UPK3A+ umbrella cell damage mediated by TLR3-NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome.

Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner-type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single-cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A+ umbrella cells and a simultaneous increase in progenitor-like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A+ umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A+ umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A+ umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A+ umbrella cells in HIC urothelium. Finally, we conducted in vitro and in vivo experiments to confirm the potential of the TLR3-NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.

APRIL/BAFF upregulation is associated with clonal B-cell expansion in Hunner-type interstitial cystitis.

Hunner-type interstitial cystitis (HIC) is a chronic inflammatory disease of the urinary bladder with an unknown etiology. We conducted comprehensive immunogenomic profiling of bladder specimens obtained by biopsy and cystectomy from 37 patients with HIC. Next-generation RNA sequencing demonstrated abundant plasma cell infiltration with frequent light chain restriction in HIC-affected bladder tissue. Subsequent analysis of the B-cell receptor repertoire revealed spatial and temporal expansion of B-cell clones. The extent of B-cell clonal expansion was significantly correlated with the gene expression levels of TNFSF13 and TNFSF13B, which encode APRIL and BAFF, respectively. These findings indicate that APRIL and BAFF are the key regulators of clonal B-cell expansion in HIC and might serve as therapeutic targets in this debilitating disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Lactoferrin in the treatment of interstitial cystitis: a retrospective pilot study.

Interstitial cystitis (IC), defined as a painful bladder syndrome (PBS), is a chronic condition that manifests itself as a suprapubic pain associated with an enhancing of frequency/urgency of urination, and for which there is no cure. Here, we present a retrospective pilot study on women affected from IC/PBS and treated with bovine lactoferrin (bLf). A total of 31 women, affected (20) or unaffected (11) from hereditary thrombophilia (HT), presented the median of 6 episodes of IC/PBS during the 6 months before the study. Treatment consisted of 17 weeks of orally administered Valpalf® capsules, containing bLf plus sodium bicarbonate and citrate. Out of 31 patients, only 3 women had one episode of IC/PBS during the follow-up period, while no episode was observed in 28 women. In the HT group, a significant decrease in both serum IL-6 and D-dimers was found after Valpalf® treatment. Moreover, in Valpalf®-treated women, cystoscopy revealed a global improvement in the appearance of the bladder, especially in term of inflammation/irritation and presence of Hunner ulcers. Even if our results must be corroborated by randomized double-blinded controlled trials on a larger number of patients, our observations indicate that bLf treatment is efficient in relieving IC/PBS symptoms, without side effects.

Urologic Chronic Pelvic Pain Syndrome Flares: A Comprehensive, Systematic Review and Meta-Analysis of the Peer-Reviewed Flare Literature.

PURPOSE: We sought to systematically review and summarize the peer-reviewed literature on urologic chronic pelvic pain syndrome flares, including their terminology, manifestation, perceived triggers, management and prevention strategies, impact on quality of life, and insights into pathophysiologic mechanisms, as a foundation for future empirical research. MATERIALS AND METHODS: We searched 6 medical databases for articles related to any aspect of symptom exacerbations for interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. A total of 1486 abstracts and 398 full-text articles were reviewed, and data were extracted by at least 2 individuals. RESULTS: Overall, we identified 59 articles, including 36 qualitative, cross-sectional, or case-control; 15 cohort-based; and 8 experimental articles. The majority of studies described North American patients with confirmed diagnoses. "Flare" was a commonly used term, but additional terminology (eg, exacerbation) was also used. Most flares involved significant increases in pain intensity, but less data were available on flare frequency and duration. Painful, frequent, long-lasting, and unpredictable flares were highly impactful, even over and above participants' nonflare symptoms. A large number of perceived triggers (eg, diet, stress) and management/prevention strategies (eg, analgesics, thermal therapy, rest) were proposed by participants, but few had empirical support. In addition, few studies explored underlying biologic mechanisms. CONCLUSIONS: Overall, we found that flares are painful and impactful, but otherwise poorly understood in terms of manifestation (frequency and duration), triggers, treatment, prevention, and pathophysiology. These summary findings provide a foundation for future flare-related research and highlight gaps that warrant additional empirical studies.

