Dysregulation of bladder corticotropin-releasing hormone receptor in the pathogenesis of human interstitial cystitis/bladder pain syndrome

AbstractStress is associated with exacerbated symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). To investigate the mechanism of stress implicated on IC/BPS, we investigated expression of stress-response receptor corticotropin-releasing hormone receptor (CRHR) in bladder from IC/BPS patients. Twenty-three IC/BPS patients with Hunner’s lesion (HIC), 51 IC/BPS patients without Hunner’s lesion (NHIC), and 24 patients with stress urinary incontinence as controls were enrolled. Cystoscopic biopsies of bladder wall including mucosa and submucosa were obtained from all patients. Western blotting was used to investigate the bladder expression of the CRHR1 and CRHR2. Immunochemical staining revealed CRHR1 expression was mainly located in the submucosa while CRHR2 expression was mainly in uroepithelial cells. Compared to control subjects, the CRHR1 expression was significantly higher, while CRHR2 expression was significantly lower in IC/BPS patients. Further analysis of patients with HIC, NHIC, and control subjects showed that bladder in patients with HIC had significantly higher expressions of CRHR1 and significantly lower CRHR2. CRHR2 expression was significantly negatively correlated with O’Leary-Sant score and bladder pain. Our results indicate dysregulation of bladder CRHR1 and CRHR2 in patients with IC/BPS, and suggest CRH signaling may be associated with IC/BPS symptoms.

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A Culture-Independent Analysis of the Microbiota of Female Interstitial Cystitis/Bladder Pain Syndrome Participants in the MAPP Research Network

Journal of Clinical Medicine ◽

10.3390/jcm8030415 ◽

2019 ◽

Vol 8 (3) ◽

pp. 415 ◽

Cited By ~ 6

Author(s):

J. Nickel ◽

Alisa Stephens-Shields ◽

J. Landis ◽

Chris Mullins ◽

Adrie van Bokhoven ◽

...

Keyword(s):

Interstitial Cystitis ◽

Pain Syndrome ◽

Bladder Pain Syndrome ◽

Research Network ◽

Molecular Diagnostic ◽

Bladder Pain ◽

Lactobacillus Gasseri ◽

Culture Independent ◽

And Control ◽

Urine Specimens

We surveyed urine microbiota of females diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) and matched control participants enrolled in the National Institutes of Health (NIH) Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network using the culture-independent methodology. Midstream urine specimens were analyzed with the Plex-ID molecular diagnostic platform that utilizes polymerase chain reaction–electrospray ionization–time-of-flight–mass spectrometry (PCR-ESI-TOF MS) to provide a comprehensive identification of bacterial and select fungal species. IC/BPS and control participants were evaluated for differences (presence, diversity, and abundance) in species and genus. Urine specimens obtained from 181 female IC/BPS and 182 female control participants detected a total of 92 species (41 genera). Mean (SD) species count was 2.49 (1.48) and 2.30 (1.28) among IC/BPS and control participants, respectively. Overall species composition did not significantly differ between IC/BPS and control participants at any level (p = 0.726 species level, p = 0.222 genus level). IC/BPS participants urine trended to an overabundance of Lactobacillus gasseri (p = 0.09) detected but had a lower prevalence of Corynebacterium compared with control participants (p = 0.002). The relative abundance data analysis mirrored the prevalence data differences with no significant differences in most species or genus abundance other than Lactobacillus gasseri and Corynebacterium (p = 0.08 and p = 0.001, respectively). No cause and/or effect conclusion can be drawn from this observation, but it suggests that a more comprehensive evaluation (vaginal, bowel, catheterized bladder and/or tissue-based specimens) of the lower urinary tract microbiota in IC/BPS patients is warranted.

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Clinical and histological findings in bladder pain syndrome/interstitial cystitis: The implication of time of symptoms

Journal of Clinical Urology ◽

10.1177/2051415817747474 ◽

2018 ◽

Vol 11 (4) ◽

pp. 248-253

Author(s):

Daniele Porru ◽

Valentina Bobbi ◽

Carmelo Di Franco ◽

Alessandra Viglio ◽

Mattia Novario ◽

...

