{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:40:41Z","timestamp":1789342841961,"version":"build-2803163510"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:00:00Z","timestamp":1629936000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:00:00Z","timestamp":1629936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\u2019Leary-Sant Symptom score. Bladder biopsies were obtained following cystoscopic hydrodistention. The presence of Hunner\u2019s 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\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). Both NHIC and HIC groups demonstrated more severe lamina propria inflammatory cell infiltration than controls (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.011,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001, respectively). O\u2019Leary-Sant Symptom scores were significantly higher among patients with more severe urothelial defects (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.030). Thus, urothelium cell layer defects on EM are associated with greater clinical symptom severity.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-96810-w","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T06:05:29Z","timestamp":1629957929000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Difference in electron microscopic findings among interstitial cystitis\/bladder pain syndrome with distinct clinical and cystoscopic characteristics"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9325-9868","authenticated-orcid":false,"given":"Yu Khun","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Fong","family":"Jhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Hong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Hsiang","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Chen","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hann-Chorng","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,26]]},"reference":[{"key":"96810_CR1","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.eururo.2007.09.019","volume":"53","author":"JP van de Merwe","year":"2008","unstructured":"van de Merwe, J. P. et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome\/interstitial cystitis: An ESSIC proposal. Eur. Urol. 53, 60\u201367 (2008).","journal-title":"Eur. Urol."},{"key":"96810_CR2","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1111\/j.1442-2042.2009.02326.x","volume":"16","author":"Y Homma","year":"2009","unstructured":"Homma, Y. et al. Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome. Int. J. Urol. 16, 597\u2013615 (2009).","journal-title":"Int. J. Urol."},{"key":"96810_CR3","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1016\/j.juro.2011.03.132","volume":"186","author":"SH Berry","year":"2011","unstructured":"Berry, S. H. et al. Prevalence of symptoms of bladder pain syndrome\/interstitial cystitis among adult females in the United States. J. Urol. 186, 540\u2013544 (2011).","journal-title":"J. Urol."},{"key":"96810_CR4","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.juro.2012.08.088","volume":"189","author":"AM Suskind","year":"2013","unstructured":"Suskind, A. M. et al. The prevalence and overlap of interstitial cystitis\/bladder pain syndrome and chronic prostatitis\/chronic pelvic pain syndrome in men: Results of the rand interstitial cystitis Epidemiology male study. J. Urol. 189, 141\u2013145 (2013).","journal-title":"J. Urol."},{"issue":"Suppl 2","key":"96810_CR5","doi-asserted-by":"publisher","first-page":"S95","DOI":"10.5213\/inj.1632712.356","volume":"20","author":"JF Jhang","year":"2016","unstructured":"Jhang, J. F. & Kuo, H. C. Pathomechanism of interstitial cystitis\/bladder pain syndrome and mapping the heterogeneity of disease. Int. Neurourol. J. 20(Suppl 2), S95\u2013S104 (2016).","journal-title":"Int. Neurourol. J."},{"key":"96810_CR6","first-page":"638","volume":"4","author":"M Cervigni","year":"2015","unstructured":"Cervigni, M. Interstitial cystitis\/bladder pain syndrome and glycosaminoglycans replacement therapy. Transl. Androl. Urol. 4, 638\u2013642 (2015).","journal-title":"Transl. Androl. Urol."