Reviewing Interstitial CystitisModels and Treatments: A Focus on the Urothelium

Author

Orthopaedic Trauma Institute, San Francisco General Hospital, University of California, San Francisco, USA

Abstract

Abstract Context: Interstitial cystitis is amultifactorial chronic and debilitating disease which is commonly associated with pain localized in the bladder region, increased urinary frequency, urgency and nocturia. Due to the high prevalence of pain in the population affectedmore recently the condition is often referred to as interstitial cystitis / bladder pain syndrome (IC/BPS). Evidence Acquisition: Although IC presentswithmany different symptoms, researchers have formulated three different theories, which are notmutually exclusive, to explain IC pathology: the first is related to the alteration of the proteoglycan and protein junc- tion composition, structure and presence in the urothelium. The second is an immune induced IC resulting from an increased number of activated mast cells in the bladder internal layers, such as detrusor muscle (DM), and mucosa/submucosa. The third type, which is closely related to the second one, is due to a sensory nerve sensitization as an effect of neurotrophic factorsmolecule release. Results: Previous classification has beenmirrored in the development of various in vitro and in vivo diseasemodels created tomimic IC, aswell as in the available therapies used to treat the condition to date. Conclusions: This reviewwill summarize themost recent advances in the field, related to the different causative factors contributing to the development of the condition, the in vivomodels used as well as the evidence they provide in advancing our knowledge and their limitations. The focus will be on works report- ing on IC in the domain related to alterations in proteoglycans and cellular junction, specifically their composition, structure and appearance in the urothelium, and also discuss present and future therapies. Conclusions: This reviewwill summarize themost recent advances in the field, related to the different causative factors contribut- ing to the development of the condition, the in vivomodels used as well as the evidence they provide in advancing our knowledge and their limitations. The focus will be on works reporting on IC in the domain related to alterations in proteoglycans and cellular junction, specifically their composition, structure and appearance in the urothelium, and also discuss present and future therapies.

Keywords


  1. 1.Clauw DJ, Schmidt M, Radulovic D, Singer A, Katz P, Bresette J. The relationship between fibromyalgia and interstitial cystitis. J Psychiatr Res. 1997;31(1):125–31. doi: 10.1016/S0022-3956(96)00051-9. [PubMed: 9201654].

    1. Oravisto KJ. Epidemiology of interstitial cystitis. Ann Chir Gynaecol Fenn. 1975;64(2):75–7. [PubMed: 1137336].
    2. Lifford KL, Curhan GC. Prevalence of painful bladder syndrome in older women. Urology. 2009;73(3):494–8. doi: 10.1016/j.urology.2008.01.053. [PubMed: 19118882].
    3. Koziol JA. Epidemiology of interstitial cystitis. Urol Clin North Am. 1994;21(1):7–20. [PubMed: 8284848].
    4. Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28- 29, 1987. J Urol. 1988;140(1):203–6. doi: 10.1016/S0022-5347(17)41529-1. [PubMed: 3379688].
    5. Hanno PM, Landis JR, Matthews-Cook Y, Kusek J, Nyberg LJ. The diagnosis of interstitial cystitis revisited: lessons learned from the National Institutes of Health Interstitial Cystitis Database study. J Urol. 1999;161(2):553–7. doi: 10.1016/S0022-5347(01)61948-7. [PubMed: 9915447].
    6. Peeker R, Fall M. Treatment guidelines for classic and non-ulcer interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct. 2000;11(1):23–32. doi: 10.1007/s001920050006. [PubMed: 10738931].
    7. Fall M, Logadottir Y, Peeker R. Interstitial cystitis is bladder pain syndrome with Hunner’s lesion. Int J Urol. 2014;21 Suppl 1:79–82. doi: 10.1111/iju.12325. [PubMed: 24807507].
    8. Hand JR. Interstitial cystitis; report of 223 cases (204 women and 19 men). J Urol. 1949;61(2):291–310. doi: 10.1016/S0022-5347(17)69067-0. [PubMed: 18111850].
