Up to 80% of patients who receive pelvic radiotherapy e.g. for prostate, cervical or bladder cancer, develop bladder dysfunction during treatment; characterised by urgency, increased frequency and impaired voiding ability which have a negative impact on patient quality of life. Irradiated animal models share a similar pathophysiology. Urodynamic analysis reveals a reduced bladder capacity and/or increased urination frequency within 1 week of pelvic irradiation. Functional abnormalities are attributed, at least in part to a damaged mucosal layer, evident within 24 hours of radiation exposure. However, mechanisms leading to disturbed bladder contractility have not been elucidated. Recently the mucosal layer has been shown to have a profound influence on detrusor contractility involving local and central signalling mechanisms. The impact of the mucosa on detrusor contractility in the irradiated bladder has never been assessed. The present study describes an early radiation-induced effect on detrusor contraction in guinea-pig bladder strips, specifically mediated by the mucosal layer. Nerve-evoked contractions were significantly reduced in intact but not mucosa-free bladder strips. Importantly K+ contractions were unaffected by irradiation indicating maintenance of Ca2+-sensitive contractile mechanisms in smooth muscle cells. These results demonstrate an early radiation-induced negative signalling effect on bladder function mediated by the mucosal layer. One week following in vivo irradiation in the mouse bladder, a mucosa-mediated negative signalling which again impaired nerve-evoked contractions, as well as ATP, CCh, and K+-evoked contractions was observed. Interestingly, nerve-evoked contraction in mucosa-free strips was similar to control implying the potential for normal strength voiding contraction; however, the relative contribution of cholinergic, purinergic and residual components was altered suggesting remodelling of underlying excitation-contraction coupling pathways. In addition, disturbed IC networks in the irradiated bladder were investigated with immunohistochemistry and TEM, demonstrating their sensitivity to radiation. In keeping with mucosa-mediated damage, we also report for the first time, elevated urinary NGF in prostate cancer patients undergoing radiotherapy associated with IPSS peak symptom severity and reduced bladder capacity. In summary, the findings of the present study demonstrate for the first time that irradiation negatively impacts bladder contractility predominantly via the mucosal layer. Functional damage may involve structural and/or functional damage to bladder interstitial cells and remodelling involving NGF.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:707835 |
| Date | January 2016 |
| Creators | McDonnell, Bronagh |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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