Normal bladder urothelium consists of several layers of polyhedral (transitional) cells divided into three main layers from surface to base: umbrella, intermediate, and basal cells. Basal cells divide to form intermediate cells and intermediate cells fuse to form umbrella cells. Under normal conditions, the rate of turnover of urothelial cells is very slow ranging anywhere from 6 weeks to 1 year in the mouse bladder [5, 6]. The urothelium acts as a protective barrier that allows urine to be stored for a longer time while maintaining initial concentration.

The acute effects of radiation on urothelium are characterized by mucosal edema, hyperemia, and inflammation. Using measurements of urinary frequency and cystometry, Stewart et al. noticed that the acute phase of radiation-induced damage manifests as a dose-dependant increase in urinary frequency. Data on cellular and molecular mechanisms underlying radiation effects in the murine urinary bladder suggest that the acute effects are associated with changes in urothelial protein expression such as Uroplakin III, CD 18, CD 44, or syndecan [7]. It is hypothesized that these proteins maintain the integrity of the normal urothelial barrier to urine. Altered expression of these proteins leads to disruption of the urothelial barrier with increased exposure of underlying tissue to urine and its toxic solutes contributing to irritative voiding symptoms. Experimental studies also indicate that altered prostaglandin metabolism, with increased cyclooxygenase-II expression which regulates the tone of the bladder wall, results in increased baseline tone of the detrusor muscle corresponding to a reduction in bladder capacity. [8]. Unlike other epithelia, urinary epithelial cell depletion is not noted in the acute phase of radiation damage due to the very long turnover time of the urothelium. However, the presence of infection may complicate this early response, which may then progress to desquamation and ulceration.

Late damage is irreversible and is characterized by epithelial denudation, and ulceration with focal hyperplasia and fibrosis [9]. Kraft et al. showed that transforming growth factor-β (TGF-β) is overexpressed in the mouse urinary bladder between days 90 and 360 after radiation [10]. The increased expression was associated with increased collagen deposition in the bladder wall; however, these changes did not correlate with the functional radiation response, and hence are considered a secondary effect to organ damage rather than a primary radiation effect. In contrast, a clear correlation was noted between changes in bladder function and urothelial changes. The latter presents as focal urothelial denudation and a hyperproliferative response [10]. Jaal et al. noted that these late effects appear to be correlated with increased urothelial expression of intercellular adhesin molecule 1 (ICAM-1) [11].

Radiation-induced damage is also observed in the bladder vasculature. Edema of the vascular endothelium is noted by approximately 3 months following radiation. By 6 months to 2 years, endothelial cell proliferation, perivascular fibrosis, and vascular occlusion occur. Focal bladder wall ischemia leading to bladder wall fibrosis can be seen in severe cases [12]. The loss of balance between endothelial cell proliferation and small vessel maturation is believed to cause development of telangiectasia [13]. These thin-walled tortuous abnormally dilated vessels are prone to rupture and bleeding, resulting in microscopic or gross hematuria. Radiation effect is also noted in the smooth muscle layer of the bladder in the form of loss of smooth muscle, infiltration of fibroblasts, and increase in collagen deposition contributing to loss of bladder compliance and capacity [14].