title: Evidence for the Role of Mast Cells in Cystitis-Associated Lower Urinary Tract Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study.
abstract: Bladder inflammation frequently causes cystitis pain and lower urinary tract dysfunction (LUTD) such as urinary frequency and urgency. Although mast cells have been identified to play a critical role in bladder inflammation and pain, the role of mast cells in cystitis-associated LUTD has not been demonstrated. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and LUTD. In this study we investigated the role of mast cells in LUTD using a transgenic autoimmune cystitis model (URO-OVA) that reproduces many clinical correlates of IC/BPS. URO-OVA mice express the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and develop bladder inflammation upon introduction of OVA-specific T cells. To investigate the role of mast cells, we crossed URO-OVA mice with mast cell-deficient KitW-sh mice to generate URO-OVA/KitW-sh mice that retained urothelial OVA expression but lacked endogenous mast cells. We compared URO-OVA mice with URO-OVA/KitW-sh mice with and without mast cell reconstitution in response to cystitis induction. URO-OVA mice developed profound bladder inflammation with increased mast cell counts and LUTD, including increased total number of voids, decreased mean volume voided per micturition, and decreased maximum volume voided per micturition, after cystitis induction. In contrast, similarly cystitis-induced URO-OVA/KitW-sh mice developed reduced bladder inflammation with no mast cells and LUTD detected. However, after mast cell reconstitution URO-OVA/KitW-sh mice restored the ability to develop bladder inflammation and LUTD following cystitis induction. We further treated URO-OVA mice with cromolyn, a mast cell membrane stabilizer, and found that cromolyn treatment reversed bladder inflammation and LUTD in the animal model. Our results provide direct evidence for the role of mast cells in cystitis-associated LUTD, supporting the use of mast cell inhibitors for treatment of certain forms of IC/BPS.
authors.affiliation: Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Wujiang
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donnell
authors.affiliation: Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.|Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China.|Department of Psychology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Lutgendorf
authors.affiliation: Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Psychology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bradley
authors.affiliation: Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China.
authors.forename: Andrew
authors.initials: A
authors.lastname: Schrepf
authors.affiliation: Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Liwei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Psychology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Karl
authors.initials: K
authors.lastname: Kreder
authors.affiliation: Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004205:Cromolyn Sodium / Q000494:pharmacology; D018856:Cystitis, Interstitial / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D008407:Mast Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D017699:Pelvic Pain / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D010047:Ovalbumin; D019009:Proto-Oncogene Proteins c-kit; D004205:Cromolyn Sodium