    9. Chennamsetty A, Ehlert MJ, Peters KM, Killinger KA. Advances in diagnosis and treatment of interstitial cystitis/painful bladder syndrome. Curr Infect Dis Rep. 2015;17(1):454. doi: 10.1007/s11908-014-0454- 5. [PubMed: 25416849].
    10. Chelimsky G, Heller E, Buffington CA, Rackley R, Zhang D, Chelimsky T. Co-morbidities of interstitial cystitis. Front Neurosci. 2012;6:114. doi: 10.3389/fnins.2012.00114. [PubMed: 22907988].
    11. Griffiths D, Hofner K, van Mastrigt R, Rollema HJ, Spangberg A, Gleason D. Standardization of terminology of lower urinary tract function: pressure-flow studies of voiding, urethral resistance, and urethral obstruction. International Continence Society Subcommittee on Standardization of Terminology of Pressure-Flow Studies. Neurourol Urodyn. 1997;16(1):1–18. doi: 10.1002/(SICI)1520- 6777(1997)16:1<_x0031_:_x003a_AID-NAU1>3.0.CO;2-I. [PubMed: 9021786].
    12. Birder L, Andersson KE. Urothelial signaling. Physiol Rev. 2013;93(2):653–80. doi: 10.1152/physrev.00030.2012. [PubMed: 23589830].
    13. Apodaca G. The uroepithelium: not just a passive barrier. Traffic. 2004;5(3):117–28. doi: 10.1046/j.1600-0854.2003.00156.x. [PubMed: 15086788].
    14. Sun TT. Altered phenotype of cultured urothelial and other stratified epithelial cells: implications for wound healing. Am J Physiol Renal Physiol. 2006;291(1):F9–21. doi: 10.1152/ajprenal.00035.2006. [PubMed: 16609152]. 12 Razavi Int J Med. 2017; 5(4):e64551. Federico F
    15. Hicks RM. The mammalian urinary bladder: an accommodating organ. Biol Rev Camb Philos Soc. 1975;50(2):215–46. doi: 10.1111/j.1469- 185X.1975.tb01057.x. [PubMed: 1100129].
    16. Hurst RE, Roy JB, Min KW, Veltri RW, Marley G, Patton K, et al. A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis. Urology. 1996;48(5):817–21. doi: 10.1016/S0090- 4295(96)00322-6. [PubMed: 8911536].
    17. Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology. 2001;57(6 Suppl 1):47–55. doi: 10.1016/S0090-4295(01)01129-3. [PubMed: 11378050].
    18. Kreft ME, Romih R, Kreft M, Jezernik K. Endocytotic activity of bladder superficial urothelial cells is inversely related to their differentiation stage. Differentiation. 2009;77(1):48–59. doi: 10.1016/j.diff.2008.09.011. [PubMed: 19281764].
    19. Cox PJ. Cyclophosphamide cystitis–identification of acrolein as the causative agent. Biochem Pharmacol. 1979;28(13):2045–9. doi: 10.1016/0006-2952(79)90222-3. [PubMed: 475846].
    20. Cox PJ, Abel G. Cyclophosphamide cystitis. Studies aimed at its minimization. Biochem Pharmacol. 1979;28(24):3499–502. doi: 10.1016/0006-2952(79)90390-3. [PubMed: 231445].
    21. Batista CK, Brito GA, Souza ML, Leitao BT, Cunha FQ, Ribeiro RA. A model of hemorrhagic cystitis induced with acrolein in mice. Braz J Med Biol Res. 2006;39(11):1475–81. [PubMed: 17146560].
    22. Tzan CJ, Berg J, Lewis SA. Effect of protamine sulfate on the permeability properties of the mammalian urinary bladder. J Membr Biol. 1993;133(3):227–42. doi: 10.1007/BF00232022. [PubMed: 8331646].
    23. Lavelle J, Meyers S, Ramage R, Bastacky S, Doty D, Apodaca G, et al. Bladder permeability barrier: recovery from selective injury of surface epithelial cells. Am J Physiol Renal Physiol. 2002;283(2):F242–53. doi: 10.1152/ajprenal.00307.2001. [PubMed: 12110507].