},{"issue":"225","key":"96810_CR7","first-page":"e13","volume":"80","author":"HT Liu","year":"2012","unstructured":"Liu, H. T., Shie, J. H., Chen, S. H., Wang, Y. S. & Kuo, H. C. Differences in mast cell infiltration, E-cadherin, and zonula occludens-1 expression between patients with overactive bladder and interstitial cystitis\/bladder pain syndrome. Urology 80(225), e13-225.e18 (2012).","journal-title":"Urology"},{"key":"96810_CR8","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1016\/j.urology.2009.02.066","volume":"74","author":"Y Sun","year":"2009","unstructured":"Sun, Y., Keay, S., Lehrfeld, T. J. & Chai, T. C. Changes in adenosine triphosphate-stimulated ATP release suggest association between cytokine and purinergic signaling in bladder urothelial cells. Urology 74, 1163\u20131168 (2009).","journal-title":"Urology"},{"key":"96810_CR9","first-page":"25","volume":"34","author":"Y Akiyama","year":"2019","unstructured":"Akiyama, Y., Homma, Y. & Maeda, D. Pathology and terminology of interstitial cystitis\/bladder pain syndrome: A review. Histol. Histopathol. 34, 25\u201332 (2019).","journal-title":"Histol. Histopathol."},{"key":"96810_CR10","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1097\/JU.0000000000000234","volume":"202","author":"Y Akiyama","year":"2019","unstructured":"Akiyama, Y. et al. Molecular taxonomy of interstitial cystitis\/bladder pain syndrome based on whole transcriptome profiling by next-generation RNA sequencing of bladder mucosal biopsies. J. Urol. 202, 290\u2013300 (2019).","journal-title":"J. Urol."},{"key":"96810_CR11","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1111\/iju.14234","volume":"27","author":"Y Homma","year":"2020","unstructured":"Homma, Y. et al. Clinical guidelines for interstitial cystitis\/bladder pain syndrome. Int. J. Urol. 27, 578\u2013589 (2020).","journal-title":"Int. J. Urol."},{"key":"96810_CR12","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1111\/j.1464-410X.1983.tb03354.x","volume":"55","author":"J Eldrup","year":"1983","unstructured":"Eldrup, J., Thorup, J., Nielsen, S. L., Hald, T. & Hainau, B. Permeability and ultrastructure of human bladder epithelium. Br. J. Urol. 55, 488\u2013492 (1983).","journal-title":"Br. J. Urol."},{"key":"96810_CR13","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/S0022-5347(01)67669-9","volume":"153","author":"TC Theoharides","year":"1995","unstructured":"Theoharides, T. C. et al. Activation of bladder mast cells in interstitial cystitis: A light and electron microscopic study. J. Urol. 153, 629\u2013636 (1995).","journal-title":"J. Urol."},{"key":"96810_CR14","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1111\/j.1365-2559.1984.tb02372.x","volume":"8","author":"ME Herd","year":"1984","unstructured":"Herd, M. E. & Williams, G. Scanning electron microscopy of normal, neoplastic and inflamed human bladder. Histopathology 8, 601\u2013610 (1984).","journal-title":"Histopathology"},{"key":"96810_CR15","doi-asserted-by":"publisher","first-page":"e0198816","DOI":"10.1371\/journal.pone.0198816","volume":"13","author":"JF Jhang","year":"2018","unstructured":"Jhang, J. F. et al. Electron microscopic characteristics of interstitial cystitis\/bladder pain syndrome and their association with clinical condition. PLoS ONE 13, e0198816 (2018).","journal-title":"PLoS ONE"},{"key":"96810_CR16","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1016\/j.eururo.2003.11.021","volume":"45","author":"J Nordling","year":"2004","unstructured":"Nordling, J. et al. Primary evaluation of patients suspected of having interstitial cystitis (IC). Eur. Urol. 45, 662\u2013669 (2004).","journal-title":"Eur. Urol."