Elucidating Mechanisms of Bladder Repair after Hyaluronan Instillation in Ketamine-Induced Ulcerative Cystitis in Animal Model

Am J Pathol. 2017 Sep;187(9):1945-1959. doi: 10.1016/j.ajpath.2017.06.004.


Ketamine-induced ulcerative cystitis (KIC) initially damaged the bladder mucosa and induced contracted bladder thereafter. Hyaluronan (hyaluronic acid; HA) instillation to the bladder has been used to treat KIC. The present study investigated bladder injury by urothelial defect and HA degeneration and bladder repair by urothelium proliferation and differentiation. This work was based on the hypothesis that HA treatment altered the bladder urothelial layer and the expression of hyaluronan-metabolizing enzymes and/or HA receptors in KIC. Cystometrogram study and tracing analysis of voiding behavior revealed that the ketamine-treated rats exhibited significant bladder hyperactivity with an increase in micturition frequency and a decrease in bladder capacity. The expression of inflammatory and fibrosis markers was also increased in the ketamine-treated group. Moreover, ketamine administration decreased the expression of urothelial barrier-associated protein, altered HA production, and induced abnormal urothelial differentiation, which might attribute to urothelial lining defects. However, HA instillation ameliorated bladder hyperactivity, lessened bladder mucosa damage, and decreased interstitial fibrosis. HA instillation also improved the level of HA receptors (CD44, Toll-like receptor-4, and receptor for HA-mediated motility) and HA synthases 1 to 3 and decreased the expression of hyaluronidases in the urothelial layer of bladder, resulting in enhanced mucosal regeneration. These findings suggested that HA could modulate inflammatory responses, enhance mucosal regeneration, and improve urothelial lining defects in KIC.

MeSH terms

  • Animals
  • Cystitis / chemically induced
  • Cystitis / metabolism
  • Cystitis / physiopathology*
  • Disease Models, Animal
  • Female
  • Hyaluronan Receptors / metabolism
  • Hyaluronic Acid / metabolism
  • Hyaluronic Acid / pharmacology
  • Hyaluronic Acid / therapeutic use*
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation / physiopathology
  • Ketamine
  • Rats
  • Rats, Sprague-Dawley
  • Toll-Like Receptor 4 / metabolism
  • Urinary Bladder / drug effects*
  • Urinary Bladder / metabolism
  • Urinary Bladder / physiopathology
  • Urothelium / metabolism
  • Urothelium / physiopathology


  • Hyaluronan Receptors
  • Toll-Like Receptor 4
  • Ketamine
  • Hyaluronic Acid