Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory condition that is difficult to characterize without precise knowledge of the symptoms and histology that characterizes the disease [1
]. Commonly observed symptoms include urinary frequency, urgency, and suprapublic pain that often drastically affect the quality of life of affected patients [2
]. It is generally thought that the development and progression of IC/BPS is associated with infection, defects in bladder permeability, immune or neuroendocrine disorders, and genetic disorders related to visceral hypersensitivity [5
]. Despite comprehensive characterization of symptoms and histology of IC/BPS in recent decades, its exact etiology remains unclear, limiting the development of effective therapeutic interventions.
Mast cells (MCs), long suspected to play a role in the onset of IC/BPS, are derived from specific precursors localized in the bone marrow [8
]. These precursors are stimulated to maturation by local tissue microenvironmental factors that vary according to the tissue types [9
]. MC stimulation has been shown to facilitate the degranulation and release of vasoactive, proinflammatory, and nociceptive mediators in the target tissue, most notably histamine, cytokines, and proteolytic enzymes [10
]. These compounds increase the sensitivity of the sensory neurons, resulting in a positive feedback loop that further activates MCs and sustains the release of increasing concentrations of inflammatory cytokines [11
]. This self-facilitating process is thought to be initiated by various factors, including extreme cold, drugs, neuropeptides, trauma, or toxins. These factors activate only small numbers of mast cells [12
] and the gradual onset of the disease process makes the causative factor difficult to identify.
Full knowledge of the mechanisms which triggers IC/BPS has yet to be elucidated. However, previous studies have shown that a cascade of MC proliferation in bladder tissue is likely to be correlated with the onset of IC/BPS symptoms [14
]. In support of this proposal, elevated levels of urinary histamine are commonly observed in patients with IC/BPS [15
] and are often used as a diagnostic factor for the condition [1
]. Other studies have demonstrated that histamine released by MCs plays a key role in neural sensitization that is responsible for the bladder and urinary pain associated with IC/BPS [16
]. Histamine levels have therefore been used as a biomarker for IC/BPS in genetic studies [17
Determination of the mechanism underlying the regulation of histamine release in MCs is required to further clarify the role of MCs in IC/BPS and provide potential targets for future development of therapeutic agents designed to reduce the impact of the condition on quality of life.
Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays diverse and important roles in many different inflammatory conditions, including rheumatoid arthritis, atherosclerosis, and neuroinflammatory disease [18
]. It has been reported that patients with IC/BPS exhibit elevated MCP-1 in both the urine and bladder tissues, suggesting a possible association between MCP-1 and the severity of IC/BPS [20
]. MCP-1 has also been implicated in the mediation of MC degranulation [21
], suggesting that it plays a critical role in MC activation processes, including those that occur over the course of IC/BPS. While the role of MCP-1 has been widely explored in other inflammatory diseases, further research is required to fully clarify the relationship between upregulation of MCP-1 and the release of histamine in amounts significant enough to trigger symptomatic IC/BPS.
Based on the previously suggested hypothesis that MCP-1 plays a critical role in the induction of histamine release from MCs in bladder tissues of patients diagnosed with IC/BPS, the current study was designed to quantify the expression of MCP-1 in bladder tissues and the levels of both MCP-1 and histamine present in urine using rat models of IC/BPS. Previous studies suggest that IC/BPS is likely to produce significant increases in MCP-1 expression and corresponding increases in the levels of MCP-1 and histamine observed in the urine. Furthermore, this study aims to provide evidence of degranulation in MCs potentially associated with the expression of surface chemokine (C-C motif) receptor 2 (CCR2). Additionally, in vitro studies were constructed to assess the effect of LPS treatment on MCP-1 release in bladder epithelial cells, likely agents in the acceleration of histamine release from MCs. Further evidence for the mechanistic relationship between MCP-1 and the release of histamine in MCs associated with IC/BPS will provide a critical groundwork necessary for the further development of interventions for the diagnosis, prevention, and treatment of IC/BPS.