},{"key":"96810_CR17","doi-asserted-by":"publisher","first-page":"e0143316","DOI":"10.1371\/journal.pone.0143316","volume":"10","author":"D Maeda","year":"2015","unstructured":"Maeda, D. et al. Hunner-type (classic) interstitial cystitis: A distinct inflammatory disorder characterized by pancystitis, with frequent expansion of clonal B-Cells and epithelial denudation. PLoS ONE 10, e0143316 (2015).","journal-title":"PLoS ONE"},{"key":"96810_CR18","doi-asserted-by":"publisher","first-page":"1451.e7","DOI":"10.1016\/j.urology.2013.08.042","volume":"82","author":"JD Lee","year":"2013","unstructured":"Lee, J. D. & Lee, M. H. Activation of extrinsic apoptotic pathway from bladder biopsy in patients with interstitial cystitis\/painful bladder syndrome. Urology 82, 1451.e7-1451.11 (2013).","journal-title":"Urology"},{"key":"96810_CR19","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1111\/bju.14097","volume":"121","author":"KJ Ko","year":"2018","unstructured":"Ko, K. J. et al. Therapeutic effects of endoscopic ablation in patients with Hunner type interstitial cystitis. BJU Int. 121, 659\u2013666 (2018).","journal-title":"BJU Int."},{"issue":"Suppl 1","key":"96810_CR20","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1111\/iju.12320","volume":"21","author":"HJ Kim","year":"2014","unstructured":"Kim, H. J. et al. Efficacy and safety of augmentation ileocystoplasty combined with supratrigonal cystectomy for the treatment of refractory bladder pain syndrome\/interstitial cystitis with Hunner\u2019s lesion. Int. J. Urol. 21(Suppl 1), 69\u201373 (2014).","journal-title":"Int. J. Urol."},{"key":"96810_CR21","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/S0090-4295(01)01166-9","volume":"57","author":"JE Tomaszewski","year":"2001","unstructured":"Tomaszewski, J. E. et al. Biopsy features are associated with primary symptoms in interstitial cystitis: results from the interstitial cystitis database study. Urology 57, 67\u201381 (2001).","journal-title":"Urology"},{"key":"96810_CR22","doi-asserted-by":"publisher","first-page":"1864","DOI":"10.1016\/j.juro.2014.06.081","volume":"192","author":"Y Funahashi","year":"2014","unstructured":"Funahashi, Y. et al. Intravesical application of rebamipide promotes urothelial healing in a rat cystitis model. J. Urol. 192, 1864\u20131870 (2014).","journal-title":"J. Urol."},{"key":"96810_CR23","first-page":"1242","volume":"20","author":"YS Lv","year":"2017","unstructured":"Lv, Y. S. et al. The role of TSG-6 and uroplakin III in bladder pain syndrome\/interstitial cystitis in rats and humans. Iran. J. Basic Med. Sci. 20, 1242\u20131249 (2017).","journal-title":"Iran. J. Basic Med. Sci."},{"key":"96810_CR24","doi-asserted-by":"publisher","first-page":"304","DOI":"10.4111\/icu.2020.61.3.304","volume":"61","author":"KJ Cho","year":"2020","unstructured":"Cho, K. J., Lee, K. S., Choi, J. B., Koh, J. S. & Kim, J. C. Changes in uroplakin expression in the urothelium of patients with ulcerative interstitial cystitis\/bladder pain syndrome. Investig. Clin. Urol. 61, 304\u2013309 (2020).","journal-title":"Investig. Clin. Urol."},{"key":"96810_CR25","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1016\/j.juro.2007.05.125","volume":"178","author":"Y Zeng","year":"2007","unstructured":"Zeng, Y. et al. Uroplakin III-delta4 messenger RNA as a promising marker to identify nonulcerative interstitial cystitis. J. Urol. 178, 1322\u20131327 (2007) (discussion 1327).","journal-title":"J. Urol."},{"key":"96810_CR26","first-page":"F886","volume":"271","author":"HO Negrete","year":"1996","unstructured":"Negrete, H. O., Lavelle, J. P., Berg, J., Lewis, S. A. & Zeidel, M. L. Permeability properties of the intact mammalian bladder epithelium. Am. J. Physiol. 271, F886\u2013F894 (1996).","journal-title":"Am. J. Physiol."},{"key":"96810_CR27","first-page":"F243","volume":"271","author":"ML Zeidel","year":"1996","unstructured":"Zeidel, M. L. Low permeabilities of apical membranes of barrier epithelia: What makes watertight membranes watertight?. Am. J. Physiol. 271, F243\u2013F245 (1996).","journal-title":"Am. J. Physiol."},{"key":"96810_CR28","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1152\/physrev.1995.75.3.561","volume":"75","author":"SA Lewis","year":"1995","unstructured":"Lewis, S. A., Berg, J. R. & Kleine, T. J. Modulation of epithelial permeability by extracellular macromolecules. Physiol. Rev. 75, 561\u2013589 (1995).","journal-title":"Physiol. Rev."