    24. Shimizu I, Kawashima K, Hosoki K. Urodynamics in acetone-induced cystitis of anesthetized rats. Neurourol Urodyn. 1999;18(2):115–27. doi: 10.1002/(SICI)1520-6777(1999)18:2<_x0031_15:_x003a_AID-NAU7>3.0.CO;2-D. [PubMed: 10081951].
    25. Keay S, Leitzell S, Ochrzcin A, Clements G, Zhan M, Johnson D. Amouse model for interstitial cystitis/painful bladder syndrome based on APF inhibition of bladder epithelial repair: a pilot study. BMC Urol. 2012;12:17. doi: 10.1186/1471-2490-12-17. [PubMed: 22682521].
    26. Lv YS, Yao YS, Rong L, Lin ME, Deng BH, Xie Y, et al. Intravesical hyaluronidase causes chronic cystitis in a rat model: a potential model of bladder pain syndrome/interstitial cystitis. Int J Urol. 2014;21(6):601–7. doi: 10.1111/iju.12358. [PubMed: 24286489].
    27. Oottamasathien S, Jia W, McCoard L, Slack S, Zhang J, Skardal A, et al. A murine model of inflammatory bladder disease: cathelicidin peptide induced bladder inflammation and treatment with sulfated polysaccharides. J Urol. 2011;186(4 Suppl):1684–92. doi: 10.1016/j.juro.2011.03.099. [PubMed: 21855919].
    28. Elbadawi A. Interstitial cystitis: a critique of current concepts with a new proposal for pathologic diagnosis and pathogenesis. Urology. 1997;49(5A Suppl):14–40. [PubMed: 9145999].
    29. Galli SJ. New concepts about the mast cell. N Engl J Med. 1993;328(4):257–65. doi: 10.1056/NEJM199301283280408. [PubMed: 8418407].
    30. Bullock AD, Becich MJ, Klutke CG, Ratliff TL. Experimental autoimmune cystitis: a potential murine model for ulcerative interstitial cystitis. J Urol. 1992;148(6):1951–6. doi: 10.1016/S0022-5347(17)37091-X. [PubMed: 1433651].
    31. Lin YH, Liu G, Kavran M, Altuntas CZ, Gasbarro G, Tuohy VK, et al. Lower urinary tract phenotype of experimental autoimmune cystitis in mouse: a potential animal model for interstitial cystitis. BJU Int. 2008;102(11):1724–30. doi: 10.1111/j.1464-410X.2008.07891.x. [PubMed: 18710451].
    32. Luber-Narod J, Austin-Ritchie T, Banner B, Hollins C3, Maramag C, Price H, et al. Experimental autoimmune cystitis in the Lewis rat: a potential animal model for interstitial cystitis. Urol Res. 1996;24(6):367– 73. doi: 10.1007/BF00389795. [PubMed: 9008331].
    33. Ratliff TL, Klutke CG, Hofmeister M, He F, Russell JH, Becich MJ. Role of the immune response in interstitial cystitis. Clin Immunol Immunopathol. 1995;74(3):209–16. doi: 10.1006/clin.1995.1031. [PubMed: 7859410].
    34. Altuntas CZ, Daneshgari F, Sakalar C, Goksoy E, Gulen MF, Kavran M, et al. Autoimmunity to uroplakin II causes cystitis in mice: a novel model of interstitial cystitis. Eur Urol. 2012;61(1):193–200. doi: 10.1016/j.eururo.2011.06.028. [PubMed: 21719190].
    35. Lavelle JP, Apodaca G, Meyers SA, Ruiz WG, Zeidel ML. Disruption of guinea pig urinary bladder permeability barrier in noninfectious cystitis. Am J Physiol. 1998;274(1 Pt 2):F205–14. [PubMed: 9458841].
    36. Ercan F, San T, Cavdar S. The effects of cold-restraint stress on urinary bladder wall compared with interstitial cystitis morphology. Urol Res. 1999;27(6):454–61. doi: 10.1007/s002400050135. [PubMed: 10651134].