Keyword(s):

Interstitial Cystitis ◽

Symptom Onset ◽

Bladder Wall ◽

Pain Syndrome ◽

Bladder Pain Syndrome ◽

Detrusor Muscle ◽

Level Of Evidence ◽

Bladder Pain ◽

Bladder Biopsy ◽

The Impact

Objective: To find out whether a correlation exists between denudation of urothelium and time of symptom onset in patients with bladder pain syndrome/interstitial cystitis (BPS/IC), and to search for a correlation between the impact of symptoms. Patients and methods: Fifty-seven consecutive patients underwent cystoscopy under anaesthesia to classify those cases suspected of being affected with BPS/IC. The time elapsed between onset of symptoms and diagnosis at the time of bladder biopsy was also defined as BPS/IC duration. Bladder biopsies were taken including detrusor muscle, three deep cold biopsies of posterior, anterior and lateral bladder wall. Results: Statistical analysis showed significant correlation between BPS/IC duration and the presence of Hunner’s lesions ( P<0.023). Hunner’s lesion with cystoscopy and histological evidence of urothelial denudation with bladder biopsy appear to be related to BPS/IC duration. Thus an early diagnosis allows an appropriate therapeutic approach to be started to prevent a more severe evolution of this multifaceted painful syndrome. Conclusions: Our study shows a correlation between the time of symptom onset and evidence of urothelial denudation and with detrusor mast cell count in the whole group of patients. BPS/IC duration did not seem to correlate with the severity of symptoms, but rather with the presence of associated diseases. Level of evidence: Not applicable for this multicentre audit.

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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

BMC Urology ◽

10.1186/s12894-019-0548-3 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 6

Author(s):

Hui Shan ◽

Er-Wei Zhang ◽

Peng Zhang ◽

Xiao-Dong Zhang ◽

Ning Zhang ◽

...

Keyword(s):

Interstitial Cystitis ◽

Western Blotting ◽

Bladder Wall ◽

Pain Syndrome ◽

Bladder Pain Syndrome ◽

Histamine Receptors ◽

Receptor Expression ◽

Bladder Pain ◽

Disease Symptoms ◽

Female Patients

Abstract Background Activation of mast cells plays an important role in the pathogenesis of bladder pain syndrome/interstitial cystitis (BPS/IC). Histamine, a mast cell-derived mediators, induced inflammation and hypersensitivity of the bladder. The present study investigated the expressions of histamine receptors in the bladder wall tissues of patients with BPS/IC, and its association with the effectiveness of antihistamine therapy and disease symptoms. Methods Bladder tissues were collected from 69 BPS/IC patients and 10 control female patients. The expression of H3R in BPS/IC was further examined in an independent cohort of 10 female patients with BPS/IC and another 10 age-matched female patients. Immunohistochemistry, Western blotting, and quantitative RT-PCR were performed to quantify the expressions of histamine receptors. Statistical analyses of the correlation of histamine receptor expression with antihistamine therapy outcome and severity of disease symptoms were also performed. Results The expression of four histamine receptors was significantly elevated in BPS/IC (H1R, P < 0.001; H2R, P = 0.031; H3R, P = 0.008; H4R, P = 0.048). Western blotting revealed that H3R were significantly reduced in the patients, whereas the mRNA levels of H3R were significantly increased. The patients were further divided into antihistamine responders (n = 38) and nonresponders (n = 22). No significant correlation was found in the expression of histamine receptors between responder and nonresponder groups. However, significant correlations between OLS and H1R (P = 0.003) and H3R (P = 0.045) were found. Conclusion The present study showed that expression of all the 4 histamine receptors were elevated in BPS/IC. There were no statistical significant correlations between the expression levels of the four different histamine receptors and the treatment outcome of antihistamine therapy (amtitriptyline or cimetidine).

