The role of vascular adhesion protein (VAP)-1 during inflammatory liver disease

Tickle, Joseph (2018). The role of vascular adhesion protein (VAP)-1 during inflammatory liver disease. University of Birmingham. Ph.D.

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Abstract

Liver disease is the fifth largest killer in the United Kingdom and with the numbers of diagnoses increasing each year there is an urgent need for novel therapeutic interventions. This thesis examines one potential target, Vascular Adhesion Protein (VAP)-1: an amine oxidase enzyme with reported adhesin functionality. The results herein confirm a primarily sinusoidal localisation of VAP-1, expression of which was upregulated in the liver during chronic inflammation correlated with diminished enzyme activity. Functional analysis of sinusoidal VAP-1 in vitro did not demonstrate any effect of inhibition on leukocyte recruitment, unlike that observed in other tissues. Furthermore, only neutrophils were capable of binding to recombinant VAP-1 under flow conditions. Further investigation highlighted the importance of this intimate relationship during neutrophil-endothelial interactions; revealing the first evidence that neutrophils also express catalytically active VAP-1. Neutrophil effector functions, such as the formation of extracellular traps, were also hindered by recombinant VAP-1. This was also observed in wild-type mice but not those expressing a catalytically inactive form of VAP-1 (SSAOKO). Following acute injury, these mice also exhibited expanded intrahepatic macrophage and NKT cell populations compared to control. In combination, these data highlight the complex role that VAP-1 plays during inflammatory liver disease.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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