Interstitial cystitis/bladder pain syndrome (IC/BPS) is a heterogeneous condition of uncertain etiology. We assessed bladder collagen characteristics in phenotypically characterized IC/BPS patient subgroups that may influence pathophysiology. Forty-four females (30 IC/BPS; 14 non-IC/BPS) were included. Patients were divided into groups based on Hunner lesions (HL; N=14 or non-HL; N=16) and anesthetic bladder capacity (BC) (BC≤500 cc; low BC; N=17 or BC>500 cc; non-low BC; N=13). Bladder biopsy tissue slides were stained with hematoxylin and eosin or picrosirius red and semi-quantitatively analyzed by a pathologist. CT-FIRE software was used to quantitatively assess lamina propria collagen. All patients with IC/BPS had lower collagen fiber density independent of subgroup (p<0.0001–0.0038) compared to controls. HL had more peri-muscular collagen accumulation (p=0.0061), more acute inflammation (p=0.0364), more severe chronic inflammation (p=0.0088), and narrower collagen fibers than non-HL and controls. Non-low-BC patients had lower collagen density (p=0.0075) and straighter collagen fibers (p=0.0127) than low BC. Low-BC patients had narrower collagen fibers than control (p=0.0096). IC/BPS, regardless of subgroup, is associated with a bladder lamina propria with diminished collagen density. HL, non-low-BC, and low-BC subgroups have unique collagen characteristics. These findings suggest a collagen fiber destruction and redistribution process, which differs by subgroup, and may contribute to pathophysiology of IC/BPS:
BerrySHElliottMNSuttorpMBogartLMStotoMAEggersPNybergLClemensJQ.Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol. 2011;186(2):540–4. doi:10.1016/j.juro.2011.03.132.
2.
TungAHeppZBansalADevineEB.Characterizing health care utilization, direct costs, and comorbidities associated with interstitial cystitis: a retrospective claims analysis. J Manag Care Spec Pharm. 2017;23(4):474–82. doi:10.18553/jmcp.2017.23.4.474.
3.
PayneCKJoyceGFWiseMClemensJQ, Urologic Diseases in America P. Interstitial cystitis and painful bladder syndrome. J Urol. 2007;177(6):2042–9. doi:10.1016/j.juro.2007.01.124.
4.
VillaltaDOstardoEBuzzuliniF.Interstitial cystitis: another rotation of the kaleidoscope of autoimmunity. Autoimmun Rev. 2016;15(12):1203–4. doi:10.1016/j.autrev.2016.05.001.
5.
ParsonsCLGreenbergerMGabalLBidairMBarmeG.The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol. 1998;159(6):1862–6; discussion 6–7. doi:10.1016/S0022-5347(01)63178-1.
6.
LaiHHGardnerVNessTJGereauRW4th. Segmental hyperalgesia to mechanical stimulus in interstitial cystitis/bladder pain syndrome: evidence of central sensitization. J Urol. 2014;191(5):1294–9. doi:10.1016/j.juro.2013.11.099.
7.
AydoganTBGurpinarOEserOKMathykBAErgenA.A new look at the etiology of interstitial cystitis/bladder pain syndrome: extraordinary cultivations. Int Urol Nephrol. 2019;51(11):1961–7. doi:10.1007/s11255-019-02248-5.
8.
SandbergMWolffDTWhitmanWBadlaniGMatthewsCAEvansRWalkerSJ.Bladder capacity as a benchmark for patient stratification in interstitial cystitis/bladder pain syndrome. Continence. 2023;8:101051. doi:10.1016/j.cont.2023.101051.
9.
FallMNordlingJCervigniMDinis OliveiraPFarielloJHannoPKåbjörn-GustafssonCLogadottirYMeijlinkJMishraNMoldwinRNastaLQuaghebeurJRatnerVSairanenJTanejaRTomoeHUedaTWennevikGWhitmoreKWyndaeleJJZaitcevA.Hunner lesion disease differs in diagnosis, treatment and outcome from bladder pain syndrome: an ESSIC working group report. Scand J Urol. 2020;54(2):91–8. doi:10.1080/21681805.2020.1730948.
10.
SchacharJSEvansRJParksGEZambonJBadlaniGWalkerSJ.Histological evidence supports low anesthetic bladder capacity as a marker of a bladder-centric disease subtype in interstitial cystitis/bladder pain syndrome. Int Urogynecol J. 2019;30(11):1863–70. doi:10.1007/s00192-019-04038-0.
11.
ColacoMKoslovDSKeysTEvansRJBadlaniGHAnderssonKEWalkerSJ.Correlation of gene expression with bladder capacity in interstitial cystitis/bladder pain syndrome. J Urol. 2014;192(4):1123–9. doi:10.1016/j.juro.2014.05.047.
12.
FryCHKitneyDGPanikerJDrakeMJKanaiAAnderssonKE.Fibrosis and the bladder, implications for function ICI-RS 2017. Neurourol Urodyn. 2018;37(S4):S7–12. doi:10.1002/nau.23725
13.
