Introduction
The exact aetiology of BPS/IC is unknown or at least debated. Literature describes certain features that characterize BPS/IC in general. These include a deficient urothelial barrier function and bladder wall inflammation. The influx or presence of immune cells in the bladder wall is well documented, and the hypothesis of a leaky or impaired urothelium is referred to in the ESSIC consensus statement.[3] Normal healthy urothelium expresses barrier markers that contribute to the impermeability of the bladder wall to urine and its solutes.[4] In most patients with BPS/IC, histology shows a deficiency of these barrier markers such as uroplakins, GAGs, tight junctions and adherence junctions.[5, 6] This has formed the leaky epithelium hypothesis implying that bladder pain and inflammation is generated by increased permeability of the urothelium.
Of the deficient barrier markers, the glycosaminoglycans (GAGs) are of special interest because of their location in healthy urothelium, their barrier properties and as a target for treatment. The bladder contains different GAGs including chondroitin sulfate(CS), heparan sulfate (HS), dermatan sulfate, heparin and hyaluronic acid. [7]
GAG therapy, both as instillations or oral treatments, are still used widely for the treatment of BPS-IC and other inflammatory bladder conditions, although with mixed levels of recommendations in guidelines. [1, 2] The primary aim of GAG therapy is to improve barrier function and recovery of the chronically damaged urothelium. [8] Currently clinical research still outweighs the efforts done to investigate the physiological mechanisms behind GAG therapy.
The exact location and barrier function of different GAGs in the urinary bladder have only been established in the last decade and currently there is still limited preclinical evidence of the physiological effects of oral medication such as pentosan polysulfate or intravesical GAG replenishment therapy on bladder barrier recovery.
CS is a GAG that is abundant in different areas in the bladder wall such as the lamina propria.[15] Most importantly, CS forms a layer covering the luminal side of the urothelium and thus forms the first line of defence against urinary solutes.[15] In-vitro studies have confirmed the barrier properties of the GAG-layer by transepithelial electrical resistance (TEER) before and after selective removal of CS using enzymatic digestion.[9] This enzymatic CS digestion model was later used in two in vivo studies that confirmed the role of CS in urothelial barrier. Offiah et al. also demonstrated that by removing CS and HS with enzymes in rats, it creates an inflammatory and pain pathway cascade that is comparable to what is observed in BPS-IC patients. [10, 11]
In vitro models can focus on isolated features of BPS/IC such as a deficient urothelial barrier, this allows for controlled conditions. Most of the known studies in-vivo and in-vitro , are performed using acute models. This implies mostly a single exposure of the urothelium to a harmful substance.[8] However, the chronic aspect of BPS/IC is one of its main features. This in-vitro study was aimed to 1) 1) to evaluate the therapeutic efficacy of CS replenishment therapy in a chronically damaged urothelial model and 2) establish the effects of chronic damage on the functional barrier and recovery of the bladder urothelium in a controlled environment.