Modeling of chronic radiation-induced cystitis in mice

Abstract

PurposeRadiation cystitis (RC), a severe inflammatory bladder condition, develops as a side effect of pelvic radiation therapy in cancer patients. There are currently no effective therapies to treat RC, in part from the lack of preclinical model systems. In this study, we developed a mouse model for RC and used a Small Animal Radiation Research Platform to simulate the targeted delivery of radiation as used with human patients.Methods and materialsTo induce RC, C3H mice received a single radiation dose of 20 Gy delivered through 2 beams. Mice were subjected to weekly micturition measurements to assess changes in urinary frequency. At the end of the study, bladder tissues were processed for histology.ResultsRadiation was well-tolerated; no change in weight was observed in the weeks after treatment, and there was no hair loss at the irradiation sites. Starting at 17 weeks after treatment, micturition frequency was significantly higher in irradiated mice versus control animals. Pathological changes include fibrosis, inflammation, urothelial thinning, and necrosis. At a site of severe insult, we observed telangiectasia, absence of uroplakin-3 and E-cadherin relocalization.ConclusionsWe developed an RC model that mimics the human pathology and functional changes. Furthermore, radiation exposure attenuates the urothelial integrity long-term, allowing for potential continuous irritability of the bladder wall from exposure to urine. Future studies will focus on the underlying molecular changes associated with this condition and investigate novel treatment strategies.

Radiation cystitis modeling: A comparative study of bladder fibrosis radio‐sensitivity in C57BL/6, C3H, and BALB/c mice

“…A statistically significant lower bodyweight is observed in irradiated C3H mice in comparison to littermate controls starting at 20 weeks post-radiation ( Figure S1a). This has not previously been observed by us or other groups in C3H mice after irradiation (Zwaans et al, 2016). By 12 weeks post-radiation, graying of the fur, or minor hair loss appears at the site of entry and exit beam in C57BL/6 and C3H mice, respectively, and remains visible until the end of the study ( Figure S1b).…”

“…In this study, we show that radiation increases micturition frequency and decreases primary and average individual void size in C57BL/6 and, in a lesser extent, in BALB/c mice. While our methodology was not suitable to measure micturition patterns in C3H mice, previous studies have demonstrated altered micturition frequency in C3H mice after radiation (Lundbeck, Nielsen, & Stewart, ; Lundbeck, Oussoren, & Stewart, ; Zwaans et al, ). These changes are consistent with a functional decrease in bladder capacity.…”

“…First, the C3H mouse strain was destructive to the filter paper during void spot assay and therefore are not a good strain for the methodology used here. In a previous study, we measured micturition frequency in C3H mice post‐irradiation using a pH sensitive paper covered by a metal grid for an overnight study (16 hr) during which mice had unlimited access to food and water (Zwaans et al, ). Here, we did see an increase in micturition frequency starting at 17 weeks post‐irradiation.…”

“…Chronic inflammation and subsequent tissue damage is one trigger for tissue fibrosis. Factors that give rise to chronic bladder inflammation include radiation therapy (e.g., RC), chemical exposure (e.g., cyclophosphamide or ketamine cystitis), old age, diabetes, genetics, or through unknown causes (e.g., interstitial cystitis) (Droller, Saral, & Santos, ; Gharaee‐Kermani et al, ; Ikeda et al, ; Wang et al, ; Zwaans et al, ).…”

“…Several laboratories are developing preclinical models to identify pathways involved in RC and its fibrotic sequelae with the goal of formulating novel therapeutics (Ikeda et al, ; Jaal & Dorr, ; Zwaans et al, ). Many laboratories use mice as experimental models, but no study has compared bladder radio‐sensitivity across mouse strains.…”