Notch1 Signaling Contributes to Mechanical Allodynia Associated with Cyclophosphamide-Induced Cystitis by Promoting Microglia Activation and Neuroinflammation

Aims. Notch1 signaling regulates microglia activation, which promotes neuroinflammation. Neuroinflammation plays an essential role in various kinds of pain sensation, including bladder-related pain in bladder pain syndrome/interstitial cystitis (BPS/IC). However, the impact of Notch1 signaling on mechanical allodynia in cyclophosphamide- (CYP-) induced cystitis is unclear. This study is aimed at determining whether and how Notch1 signaling modulates mechanical allodynia of CYP-induced cystitis. Methods. CYP was peritoneally injected to establish a bladder pain syndrome/interstitial cystitis (BPS/IC) rat model. A γ-secretase inhibitor, DAPT, was intrathecally injected to modulate Notch1 signaling indirectly. Mechanical withdrawal threshold in the lower abdomen was measured with von Frey filaments using the up-down method. The expression of Notch1 signaling, Iba-1, OX-42, TNF-α, and IL-1β in the L6-S1 spinal dorsal horn (SDH) was measured with Western blotting analysis and immunofluorescence staining. Results. Notch1 and Notch intracellular domain (NICD) were both upregulated in the SDH of the cystitis group. Moreover, the expression of Notch1 and NICD was negatively correlated with the mechanical withdrawal threshold of the cystitis rats. Furthermore, treatment with DAPT attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of TNF-α and IL-1β. Conclusion. Notch1 signaling contributes to mechanical allodynia associated with CYP-induced cystitis by promoting microglia activation and neuroinflammation. Our study showed that inhibition of Notch1 signaling might have therapeutic value for treating pain symptoms in BPS/IC.

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Immune Cell Profiles and Cytokine Levels of Patients with Interstitial Cystitis/Bladder Pain Syndrome

10.1101/2020.12.17.20248414 ◽

2020 ◽

Author(s):

Robert M. Moldwin ◽

Vishaan Nursey ◽

Oksana Yaskiv ◽

Siddhartha Dalvi ◽

Michael Funaro ◽

...

Keyword(s):

Interstitial Cystitis ◽

Plasma Cells ◽

Immune Cell ◽

Pain Syndrome ◽

Fold Increase ◽

Bladder Pain Syndrome ◽

Bladder Tissue ◽

Bladder Pain ◽

Tnf Α ◽

Significant Difference

AbstractAimsTo quantify the number of immune cells in the bladder urothelium and concentrations of urinary cytokines in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). To identify differences in these measures in IC/BPS patients with Hunner’s lesions (IC/BPS-HL) and without Hunner’s lesions (IC/BPS-NHL).MethodsBladder tissue biopsies were obtained from 48 patients with IC/BPS-HL and unaffected controls (UC) and stained with antibodies for various immune cell markers such as CD138, CD20 and CD56. Levels of cytokines (Interferon (IFN)-γ, Interleukin (IL)-1β, IL-2, IL- 4, IL-6, IL-8, IL12P70, IL-13, and TNF-α) were measured from normalized urine obtained from 18 IC/BPS-HL, 18 IC/BPS-NHL, and 4 UC.ResultsNumbers of CD138+ plasma cells, CD20+ B cells, and CD3+ T cells were significantly increased (50 fold, 30 fold, and an almost 3 fold increase, respectively; p-values: 1.34E-06, 3.26E-04, and 2.52E-6) in the bladders of IC/BPS-HL patients compared to UC. Patients with IC/BPS-HL had significantly elevated urinary levels of IL-6 (p=0.0028) and TNF-α (p=0.009) compared to patients with IC/BPS-NHL and UC. In contrast, IL-12p70 levels were significantly higher in the patients with IC/BPS-NHL than in HL patients (p=0.033). No significant difference in IL-12p70 levels were observed between IC/BPS-HL and UC.ConclusionDifferent cytokines were elevated in the urine of IC/BPS patients with and without HL, suggesting differences in underlying disease processes. Elevated levels of CD138+, CD20+, and CD3+ cells in HL indicate B and T-cell involvement in lesion formation. Determining which cytokines and immunological pathways are present in IC/BPS-HL could elucidate the disease mechanism.

