Interstitial cystitis/bladder pain syndrome (IC/BPS) is a multifactorial, chronic bladder disorder with limited therapeutic options currently available. The present review provides an extensive overview of therapeutic approaches used in in vitro, ex vivo, and in vivo experimental models of IC/BPS. Publications were identified by electronic search of three online databases. Data were extracted for study design, type of treatment, main findings, and outcome, as well as for methodological quality and the reporting of measures to avoid bias. A total of 100 full-text articles were included. The majority of identified articles evaluated therapeutic agents currently recommended to treat IC/BPS by the American Urological Association guidelines (21%) and therapeutic agents currently approved to treat other diseases (11%). More recently published articles assessed therapeutic approaches using stem cells (11%) and plant-derived agents (10%), while novel potential drug targets identified were proteinase-activated (6%) and purinergic (4%) receptors, transient receptor potential channels (3%), microRNAs (2%), and activation of the cannabinoid system (7%). Our results show that the reported methodological quality of animal studies could be substantially improved, and measures to avoid bias should be more consistently reported in order to increase the value of preclinical research in IC/BPS for potential translation to a clinical setting.

Animal models are invaluable in the research of the pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic aseptic urinary bladder disease of unknown etiology that primarily affects women. Here, a mouse model of IC/BPS was induced with multiple low-dose cyclophosphamide (CYP) applications and thoroughly characterized by RNA sequencing, qPCR, Western blot, and immunolabeling to elucidate key inflammatory processes and sex-dependent differences in the bladder inflammatory response. CYP treatment resulted in the upregulation of inflammatory transcripts such as Ccl8, Eda2r, and Vegfd, which are predominantly involved in innate immunity pathways, recapitulating the crucial findings in the bladder transcriptome of IC/BPS patients. The JAK/STAT signaling pathway was analyzed in detail, and the JAK3/STAT3 interaction was found to be most activated in cells of the bladder urothelium and lamina propria. Sex-based data analysis revealed that cell proliferation was more pronounced in male bladders, while innate immunity and tissue remodeling processes were the most distinctive responses of female bladders to CYP treatment. These processes were also reflected in prominent histological changes in the bladder. The study provides an invaluable reference dataset for preclinical research on IC/BPS and an insight into the sex-specific mechanisms involved in the development of IC/BPS pathology, which may explain the more frequent occurrence of this disease in women.

Pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) remains poorly understood, as well as its effective diagnosis and therapy. Studying changes in tissue glycosylation patterns under pathological conditions is a promising way of discovering novel biomarkers and therapeutic targets. The glycobiology of IC/BPS is largely understudied, therefore we compared glycosylation patterns of normal human urothelium with the urothelium of IC/BPS patients using a selection of 10 plant-based lectins with different monosaccharide preferences. We also compared lectin binding to human urothelium with the two most cited experimental models of IC/BPS, specifically, TNFα-treated human urothelial cell line RT4 and cyclophosphamide-induced chronic cystitis in C57BL6/J mice. Furthermore, binding of four of the selected lectins (ConA, DSL, Jacalin and WGA) was evaluated qualitatively by means of fluorescence microscopy, and quantitatively by fluorescence intensity (F.I.) measurements. Our results reveal a significant reduction in F.I. of Jacalin, as well as a prominent change in the WGA labeling pattern in the urothelium of IC/BPS patients, suggesting their potential use as promising additional biomarkers for histopathological diagnosis of IC/BPS. We have also shown that urothelial glycosylation patterns between selected experimental models and patients with IC/BPS are similar enough to offer an adequate platform for preclinical study of IC/BPS glycobiology.

The urothelium is a vital permeability barrier that prevents the uncontrolled flow of urinary components into and out of the bladder interstitium. Our study addressed the question of possible sex-specific variations in the urothelium of healthy mice and their impact on chronic bladder inflammation. We found that healthy female bladders have a less robust barrier function than male bladders, as indicated by significant differences in transepithelial electrical resistance (TEER) values. These differences could be attributed to detected higher claudin 2 mRNA expression and a less pronounced glycocalyx in females than in males. In addition, TEER measurements showed delayed barrier recovery in chronically inflamed female bladders. We found subtle differences in the expressions of genes involved in the regulation of the actin cytoskeleton between the sexes, as well as pronounced urothelial hyperplasia in females compensating for attenuated barrier function. The identified genetic variations in glycosylation pathways may also contribute to this divergence. Our findings add to the growing body of literature on the intricate sex-specific nuances of urothelial permeability function and their implications for chronic bladder inflammation. Understanding these differences could lead to tailored diagnostic and therapeutic approaches in the treatment of bladder disorders in the future.