. I found that hepatic VAP-1 enzyme activity is greater in PSC than other autoimmune liver diseases; mirrored by high circulating serum levels that correlate with patient clinical outcomes. I then examined the effect of several potential amine substrates on VAP-1 dependent expression of MAdCAM-1 by liver endothelium, illustrating cysteamine as the most potent – an amine that is notable for inducing colitis in mice. Targeted deletion of VAP-1 enzyme function did not confer protection against early sclerosing cholangitis in \(Mdr2\)\(^–/–\) mice. However, this model does not replicate links between colitis and liver inflammation seen in clinical PSC.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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