    37. Lai H, Gereau R, Luo Y, O’Donnell M, Rudick CN, Pontari M, et al. Animal Models of Urologic Chronic Pelvic Pain Syndromes: Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network. Urology. 2015;85(6):1454–65. doi: 10.1016/j.urology.2015.03.007. [PubMed: 26099889].
    38. Cruz F. The future of pharmacologic treatment for bladder pain syndrome/interstitial cystitis: lessons from a meta-analysis. Eur Urol. 2012;61(1):54–5. doi: 10.1016/j.eururo.2011.09.015. [PubMed: 21975250] discussion 56-7.
    39. Nazif O, Teichman JM, Gebhart GF. Neural upregulation in interstitial cystitis. Urology. 2007;69(4 Suppl):24–33. doi: 10.1016/j.urology.2006.08.1108. [PubMed: 17462476].
    40. Spanos C, el-Mansoury M, Letourneau R, Minogiannis P, Greenwood J, Siri P, et al. Carbachol-induced bladder mast cell activation: augmentation by estradiol and implications for interstitial cystitis. Urology. 1996;48(5):809–16. doi: 10.1016/S0090-4295(96)00239-7. [PubMed: 8911535].
    41. Jerde TJ, Bjorling DE, Steinberg H, Warner T, Saban R. Determination of mouse bladder inflammatory response to E. coli lipopolysaccharide. Urol Res. 2000;28(4):269–73. doi: 10.1007/s002400000114. [PubMed: 11011967].
    42. Jasmin L, Janni G, Manz HJ, Rabkin SD. Activation of CNS circuits producing a neurogenic cystitis: evidence for centrally induced peripheral inflammation. J Neurosci. 1998;18(23):10016–29. [PubMed: 9822756].
    43. Rudick CN, Schaeffer AJ, Klumpp DJ. Pharmacologic attenuation of pelvic pain in a murine model of interstitial cystitis. BMC Urol. 2009;9:16. doi: 10.1186/1471-2490-9-16. [PubMed: 19909543].
    44. Pontari MA. Seeking A Rational Approach to the Diagnosis and Treatment of Interstitial Cystitis. Medscape Womens Health. 1996;1(5):2. [PubMed: 9746627].
    45. Warren JW. Bladder pain syndrome/interstitial cystitis as a functional somatic syndrome. J Psychosom Res. 2014;77(6):510–5. doi: 10.1016/j.jpsychores.2014.10.003. [PubMed: 25455811].
    46. Persu C, Cauni V, Gutue S, Blaj I, Jinga V, Geavlete P. From interstitial cystitis to chronic pelvic pain. J Med Life. 2010;3(2):167–74. [PubMed: 20968203].
    47. Theoharides TC, Pang X, Letourneau R, Sant GR. Interstitial cystitis: a neuroimmunoendocrine disorder. Ann N Y Acad Sci. 1998;840:619–34. doi: 10.1111/j.1749-6632.1998.tb09601.x. [PubMed: 9629289].
    48. Soler R, Bruschini H, Truzzi JC, Martins JR, Camara NO, Alves MT, et al. Urinary glycosaminoglycans excretion and the effect of dimethyl sulfoxide in an experimental model of non-bacterial cystitis. Int Braz J Urol. 2008;34(4):503–11. [PubMed: 18778502] discussion 511.
    49. Santos NC, Figueira-Coelho J, Martins-Silva J, Saldanha C. Multidisciplinary utilization of dimethyl sulfoxide: pharmacological, cellular, and molecular aspects. Biochem Pharmacol. 2003;65(7):1035–41. doi: 10.1016/S0006-2952(03)00002-9. [PubMed: 12663039].
    50. Smith KJ, Chess-Williams R, McDermott C. Luminal DMSO: effects on detrusor and urothelial/lamina propria function. Biomed Res Int. Razavi Int J Med. 2017; 5(4):e64551. 13 Federico F 2014;2014:347616. doi: 10.1155/2014/347616. [PubMed: 24949435].
    51. Tomoe H. In what type of interstitial cystitis/bladder pain syndrome is DMSO intravesical instillation therapy effective? Transl Androl Urol. 2015;4(6):600–4. doi: 10.3978/j.issn.2223-4683.2015.09.01. [PubMed: 26816859].
