3.1.3. Anti-Inflammatory Effect in the Urothelium

Although some histopathology studies have reported contrary evidence, most experts and guidelines currently consider bladder inflammation to be present in patients with IC/BPS—bladder inflammation is presumed to play a central role in the pathogenesis of IC/BPS [2,36–38]. The infiltration of mast cells and lympho-plasmacytic cells is increased in the lamina propria and detrusor muscle of the bladder in patients with IC/BPS [37–39]. Immunohistochemical studies also have shown increased mast-cell activity and upregulation of pro-inflammatory cytokines in the bladders of patients with IC/BPS, including inducible nitric oxide synthase, interleukin-6 (IL-6), and IL-17A [40,41]. In urine and serum from patients with IC/BPS, inflammatory cytokines (e.g., IL-1β, IL-6, IL-8, tumor necrosis factor-α, and C-reactive protein) are reportedly elevated [42,43]. Although BoNT-A is well-known for its neurotransmitter-blocking effect, there is increasing evidence that BoNT-A can inhibit the release of inflammatory cytokines in different organs. In an in-vitro study, bladders were harvested from rats with acute or chronic cystitis, then incubated in organ baths containing BoNT-A or a vehicle [22]. Reduced substance-P release in the bladder was detected in models of both acute and chronic cystitis. In another in-vivo study, BoNT-A intravesical injection was shown to reduce histological inflammation in the bladders of rats with cyclophosphamide-induced cystitis [44]. Cyclooxygenase 2 and prostaglandin E2 receptor expression levels in the bladder also were reduced in the BoNT-A injection group [44]. In the human bladder, a single BoNT-A injection does not seem to reduce bladder inflammation in patients with neurogenic detrusor overactivity, but may improve bladder fibrosis [45]. In patients with IC/BPS, our previous study showed that repeated BoNT-A injections could significantly reduce the numbers of activated mast cells in the bladder, whereas a single injection could not [46]. The vascular endothelial growth-factor expression level and apoptotic cell count in the bladder were also reduced in patients with IC/BPS after repeated BoNT-A injections; however, these levels remained significantly higher than those of the controls [41]. Additionally, urothelial barrier-function impairment is a possible pathogenic mechanism in IC/BPS [47]. Improvement in urothelial barrier function might also be a possible mechanism by which BoNT-A is used for treatment of IC/BPS. Urothelial barrier-function recovery might contribute to improvement in suburothelial inflammation. Our previous study revealed that repeated BoNT-A injections could improve the expression levels of the urothelial barrier function protein, E-cadherin, and the tight junction protein, zonula occludens-1, in patients with neurogenic detrusor overactivity [48]. However, to the best of our knowledge, the effect of BoNT-A injection on the expression levels of urothelial barrier-function proteins in patients with IC/BPS has not yet been reported.
