Modulation of nerve growth factor receptor expression in the urothelium and its relevance to ketmine induced cystitis

Kidger, Elizabeth Anne

Medicine
September 2014

Thesis or dissertation


Rights
© 2014 Elizabeth Anne Kidger. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.
Abstract

Ketamine-induced cystitis (KIC) is a form of bladder pain syndrome (BPS) that usually arises following recreational abuse. Urothelial expression of the p75 low-affinity nerve growth factor receptor (NGFR) has been implicated in the aetiopathology of BPS. The aim of this project was to examine the expression of NGFR in urothelium and KIC and to identify modulators of NGFR expression. From the literature, candidate modulators identified were: ketamine, the transcriptional regulator Early growth response (Egr-1), glucocorticoids, cytokines, brain derived neurotrophic factor (BDNF) and ibuprofen, a non-steroidal anti-inflammatory drug.

Immunoperoxidase labelling and semi-quantitative analysis was performed on normal and KIC surgical specimens for NGFR and Egr-1. Cell and organ culture systems were developed from which NGFR transcript and protein expression were assessed following exposure to the candidate modulators.

NGFR was expressed by basal cells in all normal urothelial samples and extended suprabasally in KIC samples. A case study revealed widespread urothelial destruction and a non-patent urachal remnant with normal NGFR basal expression, in comparison to NGFR suprabasal extension in Von Brunn’s nests, which were patent with the luminal surface of the bladder. Using an in vitro approach NGFR transcript was most highly expressed by proliferating normal human urothelial cell cultures and was immunolocalised basally in differentiated cell sheets and organ cultures. Glucocorticoids, cytokines, BDNF and Egr-1 did not modulate NGFR expression. Cell death inducing concentrations of ibuprofen, ketamine or G418 up-regulated NGFR transcript and protein in cell and organ cultures.

This study supports a urinary-mediated urothelial damage process in KIC and implicates NGFR upregulation in the pathogenesis. Ketamine and other toxins are able to directly up-regulate expression of NGFR in the urothelium and this study has laid the foundation for future exploration of the role of NGFR in the urothelial damage response.

Publisher
Hull York Medical School, The University of Hull and the University of York
Supervisor
Southgate, Jennifer; Baker, Simon C.
Qualification level
Doctoral
Qualification name
MD
Language
English
Extent
8 MB
Identifier
hull:11022
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