Elucidation of the pathophysiology of interstitial cystitis/bladder pain syndrome via experimental autoimmune cystitis rat model.

Although the cause of interstitial cystitis/painful bladder syndrome (IC/PBS) remains unknown, autoimmune involvement has been strongly suggested to be a contributing factor. To elucidate the pathophysiology of IC/PBS, we characterized the experimental autoimmune cystitis (EAC) in rats. Adult female Sprague-Dawley rats were divided into the EAC and control groups. The EAC rats were generated by administrating a homogenate of donor rat bladder tissue as a bladder antigen. The characteristics of the two groups were determined by evaluating pain behavior and conducting cystometry, histopathology, and molecular analyses. The EAC rats showed: 1) a decreased paw withdrawal threshold, 2) a reduced intercontraction interval on cystometry, 3) the irregular surfaces of the umbrella cells of epithelium throughout the bladder wall, 4) accumulation of stress granules in the bladder and vascular endothelium, 5)the increased expression of genes related to inflammation and ischemia at the mRNA and protein levels, 6) a significantly increased paw withdrawal threshold with pain treatment, and 7) the induction of glomerulation of the bladder wall, epithelium denudation, and lymphocyte infiltration in the interstitium by bladder distension. These results suggest that the EAC rats showed pain and frequent urination with the overexpression of inflammatory chemokines, reflecting clinical IC/BPS, and the bladder epithelium and vascular endothelium may be the primary sites of IC/BPS, and bladder injury, such as bladder distension, can cause progression from BPS to IC with Hunner lesions.NEW & NOTEWORTHY The experimental autoimmune cystitis model rats showed pain and frequent urination with the overexpression of inflammatory chemokines, reflecting clinical interstitial cystitis/painful bladder syndrome (IC/PBS), and the bladder epithelium and vascular endothelium may be the primary sites of IC/BPS, and bladder injury, such as bladder distension, can cause progression from BPS to IC with Hunner lesions.

A biophysically comprehensive model of urothelial afferent neurons: implications for sensory signalling in urinary bladder.

The urothelium is the innermost layer of the bladder wall; it plays a pivotal role in bladder sensory transduction by responding to chemical and mechanical stimuli. The urothelium also acts as a physical barrier between urine and the outer layers of the bladder wall. There is intricate sensory communication between the layers of the bladder wall and the neurons that supply the bladder, which eventually translates into the regulation of mechanical activity. In response to natural stimuli, urothelial cells release substances such as ATP, nitric oxide (NO), substance P, acetylcholine (ACh), and adenosine. These act on adjacent urothelial cells, myofibroblasts, and urothelial afferent neurons (UAN), controlling the contractile activity of the bladder. There is rising evidence on the importance of urothelial sensory signalling, yet a comprehensive understanding of the functioning of the urothelium-afferent neurons and the factors that govern it remains elusive to date. Until now, the biophysical studies done on UAN have been unable to provide adequate information on the ion channel composition of the neuron, which is paramount to understanding the electrical functioning of the UAN and, by extension, afferent signalling. To this end, we have attempted to model UAN to decipher the ionic mechanisms underlying the excitability of the UAN. In contrast to previous models, our model was built and validated using morphological and biophysical properties consistent with experimental findings for the UAN. The model included all the channels thus far known to be expressed in UAN, including; voltage-gated sodium and potassium channels, N, L, T, P/Q, R-type calcium channels, large-conductance calcium-dependent potassium (BK) channels, small conductance calcium-dependent (SK) channels, Hyperpolarisation activated cation (HCN) channels, transient receptor potential melastatin (TRPM8), transient receptor potential vanilloid (TRPV1) channel, calcium-activated chloride(CaCC) channels, and internal calcium dynamics. Our UAN model a) was constrained as far as possible by experimental data from the literature for the channels and the spiking activity, b) was validated by reproducing the experimental responses to current-clamp and voltage-clamp protocols c) was used as a base for modelling the non-urothelial afferent neurons (NUAN). Using our models, we also gained insights into the variations in ion channels between UAN and NUAN neurons.

