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.