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A Novel Intravesical Dextrose Injection Improves Lower Urinary Tract Symptoms on Interstitial Cystitis/Bladder Pain Syndrome

Frontiers in Pharmacology ◽

10.3389/fphar.2021.755615 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chin-Li Chen ◽

Chien-Chang Kao ◽

Ming-Hsin Yang ◽

Gang-Yi Fan ◽

Juin-Hong Cherng ◽

...

Keyword(s):

Growth Factors ◽

Interstitial Cystitis ◽

Bladder Wall ◽

Pain Syndrome ◽

Bladder Pain Syndrome ◽

Bladder Pain ◽

Dextrose Solution ◽

Cytokine Analysis ◽

Limited Effectiveness ◽

Significant Difference

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a painful recurrent condition characterized by the discomfort of the bladder, and current treatment options have limited effectiveness. Prolotherapy is a well-known treatment that involves the injection of non-biologic solutions to reduce pain and/or promote proliferation of soft tissue, and dextrose is the most common injectate. This study investigated the effects of dextrose prolotherapy in a rat model of IC/BPS and patients with IC/BPS. We used cyclophosphamide to induce IC/BPS in rats, and intravesical instillation of 10% dextrose solution was performed. After 1 week, we conducted a urodynamic test, bladder staining, and ECM-related gene expression analysis to examine the treatment’s efficacy. We found that dextrose treatment could recover the instability of the bladder, reduce frequent urination, and improve the glycosaminoglycan layer regeneration and the bladder wall thickness along with a significant intense expression of CD44 receptors. Furthermore, we enrolled 29 IC/BPS patients with previous hyaluronic acid/Botox treatment for more than 6 months with remained unchanged condition. In this study, they received intravesical injections of 10% dextrose solution followed by assessments for up to 12 weeks. Patient characteristics and a 3-day voiding diary before treatment were recorded. Patient responses were examined using IC/BPS-related questionnaires. Moreover, expressions of growth factors and cytokines were analyzed. The results demonstrated that dextrose prolotherapy in patients with IC/BPS reduced the frequency of treatment over time, with the mean number of treatments being 3.03 ± 1.52, and significantly reduced the incidence of nocturia and questionnaire scores associated with symptoms. Dextrose prolotherapy significantly enhanced EGF level and, in contrast, reduced the level of HGF, PIGF-1, and VEGF-D after several weeks following treatment. The cytokine analysis showed that the expressions of IL-12p70 and IL-10 were significantly up-regulated after dextrose prolotherapy in IC/BPS patients. The levels of most growth factors and cytokines in IC/BPS patients had no significant difference and showed a similar tendency as time progressed when compared to healthy controls. Overall, the alteration of growth factors and cytokines exhibited safe treatment and potential stimulation of tissue remodeling. In summary, our study demonstrated that dextrose prolotherapy is a promising treatment strategy for IC/BPS disease management.

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Possible Association between Bladder Wall Morphological Changes on Computed Tomography and Bladder-Centered Interstitial Cystitis/Bladder Pain Syndrome

Biomedicines ◽

10.3390/biomedicines9101306 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1306

Author(s):

Jia-Fong Jhang ◽

Yung-Hsiang Hsu ◽

Han-Chen Ho ◽

Yuan-Hong Jiang ◽

Cheng-Ling Lee ◽

...

Keyword(s):

