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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
Journal article   Open access   Peer reviewed

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

Xu Wang, Wujiang Liu, Michael O'Donnell, Susan Lutgendorf, Catherine Bradley, Andrew Schrepf, Liwei Liu, Karl Kreder and Yi Luo
PloS one, Vol.11(12), pp.e0168772-e0168772
2016
DOI: 10.1371/journal.pone.0168772
PMCID: PMC5176179
PMID: 28002455
url
https://doi.org/10.1371/journal.pone.0168772View
Published (Version of record) Open Access

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.
 CD8-Positive T-Lymphocytes - cytology Ovalbumin - immunology Urinary Bladder - pathology Autoimmune Diseases - etiology RNA, Messenger - metabolism Cromolyn Sodium - pharmacology Mast Cells - metabolism Proto-Oncogene Proteins c-kit - deficiency CD8-Positive T-Lymphocytes - metabolism Proto-Oncogene Proteins c-kit - genetics Pelvic Pain - metabolism Autoimmune Diseases - metabolism Cytokines - genetics Cystitis, Interstitial - metabolism Disease Models, Animal Mast Cells - immunology Cystitis, Interstitial - etiology Cytokines - metabolism Urinary Bladder - metabolism Mice, Inbred C57BL Autoimmune Diseases - immunology Cells, Cultured Behavior, Animal - physiology Mice, Transgenic Pelvic Pain - immunology Animals Cystitis, Interstitial - immunology Pelvic Pain - etiology Mast Cells - cytology Urinary Bladder - drug effects Mice CD8-Positive T-Lymphocytes - immunology

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