The role of inflammatory mediators in the overactive and bladder pain syndromes

Show simple item record

dc.contributor.advisor O'Reilly, Barry A. en
dc.contributor.advisor McMahon, Stephen B. en
dc.contributor.author Offiah, Ifeoma
dc.date.accessioned 2016-02-02T12:12:12Z
dc.date.available 2016-02-02T12:12:12Z
dc.date.issued 2015
dc.date.submitted 2015
dc.identifier.citation Offiah, I. 2015. The role of inflammatory mediators in the overactive and bladder pain syndromes. PhD Thesis, University College Cork. en
dc.identifier.endpage 290 en
dc.identifier.uri http://hdl.handle.net/10468/2240
dc.description.abstract The Overactive Bladder (OAB) and Bladder Pain Syndrome (BPS) are debilitating disorders for which the pathophysiological mechanisms are poorly understood. Injury or dysfunction of the protective urothelial barrier layer, specifically the proteoglycan composition and number, has been proposed as the primary pathological characteristic of BPS. For OAB, the myogenic theory with dysfunction of the muscarinic receptors is the most reiterated hypothesis. For both over activity of the inflammatory response has been posited to play a major role in these diseases. We hypothesise that BPS and OAB are peripheral sensory disorders, with an increase in inflammatory mediators, such as cytokines and chemokines, which are capable of activating, either directly or indirectly, sensory nerve activity causing the disease. The aim of the PhD is to identify potential new therapeutic targets for the treatment of BPS and OAB. We used medium throughput quantitative gene expression analysis of 96 inflammation associated mediators to measure gene expression levels in BPS and OAB bladder biopsies and compared them to control samples. Then we created a novel animal model of disease by specific proteoglycan deglycosylation of the bladder mucosal barrier, using the bacterial enzymes Chondroitinase ABC and Heparanase III. These enzymes specifically remove the glycosaminoglycan side chains from the urothelial proteoglycan molecules. We tested role of the identified mediators in this animal model. In addition, in order to determine on which patients peripheral treatment strategies may work, we assessed the effect of local anaesthetics on patients with bladder pain. Gene expression analysis did not reveal a difference in inflammatory genes in the OAB versus control biopsies. However, several genes were upregulated in BPS versus control samples, from which two genes, FGF7 and CLL21 were correlated with patient clinical phenotypes for ICS/PI symptom and problem indices respectively. In order to determine which patients are likely to respond to treatment, we sought to characterise the bladder pain in BPS patients. Using urodynamics and local anaesthetics, we differentiated patients with peripherally mediated pain and patients with central sensitisation of their pain. Finally to determine the role of these mediators in bladder pain, we created an animal model of disease, which specifically replicates the human pathology: namely disruption in the barrier proteoglycan molecules. CCL21 led to an increase in painrelated behaviour, while FGF7 attenuated this behaviour, as measured by cystometry, spinal c-fos expression and mechanical withdrawal threshold examination. In conclusion, we have identified CCL21 and FGF7 as potential targets for the treatment of BPS. Manipulation of these ligands or their receptors may prove to be valuable previously unexploited targets for the treatment of BPS. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2015. Ifeoma Offiah en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Bladder pain syndrome en
dc.subject Overactive bladder en
dc.subject Chemokines en
dc.subject Cytokines en
dc.subject Animal model en
dc.subject Central sensitization en
dc.subject Gene expression analysis en
dc.subject Correlation study en
dc.title The role of inflammatory mediators in the overactive and bladder pain syndromes en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral Degree (Structured) en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en
dc.check.info No embargo required en
dc.description.version Accepted Version
dc.contributor.funder MedImmune, United Kingdom en
dc.description.status Not peer reviewed en
dc.internal.school Obstetrics and Gynaecology en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out No en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
ucc.workflow.supervisor barry.oreilly@hse.ie
dc.internal.conferring Spring 2016 en


Files in this item

This item appears in the following Collection(s)

Show simple item record

© 2015. Ifeoma Offiah Except where otherwise noted, this item's license is described as © 2015. Ifeoma Offiah
This website uses cookies. By using this website, you consent to the use of cookies in accordance with the UCC Privacy and Cookies Statement. For more information about cookies and how you can disable them, visit our Privacy and Cookies statement