Bladder instillations vs onabotulinumtoxinA injection for interstitial cystitis/bladder pain syndrome: a randomized clinical trial.

BACKGROUND: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is an unpleasant sensation related to the bladder with lower urinary tract symptoms lasting more than 6 weeks, unrelated to an otherwise identifiable cause. The etiology is likely multifactorial including urothelial abnormalities, neurogenic pain upregulation, and potentially bladder and vaginal microbiome alterations. Despite treatment effectiveness of both bladder instillations and intradetrusor onabotulinumtoxinA injection for this condition, a head-to-head comparison has not been performed. OBJECTIVE: To compare the efficacy of bladder instillations and intradetrusor onabotulinumtoxinA injection for treatment of IC/BPS. STUDY DESIGN: Patients with O'Leary-Sant (OLS) questionnaire scores of ≥6, meeting clinical criteria for IC/BPS, and desiring procedural management were randomized to bladder instillations or intradetrusor onabotulinumtoxinA injection. The primary outcome was the difference in OLS scores at 2 months posttreatment between groups. Secondary outcomes included evaluation of sexual function, physical/mental health status, pain, patient satisfaction, treatment perception, retreatment, and adverse event rates. RESULTS: Forty-seven patients were analyzed with 22 randomized to bladder instillations and 25 to onabotulinumtoxinA injection. There were no differences in demographic and clinical characteristics between groups. From baseline to 2 months posttreatment, there was a decrease in OLS subscales in all patients (Interstitial Cystitis Symptom Index [ICSI] -6.3 (confidence interval [CI] -8.54, -3.95), P<.0001; Interstitial Cystitis Problem Index [ICPI] -5.9 (CI -8.18, -3.57), P<.0001). At 2 months posttreatment, patients in the onabotulinumtoxinA group had significantly lower OLS scores compared to those in the bladder instillation group (ICSI 6.3±4.5 [onabotulinumtoxinA] vs 9.6±4.2 [instillation], P=.008; ICPI 5.9±5.1 [onabotulinumtoxinA] vs 8.3±4.0 [instillation], P=.048). The difference in OLS scores between groups did not persist at 6 to 9 months posttreatment. There were no statistically significant differences between baseline and posttreatment time points for the remaining questionnaires. Eight percent of patients who received onabotulinumtoxinA injection experienced urinary retention requiring self-catheterization. Patients who underwent onabotulinumtoxinA injection were significantly less likely to receive retreatment within 6 to 9 months compared to patients who received bladder instillations (relative risk 13.6; 95% CI, 1.92-96.6; P=.0002). There were no differences between groups regarding patient satisfaction, perception of treatment convenience, or willingness to undergo retreatment. CONCLUSION: Both onabotulinumtoxinA injection and bladder instillations are safe, effective treatments for patients with IC/BPS, with significant clinical improvement demonstrated at 2 months posttreatment. Our findings suggest that intradetrusor onabotulinumtoxinA injection is a more effective procedural treatment for this condition than bladder instillation therapy and associated with decreased rates of retreatment.

The microbiota in patients with interstitial cystitis/bladder pain syndrome: a systematic review.