},{"key":"96810_CR29","doi-asserted-by":"publisher","first-page":"F540","DOI":"10.1152\/ajprenal.2000.278.4.F540","volume":"278","author":"JP Lavelle","year":"2000","unstructured":"Lavelle, J. P. et al. Urothelial pathophysiological changes in feline interstitial cystitis: A human model. Am. J. Physiol. Ren. Physiol. 278, F540\u2013F553 (2000).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"96810_CR30","doi-asserted-by":"publisher","first-page":"F242","DOI":"10.1152\/ajprenal.00307.2001","volume":"283","author":"J Lavelle","year":"2002","unstructured":"Lavelle, J. et al. Bladder permeability barrier: Recovery from selective injury of surface epithelial cells. Am. J. Physiol. Ren. Physiol. 283, F242\u2013F253 (2002).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"96810_CR31","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1097\/01.ju.0000135009.55905.cb","volume":"172","author":"M Tamaki","year":"2004","unstructured":"Tamaki, M., Saito, R., Ogawa, O., Yoshimura, N. & Ueda, T. Possible mechanisms inducing glomerulations in interstitial cystitis: Relationship between endoscopic findings and expression of angiogenic growth factors. J. Urol. 172, 945\u2013948 (2004).","journal-title":"J. Urol."},{"key":"96810_CR32","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1111\/j.1464-410X.2009.08467.x","volume":"104","author":"H Kiuchi","year":"2009","unstructured":"Kiuchi, H. et al. Increased vascular endothelial growth factor expression in patients with bladder pain syndrome\/interstitial cystitis: Its association with pain severity and glomerulations. BJU Int. 104, 826\u2013831 (2009) (discussion 831).","journal-title":"BJU Int."},{"key":"96810_CR33","first-page":"624","volume":"4","author":"G Ens","year":"2015","unstructured":"Ens, G. & Garrido, G. L. Role of cystoscopy and hydrodistention in the diagnosis of interstitial cystitis\/bladder pain syndrome. Transl. Androl. Urol. 4, 624\u2013628 (2015).","journal-title":"Transl. Androl. Urol."},{"key":"96810_CR34","first-page":"555","volume":"4","author":"R Saban","year":"2015","unstructured":"Saban, R. Angiogenic factors, bladder neuroplasticity and interstitial cystitis-new pathobiological insights. Transl. Androl. Urol. 4, 555\u2013562 (2015).","journal-title":"Transl. Androl. Urol."},{"key":"96810_CR35","doi-asserted-by":"publisher","first-page":"F36","DOI":"10.1152\/ajprenal.00075.2017","volume":"315","author":"W Yang","year":"2018","unstructured":"Yang, W., Searl, T. J., Yaggie, R., Schaeffer, A. J. & Klumpp, D. J. A MAPP Network study: Overexpression of tumor necrosis factor-\u03b1 in mouse urothelium mimics interstitial cystitis. Am. J. Physiol. Renal Physiol. 315, F36\u2013F44 (2018).","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"96810_CR36","doi-asserted-by":"publisher","first-page":"F741","DOI":"10.1152\/ajprenal.00081.2006","volume":"291","author":"MC Chen","year":"2006","unstructured":"Chen, M. C., Mudge, C. S. & Klumpp, D. J. Urothelial lesion formation is mediated by TNFR1 during neurogenic cystitis. Am. J. Physiol. Renal Physiol. 291, F741\u2013F749 (2006).","journal-title":"Am. J. Physiol. Renal Physiol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96810-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96810-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96810-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T08:07:43Z","timestamp":1670054863000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96810-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,26]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["96810"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-96810-w","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.740707707.793588445","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,26]]},"assertion":[{"value":"5 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17258"}}