    52. Parsons CL, Koziol JA, Proctor JG, Zupkas P, Argade S. Heparin and alkalinized lidocaine versus alkalinized lidocaine for treatment of interstitial cystitis symptoms. Can J Urol. 2015;22(2):7739–44. [PubMed: 25891339].
    53. Parsons CL, Forrest J, Nickel JC, Evans R, Lloyd LK, Barkin J, et al. Effect of pentosan polysulfate therapy on intravesical potassium sensitivity. Urology. 2002;59(3):329–33. doi: 10.1016/S0090-4295(01)01586-2. [PubMed: 11880064].
    54. Kalota SJ, Stein PC, Parsons CL. Prevention of acrolein-induced bladder injury by pentosanpolysulfate. J Urol. 1992;148(1):163–6. doi: 10.1016/S0022-5347(17)36545-X. [PubMed: 1377288].
    55. Chiang G, Patra P, Letourneau R, Jeudy S, Boucher W, Green M, et al. Pentosanpolysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in interstitial cystitis. J Urol. 2000;164(6):2119–25. doi: 10.1016/S0022-5347(05)66981-9. [PubMed: 11061939].
    56. Kelly JD, Young MR, Johnston SR, Keane PF. Clinical response to an oral prostaglandin analogue in patients with interstitial cystitis. Eur Urol. 1998;34(1):53–6. doi: 10.1159/000019679. [PubMed: 9676414].
    57. Kuschert GS, Coulin F, Power CA, Proudfoot AE, Hubbard RE, Hoogewerf AJ, et al. Glycosaminoglycans interact selectively with chemokines and modulate receptor binding and cellular responses. Biochemistry. 1999;38(39):12959–68. doi: 10.1021/bi990711d. [PubMed: 10504268].
    58. Stern R. Hyaluronan catabolism: a new metabolic pathway. Eur J Cell Biol. 2004;83(7):317–25. doi: 10.1078/0171-9335-00392. [PubMed: 15503855].
    59. Sinanoglu O, Dogan Ekici I, Ekici S. Comparison of intravesical application of chondroitin sulphate and colchicine in rat protamine/lipopolysaccharide induced cystitis model. Urol J. 2014;11(1):1296–300. [PubMed: 24595940].
    60. Eggli PS, Graber W. Cytochemical localization of hyaluronan in rat and human skin mast cell granules. J Invest Dermatol. 1993;100(2):121– 5. doi: 10.1111/1523-1747.ep12462777. [PubMed: 8429234].
    61. Fiander N. Painful bladder syndrome and interstitial cystitis: treatment options. Br J Nurs. 2013;22(9):S26. [PubMed: 23752572] S28-33.
    62. Toole BP. Hyaluronan and its binding proteins, the hyaladherins. Curr Opin Cell Biol. 1990;2(5):839–44. doi: 10.1016/0955-0674(90)90081-O. [PubMed: 1707285].
    63. Shao Y, Lu GL, Shen ZJ, He HC. Reduction of intercellular adhesion molecule 1 may play a role in anti-inflammatory effect of hyaluronic acid in a rat model of severe non-bacterial cystitis. World J Urol. 2013;31(3):535–40. doi: 10.1007/s00345-012-0839-8. [PubMed: 22358112].
    64. Arance I, Ramon de Fata F, Angulo JC, Gonzalez-Enguita C, Errando C, Cozar JM, et al. [Available evidence about efficacy of different restoring agents of glycosaminoglycans for intravesical use in interstitial cystitis]. Actas Urol Esp. 2013;37(2):92–9. doi: 10.1016/j.acuro.2012.10.002. [PubMed: 23260184].
    65. Negrete HO, Lavelle JP, Berg J, Lewis SA, Zeidel ML. Permeability properties of the intact mammalian bladder epithelium. Am J Physiol. 1996;271(4 Pt 2):F886–94. [PubMed: 8898019].
    66. Kaufman J, Tyagi V, Anthony M, Chancellor MB, Tyagi P. State of the art in intravesical therapy for lower urinary tract symptoms. Rev Urol. 2010;12(4):e181–9. [PubMed: 21234261].
