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.
Highlights
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and lower urinary tract dysfunction (LUTD) such as urinary frequency and urgency [1]
We previously developed a transgenic Experimental autoimmune cystitis (EAC) model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and develops bladder inflammation at 7–14 days after adoptive transfer of OVA-specific T cells for cystitis induction [25,26]
To support the human study observations, animal studies have demonstrated that mast cells are indispensable for the development of bladder inflammation and pain seen in IC/BPS patients [7,8,9,10]
Summary
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and lower urinary tract dysfunction (LUTD) such as urinary frequency and urgency [1]. IC/BPS patients exhibit an increased number of mast cells in the bladder and elevated levels of mast cell mediators in the urine such as interleukin (IL)-6, nerve growth factor (NGF), histamine/methyhistamine, and tryptase [2,3]. Since these mediators are vasoactive, nociceptive and pro-inflammatory, mast cells are considered to play an important role in the pathophysiology of IC/BPS [2]. In line with human studies, animal studies have demonstrated that mast cells are responsible for bladder inflammation and pain in diverse models [7,8,9,10] Despite these studies, the role of mast cells in cystitisassociated LUTD has not been identified
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