OBJECTIVE: To comprehensively review and critically assess the literature on microbiota differences between patients with interstitial cystitis (IC)/bladder pain syndrome (BPS) and normal controls and to provide clinical practice guidelines. MATERIALS AND METHODS: In this systematic review, we evaluated previous research on microbiota disparities between IC/BPS and normal controls, as well as distinctions among IC/BPS subgroups. A comprehensive literature search was conducted across PubMed/MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. Relevant studies were shortlisted based on predetermined inclusion and exclusion criteria, followed by quality assessment. The primary focus was identifying specific taxonomic variations among these cohorts. RESULTS: A total of 12 studies met the selection criteria. Discrepancies were adjudicated by a third reviewer. The Newcastle-Ottawa Scale was used to assess study quality. Predominantly, the studies focused on disparities in urine microbiota between IC/BPS patients and normal controls, with one study examining gut microbiota differences between the groups, and two studies exploring vaginal microbiota distinctions. Unfortunately, analyses of discrepancies in other microbiota were limited. Our findings revealed evidence of distinct bacterial abundance variations, particularly involving Lactobacillus, alongside variations in specific metabolites among IC/BPS patients compared to controls. CONCLUSIONS: Currently, there is evidence suggesting significant variations in the diversity and species composition of the urinary microbiota between individuals diagnosed with IC/BPS and control groups. In the foreseeable future, urologists should consider urine microbiota dysbiosis as a potential aetiology for IC, with potential clinical implications for diagnosis and treatment.

Classification systems for chronic pelvic pain in males: a systematic review.

OBJECTIVE: To systematically review the classification systems for male chronic pelvic pain (CPP). METHODS: The Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), and Web of Science were searched. Any publication, with no restriction to publication date, was eligible. Publications had to propose a classification system for CPP in males or provide additional information of a system that had been identified. Systems were assessed with an adapted Critical Appraisal of Classification Systems tool. RESULTS: A total of 33 relevant publications were identified, with 22 proposing an original classification system. Systems aimed to: (i) diagnose CPP and/or differentially diagnose CPP from other conditions, (ii) differentially diagnose subtypes within CPP, or (iii) identify features that could inform underlying mechanisms and/or treatment selection. Conditions referred to as chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis/bladder pain syndrome were most represented. Clinical signs/symptoms, pathoanatomical investigations, and presumed pain mechanisms were used for classification. Quality of systems was low to moderate, implying limitations to consider for their interpretation. CONCLUSIONS: Many classification systems for CPP in males exist. Careful consideration of their intended purpose is required. Future work should examine whether outcomes for patients are improved when decisions are guided by their use.

Psychosexological correlates of 372 women with vulvodynia, overactive pelvic floor, postcoital cystitis, and interstitial cystitis.

BACKGROUND: Among the plethora of urogynecological conditions possibly affecting women, some of them, less explored, have significant impacts on sexological and psychological health, with a mutual influence. AIM: The aim of this study was to investigate the sexological and psychological correlates of four urogynecological pathologies in a sample of women of childbearing age: overactive pelvic floor, vulvodynia, postcoital cystitis, and interstitial cystitis. Women cured of these conditions were also included, to assess the same aspects after the remission of physical symptoms. METHODS: We recruited 372 women with an average age of 33.5 years through an online platform shared by a popular forum for women with urogynecological pathologies between March and May 2021. The participants filled out a socio-anamnestic questionnaire and a set of psychometric tests. OUTCOMES: Participant data were collected by use of the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Toronto Alexithymia Scale-20, Female Sexual Function Index, and Orgasmometer-F, and the SPSS (Statistical Package for Social Sciences) v.26 was used for data analysis. RESULTS: Overactive pelvic floor was reported by 66.4% of the women, vulvodynia by 55%, postcoital cystitis by 58.8%, and interstitial cystitis by 8.3%, and these conditions were often comorbid with each other, with 9.4% and 7% of women reporting having suffered psychological and sexual abuse, respectively. The presence of past abuse was correlated with overactive pelvic floor (P < .05), vulvodynia (P < .01), and major depression (P < .01). Significantly more depression occurred in women with vulvodynia than in the other subgroups (P < .05), except for women with only an overactive pelvic floor. There was no difference between the subgroups in the occurrence of alexithymia, sexual function, and orgasm (P < .05). Interestingly, the prevalence of sexual dysfunction increased in cured women. CLINICAL IMPLICATIONS: The lack of significant differences, except for depression, between the pathological subgroups suggests a similar clinical and psychological relevance of the four pathologies studied. The persistence of sexual dysfunctions in cured women may be related to a residual dysfunctional relational modality with the partner. STRENGTHS AND LIMITATIONS: The evaluation of both psychological and sexological variables in a group of less-explored urogynecological conditions represents a strength of this study, while a lack of a face-to-face assessment could represent a limitation. CONCLUSION: The results of the present study should promote psychosexological interventions in women with these diseases, both during the pathological state and after remission.

