The Expression of Inflammatory Mediators in Bladder Pain Syndrome

Abstract

BackgroundBladder pain syndrome (BPS) pathology is poorly understood. Treatment strategies are empirical, with limited efficacy, and affected patients have diminished quality of life.ObjectiveWe examined the hypothesis that inflammatory mediators within the bladder contribute to BPS pathology.Design, setting, and participantsFifteen women with BPS and 15 women with stress urinary incontinence without bladder pain were recruited from Cork University Maternity Hospital from October 2011 to October 2012. During cystoscopy, 5-mm bladder biopsies were taken and processed for gene expression analysis. The effect of the identified genes was tested in laboratory animals.Outcome measures and statistical analysisWe studied the expression of 96 inflammation-related genes in diseased and healthy bladders. We measured the correlation between genes and patient clinical profiles using the Pearson correlation coefficient.Results and limitationsAnalysis revealed 15 differentially expressed genes, confirmed in a replication study. FGF7 and CCL21 correlated significantly with clinical outcomes. Intravesical CCL21 instillation in rats caused increased bladder excitability and increased c-fos activity in spinal cord neurons. CCL21 atypical receptor knockout mice showed significantly more c-fos upon bladder stimulation with CCL21 than wild-type littermates. There was no change in FGF7-treated animals. The variability in patient samples presented as the main limitation. We used principal component analysis to identify similarities within the patient group.ConclusionsOur study identified two biologically relevant inflammatory mediators in BPS and demonstrated an increase in nociceptive signalling with CCL21. Manipulation of this ligand is a potential new therapeutic strategy for BPS.Patient summaryWe compared gene expression in bladder biopsies of patients with bladder pain syndrome (BPS) and controls without pain and identified two genes that were increased in BPS patients and correlated with clinical profiles. We tested the effect of these genes in laboratory animals, confirming their role in bladder pain. Manipulating these genes in BPS is a potential treatment strategy.

Improving the barrier function of damaged cultured urothelium using chondroitin sulfate

“…The stainings show the effect of the two secondary antibodies used, Alexa 488 donkey antimouse, and donkey antirabbit in A and B, respectively, with the omission of the primary antibodies animal models have established that it contributes to the barrier function. 5,8,9,11 An in vitro study by Janssen et al 8 showed that specific removal of CS with the enzyme chondroitinase significantly reduced barrier function as measured by TEER. One main treatment strategy in BPS/ IC aims at recovery of the barrier function through exogenous GAG-replenishment.…”

“…8 These results were later confirmed in vivo in a mouse and a rat model. [10][11][12] Offiah demonstrated that removing the urothelial GAGs in the rat bladder induces comparable symptoms as seen in BPS/IC patients such as inflammation, pain, and increased excitability of the urinary bladder. 11 In BPS/IC patients, intravesical GAGreplenishment therapy is frequently applied to restore the GAG layer, improve the urothelial barrier and thus relieve complaints.…”

“…[10][11][12] Offiah demonstrated that removing the urothelial GAGs in the rat bladder induces comparable symptoms as seen in BPS/IC patients such as inflammation, pain, and increased excitability of the urinary bladder. 11 In BPS/IC patients, intravesical GAGreplenishment therapy is frequently applied to restore the GAG layer, improve the urothelial barrier and thus relieve complaints. 13 In addition to BPS/IC, other indications for GAG-replenishment therapy are being investigated, such as chronic forms of cystitis including postradiation cystitis and recurrent urinary tract infections could possibly benefit from this therapy.…”

Interstitial cystitis, bladder pain syndrome, hypersensitive bladder, and interstitial cystitis/bladder pain syndrome – clarification of definitions and relationships

“…Gene expression studies have uniformly indicated over-expression of pro-inflammatory cytokines and ligands or cellular receptors to noxious stimuli. [9][10][11][12][13][14][15] Further studies demonstrate B-cell dominant lymphocytic infiltration and activation of the infiltrating B-cells. Furthermore, light-chain restriction, index of the clonal Y HOMMA expansion of B-cells, is frequently observed in the infiltrating B-cells of HIC bladder.…”

“…In other words, HIC is pan‐cystitis associated with epithelial denudation. Gene expression studies have uniformly indicated over‐expression of pro‐inflammatory cytokines and ligands or cellular receptors to noxious stimuli . Further studies demonstrate B‐cell dominant lymphocytic infiltration and activation of the infiltrating B‐cells.…”