Urothelial dysfunction may be a key pathomechanism underlying interstitial cystitis/bladder pain syndrome (IC/BPS). We therefore examined if clinical severity is associated with the extent of urothelial damage as revealed by electron microscopic (EM) analysis of biopsy tissue. One hundred IC/ BPS patients were enrolled and 24 patients with stress urinary incontinence served as controls. Clinical symptoms were evaluated by visual analog scale pain score and O'Leary-Sant Symptom score. Bladder

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... psies were obtained following cystoscopic hydrodistention. The presence of Hunner's lesions and glomerulation grade after hydrodistention were recorded and patients classified as Hunner-type IC (HIC) or non-Hunner-type IC (NHIC). HIC patients exhibited more severe defects in urothelium cell layers, including greater loss of umbrella cells, umbrella cell surface uroplakin plaque, and tight junctions between adjacent umbrella cells, compared to control and NHIC groups (all p < 0.05). Both NHIC and HIC groups demonstrated more severe lamina propria inflammatory cell infiltration than controls (p = 0.011, p < 0.001, respectively). O'Leary-Sant Symptom scores were significantly higher among patients with more severe urothelial defects (p = 0.030). Thus, urothelium cell layer defects on EM are associated with greater clinical symptom severity. Interstitial cystitis/bladder pain syndrome (IC/BPS) is chronic condition characterized by frequent bladder pain, pressure, and discomfort accompanied by persistent urge to void or high urination frequency in the absence of confusable diseases 1 . Although there are no standardized diagnostic criteria, estimated prevalence of IC/BPS ranges from 0.01 to 2.3%, with higher prevalence in females 2 . In the United State, high-sensitivity assessment criteria have identified IC/BPS in 6.5% of females and 1.9% of males, while higher specificity assessments have still found IC/BPS in 2.7% of females and 1.9% of males 3, 4 . The underlying pathogenesis for IC/BPS remains unclear 1 , although several studies have suggested urothelial dysfunction as a one potential mechanism 5 . For instance, increased urothelial permeability resulting from loss of surface glycosaminoglycans 6 , and significantly reduced expression levels of the tight junction proteins zonula occludens-1 (ZO-1) and adhesive junction protein have been reported in the bladder of IC/BPS patients 7 . In addition, some patients demonstrate upregulation of the purinoceptor P2X3, which can drive sensitization of bladder afferents in response to adenosine triphosphate release from the urothelium and contribute to bladder oversensitivity 8 . According to characteristic endoscopic findings and histopathology, IC/BPS can be been divided into Hunnertype IC (HIC) and non-Hunner-type IC (NHIC) subtypes 9, 10 . Chronic inflammation and epithelial denudation are the key histological features of HIC. In contrast, NHIC patients show less severe inflammatory changes and the epithelium is usually indistinguishable from that of the normal bladder 11 . Several previous electron microscopy (EM) studies have described various ultrastructure changes in the bladder urothelium of IC/BPS patients, including defects in junctional complexes, epithelial cell pleomorphisms, loss