    67. Tyagi P, Chancellor M, Yoshimura N, Huang L. Activity of different phospholipids in attenuating hyperactivity in bladder irritation. BJU Int. 2008;101(5):627–32. doi: 10.1111/j.1464-410X.2007.07334.x. [PubMed: 18070198].
    68. Nirmal J, Tyagi P, Chancellor MB, Kaufman J, Anthony M, Chancellor DD, et al. Development of potential orphan drug therapy of intravesical liposomal tacrolimus for hemorrhagic cystitis due to increased local drug exposure. J Urol. 2013;189(4):1553–8. doi: 10.1016/j.juro.2012.10.123. [PubMed: 23127767].
    69. Shao Y, Shen ZJ, Rui WB, Zhou WL. Intravesical instillation of hyaluronic acid prolonged the effect of bladder hydrodistention in patients with severe interstitial cystitis. Urology. 2010;75(3):547–50. doi: 10.1016/j.urology.2009.09.078. [PubMed: 20022087].
    70. Lv YS, Zhou HL, Mao HP, Gao R, Wang YD, Xue XY. Intravesical hyaluronic acid and alkalinized lidocaine for the treatment of severe painful bladder syndrome/interstitial cystitis. Int Urogynecol J. 2012;23(12):1715–20. doi: 10.1007/s00192-012-1802-3. [PubMed: 22576327].
    71. Giberti C, Gallo F, Cortese P, Schenone M. Combined intravesical sodium hyaluronate/chondroitin sulfate therapy for interstitial cystitis/bladder pain syndrome: a prospective study. Ther Adv Urol. 2013;5(4):175–9. doi: 10.1177/1756287213490052. [PubMed: 23904856].
    72. Song M, Lim J, Yu HY, Park J, Chun JY, Jeong J, et al. Mesenchymal Stem Cell Therapy Alleviates Interstitial Cystitis by Activating Wnt Signaling Pathway. Stem Cells Dev. 2015;24(14):1648–57. doi: 10.1089/scd.2014.0459. [PubMed: 25745847].
    73. Zhang J, Planey SL, Ceballos C, Stevens SJ, Keay SK, Zacharias DA. Identification of CKAP4/p63 as a major substrate of the palmitoyl acyltransferase DHHC2, a putative tumor suppressor, using a novel proteomics method. Mol Cell Proteomics. 2008;7(7):1378–88. doi: 10.1074/mcp.M800069-MCP200. [PubMed: 18296695].
    74. Yang W, Chung YG, Kim Y, Kim TK, Keay SK, Zhang CO, et al. Quantitative proteomics identifies a beta-catenin network as an element of the signaling response to Frizzled-8 protein-related antiproliferative factor. Mol Cell Proteomics. 2011;10(6):M110 007492. doi: 10.1074/mcp.M110.007492. [PubMed: 21422242].
    75. Shahjee HM, Koch KR, Guo L, Zhang CO, Keay SK. Antiproliferative factor decreases Akt phosphorylation and alters gene expression via CKAP4 in T24 bladder carcinoma cells. J Exp Clin Cancer Res. 2010;29:160. doi: 10.1186/1756-9966-29-160. [PubMed: 21143984].
    76. Tao YX, Heit M, Lei ZM, Rao CV. The urinary bladder of a woman is a novel site of luteinizing hormone-human chorionic gonadotropin receptor gene expression. Am J Obstet Gynecol. 1998;179(4):1026–31. doi: 10.1016/S0002-9378(98)70222-4. [PubMed: 9790392].
    77. Rao CV. Therapeutic Potential of Human Chorionic Gonadotropin Against Painful Bladder Syndrome/Interstitial Cystitis. Reprod Sci. 2016;23(11):1451–8. doi: 10.1177/1933719116639139. [PubMed: 27004802].
    78. Barthelmes J, Perera G, Hombach J, Dunnhaupt S, Bernkop-Schnurch A. Development of a mucoadhesive nanoparticulate drug delivery system for a targeted drug release in the bladder. Int J Pharm. 2011;416(1):339–45. doi: 10.1016/j.ijpharm.2011.06.033. [PubMed: 21726619]