KimAHanJYRyuCMYuHYLeeSKimYJeongSUChoYMShinDMChooMS.Histopathological characteristics of interstitial cystitis/bladder pain syndrome without Hunner lesion. Histopathology. 2017;71(3):415–24. doi:10.1111/his.13235.
14.
KastrupJHaldTLarsenSNielsenVG.Histamine content and mast cell count of detrusor muscle in patients with interstitial cystitis and other types of chronic cystitis. Br J Urol. 1983;55(5):495–500. doi:10.1111/j.1464-410x.1983.tb03356.x.
15.
HannoPMEricksonDMoldwinRFaradayMM, American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545–53. doi:10.1016/j.juro.2015.01.086.
16.
JunqueiraLCBignolasGBrentaniRR.Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J. 1979;11(4):447–55. doi:10.1007/BF01002772.
17.
ZwaansBMMWegnerKABartoloneSNVezinaCMChancellorMBLambLE. Radiation cystitis modeling: a comparative study of bladder fibrosis radio-sensitivity in C57BL/6, C3H, and BALB/c mice. Physiol Rep. 2020;8(4):e14377. doi:10.14814/phy2.14377.
18.
WegnerKAKeikhosraviAEliceiriKWVezinaCM.Fluorescence of picrosirius red multiplexed with immunohistochemistry for the quantitative assessment of collagen in tissue sections. J Histochem Cytochem. 2017;65(8):479–90. doi:10.1369/0022155417718541.
19.
BredfeldtJSLiuYPehlkeCAConklinMWSzulczewskiJMInmanDRKeelyPJNowakRDMackieTREliceiriKW.Computational segmentation of collagen fibers from second-harmonic generation images of breast cancer. J Biomed Opt. 2014;19(1):16007. doi:10.1117/1.JBO.19.1.016007.
20.
RuettenHWegnerKARomeroMFWoodMWMarkerPCStrandDColopySAVezinaCM.Prostatic collagen architecture in neutered and intact canines. Prostate. 2018;78(11):839–48. doi:10.1002/pros.23641.
21.
RuettenHSandhuJMuellerBWangPZhangHLWegnerKACadenaMSandhuSAblerLZhuJO’DriscollCAChelgrenBWangZShenTBaraschJBjorlingDEVezinaCM.A uropathogenicE.coli UTI89 model of prostatic inflammation and collagen accumulation for use in studying aberrant collagen production in the prostate. Am J Physiol Renal Physiol. 2021;320(1):F31–46. doi:10.1152/ajprenal.00431.2020.
22.
RuettenHMLankfordSSAbdolmalekiASEdenhofferNBadlaniGWilliamsJK.Local tissue response to a C-X-C motif chemokine ligand 12 therapy for fecal incontinence in a rabbit model. Am J Physiol Gastrointest Liver Physiol. 2025;328(2):G136–44. doi:10.1152/ajpgi.00343.2024.
23.
SheaMPO’LearyKAWegnerKAVezinaCMSchulerLA.High collagen density augments mTOR-dependent cancer stem cells in ERalpha+ mammary carcinomas, and increases mTOR-independent lung metastases. Cancer Lett. 2018;433:1–9. doi:10.1016/j.canlet.2018.06.025.
24.
JhangJFHsuYHJiangYHHoHCKuoHC.Clinical Relevance of bladder histopathological findings and their impact on treatment outcomes among patients with interstitial cystitis/bladder pain syndrome: an investigation of the European society for the study of interstitial cystitis histopathological classification. J Urol. 2021;205(1):226–35. doi:10.1097/JU.0000000000001334.
25.
AkiyamaYMorikawaTMaedaDShintaniYNiimiANomiyaANakayamaAIgawaYFukayamaMHommaY.Increased CXCR3 expression of infiltrating plasma cells in Hunner type interstitial cystitis. Sci Rep. 2016;6:28652. doi:10.1038/srep28652.
26.
AkiyamaYSoneharaKMaedaDKatohHNaitoTYamamotoKBiobank JapanPMorisakiTIshikawaSUshikuTKumeHHommaYOkadaY.Genome-wide association study identifies risk loci within the major histocompatibility complex region for Hunner-type interstitial cystitis. Cell Rep Med. 2023;4(7):101114. doi:10.1016/j.xcrm.2023.101114.
27.
WalkerSJPlairAHemalKLangefeldCDMatthewsCBadlaniGZambonJHeathHEvansRJ.Bladder hydrodistention does not result in a significant change in bladder capacity for interstitial cystitis/bladder pain syndrome patients. Urology. 2019;132:81–6. doi:10.1016/j.urology.2019.06.031.
28.
MazeaudCRigaudJLevesqueAMadecFXLe ClercQCWackMLe NormandLRiantTPerrouin-VerbeMA.Stratification of patients with interstitial cystitis/bladder pain syndrome according to the anatomical bladder capacity. Urology. 2019;123:87–92. doi:10.1016/j.urology.2018.07.046.
29.
MatthewsCAEschenroederABadlaniGEvansRWalkerSJ.Evaluation of the efficacy of postmortem human bladder tissue as a normal comparator for case-controlled gene expression studies in urology. Neurourol Urodyn. 2017;36(4):1076–80. doi:10.1002/nau.23097.
