Vale, Justin Alastair; (1992) The late irradiation injury of the urinary bladder. Doctoral thesis (M.S.), University College Hospital Medical School.

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Abstract

Following radical radiotherapy for pelvic malignancy, as many as 50% of patients develop symptoms of urinary frequency and urgency as a late complication. The mechanism of this injury is poorly understood, and it is often attributed to fibrosis. The aim of this research was to study some of the structural and functional changes which may contribute to post-irradiation bladder dysfunction. The first requirement was to establish a small animal model which was both suitable for urodynamic study, and could be demonstrated to show reproducible cystometric changes following X-irradiation. The female Wistar rat was used, and demonstrated a biphasic change in compliance following X-irradiation in the dose range 15-25 Gy. The first reduction in compliance developed at about 4 weeks post-irradiation, and was by as much as 40% in the 25 Gy dose group. Following a transient recovery period, a second reduction in compliance started at 3-4 months. This was irreversible, and compliance was reduced by as much as 50%. Bladder tissue was taken from the animals at the time of this late reduction in compliance, and studied histologically, electron microscopically, and in an organ bath. Histological study demonstrated an increased mast cell density in the irradiated bladders, but was otherwise non-specific; fibrosis was discernible in less than half of the 18 animals studied. Electron microscopy showed focal degeneration of smooth muscle cells, and in some areas there was evidence of selective degeneration of unmyelinated axon profiles. Organ bath study demonstrated an increase in the purinergic sensitivity of irradiated detrusor muscle (n=18) as compared to control (n=10). This was highly significant (p-value 0.0078 at a methylene-ATP concentration of 1 X 10"4 mol/1; Mann-Whitney U test). There was no difference in sensitivity to cholinergic or noradrenergic stimulation. This research has helped establish a urodynamic model for the study of postirradiation bladder dysfunction, and a number of interesting features about this condition have been demonstrated. The histological findings suggest that fibrosis does 1 not play a prominent role. The electron microscopic evidence of neural injury, and the organ bath finding of a purinergic hypersensitivity, raise the possibility that a denervation supersensitivity phenomenon may contribute to the pathophysiology of post-irradiation bladder dysfunction. This is an entirely new concept, and has important therapeutic implications if the findings are confirmed in human bladder tissue.

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