EBV infection mediated BDNF expression is associated with bladder inflammation in interstitial cystitis/bladder pain syndrome with Hunner's lesion.

Interstitial cystitis/bladder pain syndrome with Hunner's lesion (HIC) is characterized by chronic inflammation and nerve hyperplasia; however, the pathogenesis of HIC remains a mystery. In this study, we detected both Epstein-Barr virus (EBV) latency infection genes EBNA-1 and LMP-1 and EBV lytic infection BZLF-1 and BRLF-1 expression in the HIC bladders, indicating the coexistence of EBV persistence and reactivation in the B cells in HIC bladders. Upregulation of EBV-associated inflammatory genes in HIC bladders, such as TNF-α and IL-6, suggests EBV infection is implicated in the pathogenesis of bladder inflammation. Nerve hyperplasia and upregulation of brain-derived neurotrophic factor (BDNF) were noted in the HIC bladders. Double immunochemical staining and flow cytometry revealed the origin of BDNF to be EBV-infected B cells. Inducible BDNF expression was noted in B cells upon EBV infection, but not in the T cells. A chromatin immunoprecipitation study revealed BDNF transcription could be promoted by cooperation between EBV nuclear antigens, chromatin modifiers, and B-cell-specific transcription. Knockdown of BDNF in EBV-infected B cells resulted in the inhibition of cell proliferation and viability. Downregulation of phosphorylated SMAD2 and STAT3 after BDNF knockdown may play a role in the mechanism. Implantation of latent EBV-infected B cells into rat bladder walls resulted in a higher expression level of CD45 and PGP9.5, suggesting tissue inflammation and nerve hyperplasia. In contrast, implantation of BDNF depleted EBV-infected B cells abrogated these effects. This is the first study to provide insights into the mechanisms underlying the involvement of EBV-infected B cells in HIC pathogenesis. © 2022 The Pathological Society of Great Britain and Ireland.

Coping With Interstitial Cystitis/Bladder Pain Syndrome.

AIMS: Compensatory coping, or maladaptive alterations in behavior with the intention of preventing or managing symptoms, is increasingly being explored as a key factor in how people respond to bladder conditions. Preliminary investigations have identified relations between coping behaviors and psychological distress in urologic conditions, including interstitial cystitis/bladder pain syndrome (IC/BPS). However, previous explorations of coping have not accounted for heterogeneity in coping behaviors or addressed the likelihood that some coping behaviors may be more adaptive than others. This study sought to examine how two specific types of coping behaviors, primary control coping and disengaged coping, are related to distress and symptoms in IC/BPS, and to explore the potential role of pain phenotype in this relationship. MATERIALS AND METHODS: A secondary data analysis was conducted with a large community data set (N = 677 women with IC/BPS) and employed descriptive and inferential statistics to characterize coping patterns and explore novel predictors of distress. RESULTS: Results indicated that almost all participants engaged in at least one compensatory coping behavior within the last week. Both types of coping behaviors correlated with psychological symptoms, and when controlling for relevant clinical variables (i.e., age and severity of urinary symptoms), disengaged coping behaviors were significantly associated with psychological distress. Further, the addition of pain phenotype to multiple regression models resulted in a more effective predictive model when considering the relation between coping behaviors and depression. CONCLUSIONS: By investigating more deeply the relationship between coping and distress, understanding of potential risk factors and mechanisms is increased, offering valuable insights for intervention strategies for IC/BPS patients.

