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.

Alterations of Pro-Inflammatory Cytokines and Tissue Protein Expressions in Cats with Interstitial Cystitis

“…In fact, the elevated number of mast cells in the bladder tissue in case of inflammation induces mast cells degranulation and release of their pre-formed mediators. In light of other reports and according to our experiment during the course of FIC, MC increasingly releases TNF-in the blood which up-regulates by its role the expression of VEGF-A (Wang et al, 2016b) and because of hypoxia induced by inflammation, VEGF-A was up-regulated to induce vasodilation, hyper-vascularity and glomerations at the site of inflammation (Ramakrishnan et al, 2014). This explains the significant increase in the VEGF-A immunohistochemical staining which was highly distributed in urolithium and sub-urolithial layers of the affected cats.…”

Time of symptom onset and histologic findings in bladder pain syndrome/interstitial cystitis: new findings on useful correlations

“…Although some studies suggested that the presence of mast cells in the detrusor muscle is quite specific of IC, 10,11 other data suggest that this cannot be confirmed. 12,13 Article The importance of an early diagnosis for predicting the clinical evolution of the disease and the development of associated diseases of other organs or body sites has not yet been properly investigated.…”

“…Some clinicians now consider that many of the pathological features usually described are non-specific. [9][10][11] However, intrafascicular fibrosis, an increase in the number of mast cells in the detrusor, denudation of urothelium in patients with a diagnosis of with BPS/IC are observations described in many studies. 11 There are conflicting data on the usefulness of mast cell count to diagnose IC.…”

Infiltration of Lymphocytes and Mast Cells to Bladder Tissues in Experimental Models of Interstitial Cystitis/Bladder Pain Syndrome

“…The data of histopathology of the bladder revealed the role of cell-mediated immunity in IC/BPS, which does not exclude the possibility that autoimmune inflammation is probably a component of pathophysiology in patients with this disease (7). Although mast cells are characteristic features of this disease, there is no consensus on their specificity and diagnostic significance.…”

“…Different degrees of severity of inflammation are detected in the biopsy specimens of the bladder; however, cellular mechanisms of inflammation in IC/BPS and the pro-cesses leading to tissue damage and fibrosis are not yet clear (6,7). Among many suggested causes, mast cell activation is noteworthy (8).…”