Computed Tomography ◽

Interstitial Cystitis ◽

Morphological Changes ◽

Bladder Wall ◽

Pain Syndrome ◽

Bladder Capacity ◽

Bladder Pain Syndrome ◽

Wall Thickening ◽

Bladder Pain ◽

Urinary Bladder Wall

This study aimed to evaluate the clinical significance of urinary bladder wall thickening on computed tomography (CT) among patients with interstitial cystitis/bladder pain syndrome (IC/BPS). Patients with IC/BPS were prospectively enrolled and classified into three groups according to bladder CT finding: smooth bladder wall, focal bladder thickening, and diffuse bladder thickening. Among the 100 patients with IC/BPS, 49, 36, and 15 had smooth bladder wall, focal bladder thickening, and diffuse bladder thickening on CT, respectively. Patients with Hunner’s lesion showed a higher proportion of diffuse and focal bladder thickening compared to those without the same (p < 0.001). Patients with diffuse bladder thickening displayed smaller first sensation of filling, cystometric bladder capacity, and voided volume compared to the rest (all p < 0.001). Patients with focal and diffuse thickening had a higher proportion of inflammatory cell infiltration, uroepithelial cell denudation, and granulation tissue compared to those with smooth bladder wall (p = 0.045, 0.002, and 0.005, respectively). Bladder wall thickening on CT was correlated with clinical phenotypes of IC/BPS, including histopathological findings. Focal or diffuse bladder wall thickening on CT might indicate the presence of chronic bladder wall inflammation and fibrosis and could be used to differentiate bladder-centered IC/BPS.

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LOCAL IMMUNE RESPONSE IN PATIENTS WITH CLASSIC AND NON-ULCER TYPE OF INTERSTITIAL CYSTITIS / BLADDER PAIN SYNDROME

Russian Journal of Infection and Immunity ◽

10.15789/2220-7619-lir-1644 ◽

2021 ◽

Author(s):

R. F. Sholan

Keyword(s):

Mast Cells ◽

Interstitial Cystitis ◽

Plasma Cells ◽

Bladder Wall ◽

Pain Syndrome ◽

Bladder Pain Syndrome ◽

Bladder Pain ◽

Group I ◽

Tnf Α ◽

Group Ii

Several hypotheses regarding the pathophysiology of interstitial cystitis / bladder pain syndrome (IC / BPS) have been put forward, but no consensus has yet been reached. It is suggested that cytokines are involved in IC / BPS, as well as in inflammatory autoimmune diseases. Examining various biomarkers of bladder tissue, including mast cells is underway. However, few reports on a consistent immune activity profile are available. The aim of the study was to assess the cytokine profile, counts of mast cells and plasma cells as well as their relationship in patients with IC / BPS with and without Hunner's lesions. 44 women with Hunner's lesions of IC / BPS (group I) and 82 women with non-ulcer type (group II) were examined. Patients were questioned on the Pelvic Pain Symptom Scale, Urinary Frequency Scale (PUF), Visual Analogue Scale (VAS) and O'Leary-Santa Interstitial Cystitis Symptom Index (ICSI). Cystoscopy and hydrodistension of the bladder were performed under general anesthesia. In biopsies of the bladder wall, the number of plasma cells and mast cells was assessed, in urine - IL-1β, IL-6, IL-8, TNF-α. Statistical processing of the results was carried out using the Statistica software for Microsoft Excel release 6 (StatSoft, USA). The Student's t-test, Spearman's correlation coefficient were calculated. In patients with the Hunner type of IC / BPS, there was an insignificant increase in the scale indices and decreased magnitude for average volume, urination frequency, and maximum emptying volume. The maximum bladder capacity during hydrodistension was lowered by 42.01% (p <0.001). The level of IL-8 in group I was higher on average by 28.57% (p = 0.434) as compared with that in group II, IL-6 - by 13.46% (p = 0.638), TNF-α - by 9.09% (p = 0.244) and IL-1β – by 4.13% (p = 0.859). The number of mast cells in patients of group I vs. group II was higher by 40.65% (p <0.05). In group I, a marked relationship was found between count of mast cells and plasma cells (r = -0.555, p> 0.05), as well as between count of plasma cells and IL-6 level (r = -0.639, p <0.05). In group II, a significant connection was found between count of mast cells and TNF-α level (r = +0.562, p <0.05). Patients with Hunner's IC / BPS are characterized by severe inflammation, wherein mast cells are involved in induction. Determination of cytokines in urine can provide a non-invasive division of IC / BPS into ulcerative and non-ulcerative groups.

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