Multi-omics analyses uncover metabolic signatures and gene expression profiles of interstitial cystitis/bladder pain syndrome.

BACKGROUND AND OBJECTIVE: We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets. METHODS: Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. RESULTS: We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. CONCLUSIONS: Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.

Brainstem nuclei responsive to cystometry in both endometriosis and cystitis rat models: C-fos immunohistochemistry study.

PURPOSE: Although the co-occurrence of interstitial cystitis (IC) and endometriosis (ENDO) is remarkably high, the exact pathophysiology for this co-occurrence is unknown. The convergence of the inputs from the involved structures to the same neuronal centers may suggest neuronal hyperexcitability as a mechanism for this co-occurrence. METHODS: The present study aimed to investigate the association between IC and ENDO, by studying the changes in brainstem responses to cystometry in a rat model of ENDO and cyclophosphamide (CYP)-induced IC using c-fos immunohistochemistry. RESULTS: Following cystometry the brainstem areas that had significant increase in c-fos expression in ENDO alone included: periaqueductal gray (PAG) nuclei, dorsal raphe nucleus, raphe obscurus nucleus, kolliker- Fuse areas, and area postrema. However, the brainstem areas that had increased significantly in the c-fos expression in the ENDO and CYP treated animals included: gigantocellular nucleus, lateral paragigantocellular nucleus, caudoventrolateral nucleus, rostroventrolateral/caudoventrolateral nucleus, lateral reticular nucleus, locus coeruleus, lateral PAG, raphe pallidus nucleus, raphe magnus nucleus, rostroventrolateral nucleus, dorsal motor nucleus of vagus, and solitary tract nucleus. Whereas only lateral parabrachial nucleus showed significant increase in c-fos expression in CYP treated animals alone. CONCLUSIONS: The results of the present study demonstrate the overlap of brainstem nuclei that are excited by urinary bladder under ENDO and IC conditions. The pattern of hyperexcitability of the brainstem nuclei may help in understating the pathophysiology of IC and ENDO conditions.

The effects of a galectin-3 inhibitor on bladder pain syndrome in mice with cyclophosphamide-induced cystitis.

AIMS: To explore the effect of blocking galectin-3 in the bladder pain syndrome associated with interstitial cystitis. METHODS: A galectin-3 inhibitor was used to treat mice with cyclophosphamide-induced cystitis. The expression of galectin-3 in bladder tissues and urine was examined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Suprapubic-pelvic pain, bladder voiding, bladder pain-like nociceptive behavior, and referred hyperalgesia were assessed. The weights of the bladders were also measured, and inflammatory cell infiltration and inflammatory cytokine levels were examined by histopathological evaluation. The inflammatory cytokines interleukin 1ß (IL-1ß), nerve growth factor (NGF), IL-6, and tumor necrosis factor α (TNF-α) were measured by ELISA. RESULTS: Increases in galectin-3 levels, inflammation, bladder weight, and bladder pain-related symptoms were observed in bladders with cyclophosphamide-induced cystitis. Administration of the galectin-3 inhibitor significantly mitigated bladder pain-related symptoms and inflammatory response. In response to the 500 µM dose of the galectin-3 inhibitor, nociceptive behaviors, nociceptive score, and bladder-to-body weight ratios were reduced by 65.1%, 65.3%, and 40.3%, respectively, while 500 µM Gal-3 inhibitor increased pelvic pain threshold by 86.7%. Moreover, galectin-3 inhibitor treatment inhibited the inflammation. Compared to untreated CYP-induced mice, there were significant changes in the levels of IL-1ß (41.72 ± 2.05 vs. 18.91 ± 2.26 pg/mg tissues), NGF (9.64 ± 0.38 vs. 1.88 ± 0.05 pg/mg tissues), IL-6 (42.67 + 1.51 vs. 21.26 + 2.78 pg/mg tissues, and TNF-α (22.02 ± 1.08 vs. 10.70 ± 0.80 pg/mg tissues) in response to the highest dose of the Gal-3 inhibitor subgroup (500 µM), and 500 µM Gal-3 inhibitor reduced mast cell infiltration ratios by 71.8%. CONCLUSIONS: The galectin-3 inhibitor relieved pelvic pain, urinary symptoms, and bladder inflammation in mice with cyclophosphamide-induced cystitis. Thus, galectin-3 inhibitors may be novel agents in interstitial cystitis treatment.

