Voiding defects in acute radiation cystitis driven by urothelial barrier defect through loss of E-cadherin, ZO-1 and Uroplakin III

Abstract

Long term-side effects from cancer therapies are a growing health care concern as life expectancy among cancer survivors increases. Damage to the bladder is common in patients treated with radiation therapy for pelvic cancers and can result in radiation (hemorrhagic) cystitis (RC). The disease progression of RC consists of an acute and chronic phase, separated by a symptom-free period. Gaining insight in tissue changes associated with these phases is necessary to develop appropriate interventions. Using a mouse preclinical model, we have previously shown that fibrosis and vascular damage are the predominant pathological features of chronic RC. The goal of this study was to determine the pathological changes during acute RC. We identified that radiation treatment results in a temporary increase in micturition frequency and decrease in void volume 4–8 weeks after irradiation. Histologically, the micturition defect is associated with thinning of the urothelium, loss of urothelial cell–cell adhesion and tight junction proteins and decrease in uroplakin III expression. By 12 weeks, the urothelium had regenerated and micturition patterns were similar to littermate controls. No inflammation or fibrosis were detected in bladder tissues after irradiation. We conclude that functional bladder defects during acute RC are driven primarily by a urothelial defect.

Inflammation and Barrier Function Deficits in the Bladder Urothelium of Patients with Chronic Spinal Cord Injury and Recurrent Urinary Tract Infections

“…E-cadherin, UPK-3 and ZO-1 are key factors associated with bladder barrier function and permeability. E-cadherin is an essential factor involved in the cell-cell adhesion necessary to maintain epidermal barrier function [ 23 , 24 ], the uroplakins play important roles in maintaining the urothelial apical surface and are involved in urothelial permeability, and ZO-1 is a tight junction protein expressed in the bladder urothelium [ 25 , 26 ]. Altered bladder barrier function and urothelial morphology were described in animal models of SCI [ 27 ].…”

Intravesical IR‐780 instillation prevents radiation cystitis by protecting urothelial integrity

“…The urinary mucosa initially defends the underlying muscularis propria against pathogenic, chemical, and mechanical stimuli. The biphasic effect of radiation on the urothelium is well depicted in preclinical models 15–18 . An early phase with loss of urothelium cell number was delineated before 15,16 .…”

“…The biphasic effect of radiation on the urothelium is well depicted in preclinical models. [15][16][17][18] An early phase with loss of urothelium cell number was delineated before. 15,16 Zwaans et al 17 uncovered that the expression of uroplakin 3 in umbrella cells and adherens junction protein E-cadherin decreased at 4 and 8 weeks postirradiation.…”

“…[15][16][17][18] An early phase with loss of urothelium cell number was delineated before. 15,16 Zwaans et al 17 uncovered that the expression of uroplakin 3 in umbrella cells and adherens junction protein E-cadherin decreased at 4 and 8 weeks postirradiation. Interestingly, Krischak et al 18 described the expression of E-cadherin and β-catenin compensatively increased to restore the urinary barrier in the early phase.…”

“…Interestingly, Krischak et al 18 described the expression of E‐cadherin and β‐catenin compensatively increased to restore the urinary barrier in the early phase. Urothelial hyperplasia is characterized by cell number, 15,16 Ki67, 16 EGFR, 16 uroplakin 3 17 and E‐cadherin 18 expression was observed compared with nonirradiated control by the late response phase. During the clinical course of radiation cystitis, the urothelium will also exhibit a proliferative activity dependent on irradiation dose at around 6–12 months 4 .…”