What’s known on the subject? and What does the study add? Interstitial cystitis/painful bladder syndrome (IC/PBS) is considered to result from long‐standing inflammation of the bladder. Urothelial dysfunction and increased urothelial permeability are known to result in clinical symptoms such as pain and urgency, however the actual pathophysiology remains unclear. This study demonstrated increased cell apoptosis, decreased cell proliferation, increased mast cell activation, and impaired expression of E‐cadherin were significant in IC/PBS bladders. There was a significant correlation between mast cell activation and urothelial cell apoptosis and the reduced E‐cadherin expression was significantly correlated with clinical pain VAS scale, suggesting the barrier defect of the bladder wall may lead to increasing bladder sensitivity and pain. OBJECTIVE • To investigate the relationships between suburothelial inflammation and urothelial dysfunction in interstitial cystitis/painful bladder syndrome (IC/PBlS). MATERIALS AND METHODS • Immunofluorescence staining of ki‐67 (to assess cell proliferation), junction protein E‐cadherin, tryptase (to assess mast cell activation) and TUNEL (to assess urothelial apoptosis) were performed in bladder tissues from 20 patients with IC/PBlS and from 6 control patients. • The fluorescence intensity of E‐cadherin was measured using the ImageJ method. • The percentage of apoptotic cells, proliferated cells and activated mast cells were measured and quantified as positive cells (±SD) per area unit (4 µm2). RESULTS • The ratio of ki‐67‐positive cells in the bladder tissue of the patients with IC/PBlS was significantly down‐regulated compared with that of the control patients (0.559 ± 0.658 vs. 1.23 ± 1.28, P= 0.001). • TUNEL staining revealed a significantly higher number of apoptotic cells in the IC/PBlS bladder tissue compared with control bladder tissue (2.26 ± 2.04 v 0.051 ± 0.124, P= 0.000). • The tryptase signal was significantly stronger in the IC/PBlS bladder tissue compared with that of control patients (6.16 ± 4.35 v 1.15 ± 0.436, P= 0.000). • The apoptotic cell number in IC/PBlS bladder tissue correlated significantly with mast cell activation (P= 0.021). • Immunofluorescence also showed a significantly lower distribution of E‐cadherin in IC/PBlS bladder tissue compared with that of control patients (8.50 ± 6.83 v 17.2 ± 11.9, P= 0.000). • Lower expression of E‐cadherin in IC/PBlS bladder tissue was significantly correlated with higher visual analogue pain scores in patients with IC/PBlS (P= 0.008). CONCLUSIONS • The results of the present study suggest that urothelial homeostasis in IC/PBlS bladders was impaired, and abnormal urothelial function was significantly associated with chronic inflammation. • The junctions between urothelial cells in IC/PBlS bladders were abnormal, which was associated with the patient’s self‐report pain scales.

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What's known on the subject? and What does the study add? A single set of botulinum toxin A (BoNT‐A) injections relieves clinical symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), but lacks long‐term effect. An inadequate anti‐inflammatory effect is likely to cause treatment failure. The study shows that chronic inflammation and apoptotic signalling molecules are significantly reduced after repeated intravesical BoNT‐A injection in patients with IC/BPS. It also shows that repeated BoNT‐A injections are necessary to achieve greater success in the treatment of IC/BPS. Objective To investigate the mechanisms of action of botulinum toxin A (BoNT‐A) treatment on interstitial cystitis/bladder pain syndrome (IC/BPS). Patients and Methods A total of 23 women with IC/BPS who received single intravesical BoNT‐A injection were studied. Among them, 11 received three repeated injections every 6 months to improve their symptoms. Bladder biopsy was obtained before each BoNT‐A injection and the clinical symptoms and urodynamic variables were recorded. Immunohistochemical (IHC) staining for TUNEL and mast cell activity, and western blotting analysis of tryptase, cytokines, Bax and phospho‐p38 (p‐p38) were carried out. We compared the clinical results and IHC data among baseline, single or repeated BoNT‐A treatments. Results Single BoNT‐A injection improved clinical symptoms, pain score and daytime urinary frequency. Mast cell activity and apoptotic cell count did not decrease significantly, while Bax and p‐p38, but not tryptase, decreased significantly after a single BoNT‐A injection. The 11 patients who received three repeated BoNT‐A injections had significantly lower pain scores than the remaining patients (mean [SD]: 5.80 [2.27] vs. 3.03 [2.30], P = 0), glomerulation degree (mean [SD]: 1.80 [1.06] vs. 1.20 [1.06], P = 0.026) and global response scores (mean [SD]: 0.30 [0.92] vs. 1.20 [1.06], P = 0) after treatment. Tryptase, Bax, p‐p38 and apoptotic cell counts all decreased significantly. 25‐kD synaptosomal‐associated protein also decreased after BoNT‐A treatments, which confirmed the therapeutic effect of repeated BoNT‐A injections. Conclusions Chronic inflammation and apoptotic signalling molecules were significantly reduced after repeated BoNT‐A injections in patients with IC/BPS. The IHC improvement was associated with clinical symptom improvement. Repeated BoNT‐A injections are necessary to achieve a greater success rate in the treatment of IC/BPS.

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