Changes to the bladder epithelial barrier are associated with ketamine-induced cystitis

Abstract

The aim of the present study was to investigate the changes of the bladder epithelial barrier in the pathogenesis of ketamine-induced cystitis (KIC). A total of 60 female mice were randomly allocated into control and ketamine groups, which received daily intraperitoneal injections of saline and ketamine, respectively. Micturition behavior was recorded in 2-h intervals at the end of 4, 8 and 12 weeks, and bladders were harvested for subsequent analyses. Routine hematoxylin and eosin staining was performed on the bladders and histopathological changes were analyzed using light microscopy. The distribution of zonula occludens-1 (ZO-1) protein was determined by immunohistochemical analysis. The ultrastructure of umbrella cells was observed using a transmission electron microscope (TEM). Ketamine-addicted mice exhibited a significantly increased frequency of micturitions following 8 and 12 weeks of ketamine treatment (P<0.05 and P<0.01, respectively). Suburothelial congestion and infiltration of mononuclear cells was observed in ketamine-addicted mice following 8 and 12 weeks of treatment. Immunohistochemical examination demonstrated that there was an increased abnormal distribution of ZO-1 in the bladders of ketamine-treated mice compared with control mice. TEM analysis demonstrated that the surface of bladder urothelium became flattened, the tight junctions between umbrella cells became thinner and the endothelial cells exhibited cell body shrinkage, chromatin condensation and layer denudation in mice treated with ketamine. The present study indicated that the structural and functional changes to the bladder epithelial barrier caused by long-term use of ketamine may be key mechanisms in the development of KIC.

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

“…The present results suggested that high-dosage long-term ketamine administration promoted inflammatory cell infiltration and vascular congestion in the submucosal layer of the bladder, which were observed in patients with long-term ketamine abuse ( 39 , 40 ). Although the induced inflammatory response was not present in all mice, the pathological outcome was consistent with previous studies using an identical mouse strain, C57BL/6, and a similar ketamine regimen, 100 mg/kg/day ( 10 , 41 ). However, previous studies performed on rat models identified a pronounced and consistent inflammatory response ( 7 , 42 ).…”

Comparison of Intravesical Hyaluronic Acid, Chondroitin Sulfate, and Combination of Hyaluronic Acid-Chondroitin Sulfate Therapies in Animal Model of Interstitial Cystitis

“…ZO-1 has been accepted as a specific and sensitive biomarker for IC patients [ 24 ]. In a ketamine-induced IC model, Duan et al [ 25 ] detected that the abnormal distribution of ZO-1 proteins after 8 weeks was 90%, as opposed to 0% in the control group. We showed that abnormal expression of ZO-1 was significantly higher in group II than in groups I, III, and V.…”

Molecular pathways underlying tissue injuries in the bladder with ketamine cystitis

“…Urothelium barrier dysfunction is proposed as a major mechanism in the pathogenesis of KC 12,14‐16,21 . The barrier function comprises multiple defensive molecules including glycosaminoglycans (GAGs), uroplakin plaques, and tight and adherent junctions 15,22 .…”

“…Previous studies reported that a contracted bladder with urothelium denudation and lamina propria fibrosis and inflammation were the common pathological features 10‐12 . The urothelium is in direct contact with ketamine and its metabolites in the urine, and has been shown to suffer a loss of junction proteins such as zonula occludens (ZO)‐1 and E‐cadherin and to become more apoptotic 13‐16 . Based on these findings and the urothelium pathological features, urothelial barrier dysfunction has been indicated as the major pathogenesis of KC.…”