The efficacy and safety of monoclonal antibody therapies for interstitial cystitis/bladder pain syndrome: A meta-analysis of randomized controlled trials.

OBJECTIVES: This study aimed to assess the efficacy and safety of monoclonal antibody therapies (MATs) for interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: A systematic search was conducted across databases including PubMed, Embase, clinicalTrial.gov, and the Cochrane Library Central Register of Controlled Trials. Randomized controlled trials (RCTs) comparing MATs versus placebo were included. Primary outcomes comprised the Global Response Assessment (GRA) scale and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI). Additional analyses encompassed mean daily frequency of voids, the O'Leary-Sant Interstitial Cystitis Problem Index, pain scores, and complications. Statistical analyses were performed using Review Manager 5.3. RESULTS: Five high-quality RCTs, comprising 263 patients with IC/BPS, were ultimately selected. MATs were generally effective in treating IC/BPS. Patients receiving MATs exhibited a higher satisfaction rate (odds ratio [OR]: 2.7, confidence interval [CI]: 1.31-5.58, p = 0.007) and lower ICSI scores (mean difference [MD]: -1.44, CI: -2.36 to -0.52, p = 0.002). Moreover, MAT recipients experienced reduced pain (MD: -0.53, CI: -0.79 to -0.26, p < 0.0001) and decreased frequency of urination (MD: -1.91, CI: -2.55 to -1.27, p < 0.00001). Importantly, there were no disparities regarding complication incidence in the MAT and control groups. CONCLUSIONS: The current findings indicate that MATs are effective and safe for treating IC/BPS. Nonetheless, future RCTs with larger sample sizes and long-term follow-up are warranted.

Validation of a simple body map to measure widespread pain in urologic chronic pelvic pain syndrome: A MAPP Research Network study.

PURPOSE: In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only. MATERIALS AND METHODS: A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site. RESULTS: Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations. CONCLUSIONS: These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes.

A systematic and comprehensive review of the role of microbiota in urinary chronic pelvic pain syndrome.

BACKGROUND: Many genitourinary tract disorders could be attributed partly to the microbiota. This study sought to conduct a systematic review of the role of the microbiota in urinary chronic pelvic pain syndrome (UCPPS). METHODS: We searched Embase, Scopus, Web of Science, and PubMed with no time, language, or study type restrictions until December 1, 2023. The JBI Appraisal Tool was used to assess the quality of the studies. Study selection followed the PRISMA statement. Studies addressing microbiome variations among patients suffering from interstitial cystitis/bladder pain syndrome (IC/BPS) or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and a control group were considered eligible. RESULTS: A total of 21 studies (1 UCPPS, 12 IC/BPS, and 8 CP/CPPS) comprising 1125 patients were enrolled in our final data synthesis. It has been shown that the reduced diversity and discrepant composition of the gut microbiota may partly be attributed to the UCPPS pathogenesis. In terms of urine microbiota, some operational taxonomic units were shown to be elevated, while others became less abundant. Furthermore, various bacteria and fungi are linked to specific clinical features. Few investigations denied UCPPS as a dysbiotic condition. CONCLUSIONS: Urinary and intestinal microbiota appear to be linked with UCPPS, comprising IC/BPS and CP/CPPS. However, given the substantial disparity of published studies, a battery of prospective trials is required to corroborate these findings.

