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

Sci Rep. 2021 Sep 29;11(1):19277. doi: 10.1038/s41598-021-98303-2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / analysis
  • Cadherins / metabolism
  • Cystitis / etiology
  • Cystitis / pathology
  • Cystitis / physiopathology*
  • Female
  • Humans
  • Mice
  • Pelvic Neoplasms / radiotherapy
  • Radiation Injuries, Experimental / etiology
  • Radiation Injuries, Experimental / pathology
  • Radiation Injuries, Experimental / physiopathology*
  • Urinary Bladder / pathology*
  • Urinary Bladder / physiopathology
  • Urinary Bladder / radiation effects
  • Urination / physiology
  • Urination / radiation effects*
  • Uroplakin III / analysis
  • Uroplakin III / metabolism
  • Urothelium / pathology
  • Urothelium / radiation effects
  • Zonula Occludens-1 Protein / analysis
  • Zonula Occludens-1 Protein / metabolism

Substances

  • Cadherins
  • Cdh1 protein, mouse
  • Tjp1 protein, mouse
  • Upk3a protein, mouse
  • Uroplakin III
  • Zonula Occludens-1 Protein