Differential expression of histamine receptors in the bladder wall tissues of patients with bladder pain syndrome/interstitial cystitis – significance in the responsiveness to antihistamine treatment and disease symptoms

Bladder pain syndrome/Interstitial cystitis (BPS/IC), or bladder pain syndrome, is a complex bladder dysfunction characteristized by chronic (> 6 months) urinary bladder pain or discomfort, accompanied by other urinary symptom such as persistent urge to void [1]. BPS/IC can contribute to chronic pelvic pain and poor quality of life, which is now recognized as a serious medical condition. The disease occurs mostly in young and middle-aged women, with no known etiology. A survey conducted in US indicated that 575 in every 100,000 women had IC [2], and the prevalence rate of self-reported BPS/IC among community-dwelling adult women was around 4% [3].

Several etiologies have been proposed, including abnormalities in urine, infection, inflammation resulted from autoimmunity, activation of mast cells, neurogenic inflammation, and disturbance in permeability of the bladder wall [4]. Evidence from in vitro and clinical studies suggested that mast cells play a critical role in the pathogenesis and pathophysiology of BPS/IC [5, 6]. Upon the activation of mast cells, histamine is released; and the binding of histamine to the receptors on bladder wall could induce inflammation and hypersensitivity of the bladder [7, 8]. Treatments of BPS/IC include behavioral therapy, mucosal protection, histamine receptor antagonism, analgesia, and surgical treatment, whereas the most common interventions include bladder mucosal protective agents and anti-histamines [9].

There are four subtypes of histamine receptors: H1R, H2R, H3R, and H4R. It has been confirmed that the expression of all the four subtypes of histamine receptors were found in BPS/IC animal model, in which the receptors were expressed mainly in bladder epithelial cells. Significant differences were found in the expression of H1R, H2R, and H3R before and after BPS/IC [10]. However, it remains unclear on the pattern of expressions of the four histamine receptors in patients with IC. Also, it is not known whether there is an association between histamine receptor expression and efficacy of antihistamines.

In the current study, we analyze the correlation between expressions of histamine receptors and the severity of BPS/IC (as assessed by OLS score), as well as the effectiveness of antihistamine therapy.

The present study examined the differential expression of 4 histamine receptors (H1R, H2R, H3R, and H4R) in the bladder tissues of patients with BPS/IC, showing all the receptors were significantly elevated in BPS/IC. Our analysis also suggested that although histamine receptors are biologically relevant to BPS/IC pathogenesis, there were no significant correlations between the expression levels of the four different histamine receptors and the treatment outcome of antihistamine therapy.

Despite the accumulated studies over the decades, the etiology of BPS/IC have yet to be fully studied [12]. Different hypothesized etiologies have been proposed, including abnormalities in urine, infection, inflammation resulted from autoimmunity, activation of mast cells, neurogenic inflammation, and disturbance in permeability of the bladder wall [4]. Epithelial antiproliferative factor plays a key role in inhibiting the growth of endothelial cell of the bladder. Baltimore et al. recently identified that the mutation of FZB8 gene would affect the normal functions of epithelial antiproliferative factor, disrupting the integrity of bladder mucosa, resulting in an increase in the permeability of the bladder [4, 7, 13]. Nevertheless, none of these hypotheses can fully explain the diverse clinical manifestations and differential drug responses among patients with BPS/IC.

The understanding on the pathophysiology is relatively clear comparing to the disease etiology. It has been widely accepted that BPS/IC is resulted from the chronic inflammation of the entire bladder wall, in which mast cells represent one of the key players. In patients with BPS/IC activated mast cells were found in the bladder of the patients [6]. By releasing histamine that binds to the receptors on bladder wall, the mast cells can induce inflammation and hypersensitivity of the bladder [7, 8]. In accordance with other previous studies, we herein demonstrated that all of the four histamine receptors were over expressed in the bladder wall of BPS/IC. Moreover, our examination clearly depicted the localisation of IHC signals mainly in the mucosa of bladder, with a lesser extent of reactivity could be detected in the interstitial blood vessels and the detrusor muscles. There results likely implicated that the mucosa of the bladder would be the major target of histamine released from the infiltrated mast cells, in turn, the major pathogenic sites of BPS/IC. Our study has therefore provided further evidences to support the hypothesis that BPS/IC would be resulted from the dysfunction of the bladder mucosa, and to strengthen the rationale of using antihistamine in the treatment of BPS/IC.

Histamine modulates diverse immunological responses through its activation on different histamine receptors. All the four histamine receptors are G-protein coupled receptors expressing in diverse tissues with distinct functions [14, 15]. H1R mediates inflammatory reaction [16], while H2R shows inhibitory effects on the apoptosis of mononuclear cells [17]. H3R mainly controls the inflammatory reactions by modulating the release of pro-inflammatory peptides [18], while H4R promotes the acute inflammatory responses through its enhancement on the migration of eosinophils and mast cells [19]. The pathogenic roles of H1 and H2 receptors in BPS/IC have been reported. H3R and H4R are relatively new histamine receptors, therefore, their roles in IC have remained largely unclear. In this study, we showed that the expressions of both H3R and H4R were increased in IC. The total protein of H3R, however, was reduced in an independent cohort of BPS/IC using Western blotting, suggesting a post-transcriptional modification of H3R.

We have not found significant differences in the expression of histamine receptors between responders and nonresponders. There were several possible explanations for the insignificant results: 1) the small sample size; 2) the expressions of all the four histamine receptors were relatively high in patients, however, only H1R and H2R antagonists were applied; 3) a drug treatment duration of 3 months is needed for antihistamine to achieve therapeutic effects. Some patients might fail to adhere to the medication schedule, thus the treatment outcome became sub-optimal. In future studies, H3R and H4R antagonists may be added to achieve sufficient inhibition of histamine receptors, and the correlation between the cystoscopic findings and expression of histamine receptors/ clinical outcome can be investigated. Further, H3R was significantly correlated with OLS, implicating the potential role of H3R in disease progression of BPS/IC.

In conclusion, the present study reported the increased expression of H1R, H2R, H3R, and H4R in BPS/IC. The expressions of the receptors were not statistically correlated with the outcome of antihistamine therapy (amtitriptyline or cimetidine); however, H1R and H3R were related to the disease severity as assessed by OLS, implicated the potential role of H3R in disease progression.