Cytokines in Bladder Pain Syndrome: A Review of the Literature.

INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome (BPS) is poorly understood with both the aetiology and pathophysiology being unknown. Symptoms overlap with other disorders, such as overactive bladder (OAB) and chronic pelvic pain disorders such as endometriosis, making a consensus on how to diagnosis and manage patients challenging. The development of biomarkers for BPS may be the key to understanding more about its pathophysiology, as well as aiding diagnosis, subclassification, and discovering new drug targets for its management. As inflammation is widely understood to hold a central role in BPS, the evaluation of cytokines has gained interest. This article summarises the current literature and understanding of urinary, serum, and bladder tissue cytokines found elevated in patients with bladder pain syndrome. METHODS: literature search using Pub Med with the keywords "bladder pain syndrome", "painful bladder syndrome", "bladder pain", "Interstitial cystitis" AND "cytokines" or "inflammation". This study was except from institutional approval. RESULTS: Thirty-six cytokines have been identified as being statistically significantly elevated in either the serum, urine, or bladder tissue of patients with bladder pain syndrome in the 22 studies identified in this review of the literature. These cytokines include those from the interleukin group (n = 14), the CXC chemokine group (n = 5), and the C-C chemokine group (n = 7). CONCLUSIONS: CXCL-1, CXCL-8, CXCL-9, CXCL-10, CXCL-11 from the CXC chemokine group, and CCL2, CCL4, CCL5, CCL7, and CCL11 from the C-C chemokine group have been found to be significantly elevated in patients with bladder pain in the literature. Many of these analytes also have supporting evidence for their roles in bladder pain from animal models and studies in other chronic inflammatory conditions. It is likely that a single cytokine will not serve as an adequate biomarker of disease in bladder pain syndrome for either diagnosis or disease severity. Instead, panels of inflammatory mediators may reveal more about the different pathways of inflammation leading to similar presentations of bladder pain in patients.

Believing women: a qualitative exploration of provider disbelief and pain dismissal among women with interstitial cystitis/bladder pain syndrome from the MAPP research network.

INTRODUCTION AND HYPOTHESIS: Although allusions to the importance of a good physician-patient relationship are present throughout the interstitial cystitis/bladder pain syndrome (IC/BPS) literature, qualitative analysis of patients' perspectives on the clinical encounter is lacking, particularly among women who are most commonly affected by IC/BPS. Therefore, we adopted a patient-centered experiential approach to understanding female patients' perception of clinical encounters. METHODS: We re-analyzed previously collected data from a qualitative study on patient flare experiences including eight focus groups of female IC/BPS patients (n = 57, mean = 7/group). Qualitative analysis applied grounded theory to index all physician-patient interactions, then thematically coded these interactions to elucidate common experiences of clinical encounters. RESULTS: Women with IC/BPS shared common experiences of provider disbelief and pain dismissal. Discussions with participants demonstrated the extent to which these negative encounters shape patients' health care-seeking behavior, outlook, and psychosocial well-being. Appearing in more than one guise, provider disbelief and dismissal occurred as tacit insinuations, explicit statements, silence, oversimplification, and an unwillingness to listen and discuss alternative treatment. As a result, women adopted several strategies including: rotating specialists; "testing" physicians; self-advocacy; self-management; avoiding the stigma of chronic pain; crying; and opting for alternative medicine over biomedicine. CONCLUSIONS: The prevalence of provider disbelief and pain dismissal among women with IC/BPS indicates a need to improve physician-patient communication, informed by the struggles, anxieties, and gendered inequities that female patients with chronic pain experience in their diagnostic journey. Results suggest that further investigation into the power dynamics of clinical encounters might be required.