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

Abstract

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.

Ba‐Wei‐Die‐Huang‐Wan (Hachimi‐jio‐gan) can ameliorate ketamine‐induced cystitis by modulating neuroreceptors, inflammatory mediators, and fibrogenesis in a rat model

“…In severe cases of KIC, augmentation enterocystoplasty might be beneficial in relieving refractory KIC pain and urinary symptoms but with a high risk of perioperative morbidity and long‐term complications . Researchers have attempted to develop experimental therapeutic strategies to treat KIC in patients or in animal models, including intravesical instillation of hyaluronic acid for protecting the bladder mucosa and applications of botulinum toxin A for inhibiting bladder neurotransmission. Nevertheless, the pathogenesis of KIC is complex and may result from direct toxic effects, bladder barrier dysfunction, neurogenic inflammation, and autoimmune reactions .…”

What urologists need to know about ketamine‐induced uropathy: A systematic review

“…Therefore, glycosaminoglycan instillation can achieve relief of pain, frequency, and hematuria in patients without signs of fibrosis nor complications involving the upper urinary tract. This result is probably related to the restoration of urothelium barrier function, the enhanced mucosal regeneration and the decreased interstitial fibrosis 79 …”

Ketamine‑induced bladder dysfunction is associated with extracellular matrix accumulation and impairment of calcium signaling in a mouse model

“…Previous studies using Sprague Dawley (SD) rats have demonstrated that TGF-β1 signaling (48) and EMT (9) are associated with ketamine-induced fibrosis. Furthermore, injection of human umbilical cord blood-derived mesenchymal stem cells or antifibrotic compounds, including N-acetylcysteine (49) and hyaluronic acid (50), in SD rat bladder tissue have been demonstrated to decrease fibrosis by inactivating TGF-β signaling. However, TGF-β-associated genes were unaltered in the present microarray analysis.…”