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

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dc.check.embargoformatNot applicableen
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dc.contributor.advisorO'Reilly, Barry A.en
dc.contributor.advisorMcMahon, Stephen B.en
dc.contributor.authorOffiah, Ifeoma
dc.contributor.funderMedImmune, United Kingdomen
dc.date.accessioned2016-02-02T12:12:12Z
dc.date.available2016-02-02T12:12:12Z
dc.date.issued2015
dc.date.submitted2015
dc.description.abstractThe 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.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationOffiah, I. 2015. The role of inflammatory mediators in the overactive and bladder pain syndromes. PhD Thesis, University College Cork.en
dc.identifier.endpage290en
dc.identifier.urihttps://hdl.handle.net/10468/2240
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2015. Ifeoma Offiahen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectBladder pain syndromeen
dc.subjectOveractive bladderen
dc.subjectChemokinesen
dc.subjectCytokinesen
dc.subjectAnimal modelen
dc.subjectCentral sensitizationen
dc.subjectGene expression analysisen
dc.subjectCorrelation studyen
dc.thesis.opt-outfalse
dc.titleThe role of inflammatory mediators in the overactive and bladder pain syndromesen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoral Degree (Structured)en
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisorbarry.oreilly@hse.ie
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