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THE EFFECTIVENESS OF TNF-Α INHIBITOR THERAPY IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Indonesian Journal of Urology ◽

10.32421/juri.v28i2.744 ◽

2021 ◽

Vol 28 (2) ◽

pp. 194-201

Author(s):

Ahmad Kholis ◽

Soetojo ◽

Wahjoe Djatisoesanto

Keyword(s):

Systematic Review ◽

Interstitial Cystitis ◽

Meta Analysis ◽

Pain Syndrome ◽

Response Assessment ◽

Bladder Pain Syndrome ◽

Inhibitor Therapy ◽

Global Response ◽

Bladder Pain ◽

Tnf Α

Objective: To evaluate the effectiveness of TNF-α inhibitor therapy in Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) patients compared to placebo, assessed using Global Response Assessment (GRA). Material & Methods: A systematic review and meta-analysis. Subjects were patients with moderate to severe diagnosis of BPS/IC who were given TNF-α inhibitor versus placebo, with the Global Response Assessment (GRA) (patient-reported self-reported BPS/IC treatment response scale). A systematic literature search was carried out on the English databases PubMed/MEDLINE and Science Direct, published until September 2020. Data were extracted independently and assessed the bias and quality of each selected article. Results: Initially there were 124 studies. After further selection, 2 RCT studies were included in the criteria for this study. The number of samples obtained was 85 patients. There is 1 study that used 400 mg of certolizumab pegol subcutaneously and 1 study used adalimumab 80 mg subcutaneously and followed by 40 mg subcutaneously for 2 weeks. Both studies had statistically low heterogeneity with I2 = 0% (P = 0.34), so fixed effect statistical model was used to determine the result. Furthermore, there was no significant difference (P = 0.32) between the number of GRA responders from the TNF-α inhibitor and placebo therapy groups, with odds ratio of 1.61 (CI = 0.65-4.00). Conclusion: TNF-α inhibitor therapy did not increase GRA responders when compared to placebo.

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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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Biopsychosocial predictors of suicide risk in patients with interstitial cystitis/bladder pain syndrome

Canadian Urological Association Journal ◽

10.5489/cuaj.7337 ◽

2021 ◽

Vol 15 (12) ◽

Author(s):

Dean A. Tripp ◽

Joel Dueck ◽

Ronald R. Holden ◽

Julia Moreau ◽

R. Christopher Doiron ◽

...

Keyword(s):

Interstitial Cystitis ◽

Support Groups ◽

Suicide Risk ◽

Pain Syndrome ◽

Bladder Pain Syndrome ◽

Perceived Burdensomeness ◽

Bladder Pain ◽

Pain Symptoms ◽

Risk Predictors ◽

The Impact

Introduction: The impact of interstitial cystitis/bladder pain syndrome (IC/BPS) is prevalent and severe. Studies examining the IC/BPS prevalence and predictors of suicide risk are limited by their lack of theoretically relevant suicide research variables. This research reports suicide risk prevalence its biopsychosocial predictors for a community IC/BPS sample. Methods: Self-identified female patients suffering from IC/BPS (N=813; 18–80 years, M= 46.60, standard deviation [SD] 14.10) recruited from online IC/BPS support groups completed measures of demographic, pain, symptoms, and psychosocial variables. Descriptive statistics, correlations, and multivariable logistic regressions examined prevalence, variable associations, and suicide risk prediction. Results: Suicide risk prevalence was 38.1%. Suicide risk was associated with greater odds for exposure to suicide, psychache, hopelessness, and perceived burdensomeness to others. Further, examining suicide risk by levels of pain showed that exposure to suicide and hopelessness were consistent suicide risk predictors across pain levels; psychache for lower levels of pain, perceived burdensomeness in moderate and severe pain levels, and depression in moderate levels of pain. Conclusions: The high prevalence of suicide risk is alarming and signifies an imperative for recognizing this risk within the IC/BPS population. The identified psychosocial risk factors may be used in refining screening and treatment and in directing future IC/BPS research.

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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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