Localization and Expression of Inducible Nitric Oxide Synthase in Biopsies From Patients With Interstitial Cystitis

Abstract

The increased levels of endogenously formed nitric oxide in patients with interstitial cystitis correspond to increased inducible nitric oxide synthase mRNA expression and protein levels in these patients. Furthermore, inducible nitric oxide synthase was found to be localized to the urothelium but it was also found in macrophages in the bladder mucosa. Whether high levels of endogenously formed nitric oxide are a part of the pathogenesis in interstitial cystitis and whether it has a protective or damaging role remain to be elucidated.

Nitric oxide as a marker for evaluation of treatment effect of cyclosporine A in patients with bladder pain syndrome/interstitial cystitis type 3C

“…It is also well known that cytokines induce up-regulation of iNOS, which produces high levels of NO during inflammation [2], and iNOS has been found to be localized to the urothelium of the bladder [22]. Furthermore, messenger RNA expression of iNOS in bladder biopsies from patients with BPS/IC type 3C is significantly higher than in controls [22] and those findings correlate well with the measurement of NO formation in the present study. Whether high levels of endogenously formed NO are a part of the pathogenesis of interstitial cystitis or whether it has a protective or damaging role remains to be elucidated.…”

“…CsA is known to inhibit T-cell activation by blocking the transcription of cytokine genes [21]. It is also well known that cytokines induce up-regulation of iNOS, which produces high levels of NO during inflammation [2], and iNOS has been found to be localized to the urothelium of the bladder [22]. Furthermore, messenger RNA expression of iNOS in bladder biopsies from patients with BPS/IC type 3C is significantly higher than in controls [22] and those findings correlate well with the measurement of NO formation in the present study.…”

Neural Control of the Lower Urinary Tract

“…Given that NO has a minimal direct effect on the detrusor muscle but does exert an inhibitory effect on afferent and reflex activity in the bladder (408, 492, 495, 727) and inhibits Ca 2+ channels in bladder afferent neurons (714), it is likely that NO is involved in urothelial sensory signaling mechanisms in the bladder and may have a role in modulating inflammatory and nociceptive pathways. Increases in inducible NOS expression in the urothelium and/or NO levels in the bladder have been demonstrated in BPS/IC patients, especially those with Hunner’s lesion (BPS/IC ESSIC Type 3C) (274, 338, 388). In addition NOS expression in afferent neurons is also increased in rats with chronic bladder inflammation (663) raising the possibility that pathological conditions increase the contribution of NO to bladder function.…”

Evidence for Bladder Urothelial Pathophysiology in Functional Bladder Disorders

“…These reports have been followed by many others that showed significantly abnormal expression of additional urothelial proteins and proteoglycans in bladder biopsies from BPS/IC patients as compared to controls, including decreases in chondroitin sulfate proteoglycans (both groups hydrodistended prior to biopsy) [9, 30]; uroplakin (both groups hydrodistended prior to biopsy) [9]; neurokinin receptor 1 (only BPS/IC patients underwent uroflowmetry, postvoid residual and urodynamic investigations) [10]; and the urothelial tight junction proteins zonula occludens 1 [9, 10], junctional adhesion molecule 1, occludin, and claudin 1 [10]. BPS/IC bladder biopsies have also been shown to have increased expression of many other bladder urothelial cell genes including nerve growth factor (all control groups also hydrodistended prior to biopsy in [31]; only BPS/IC group hydrodistended prior to biopsy in [32]), E-cadherin (both BPS/IC and control specimens obtained after hydrodistention) [9], inducible nitric oxide synthase (unclear whether some BPS/IC patients and controls did not undergo hydrodistention prior to biopsy) [33, 34], caveolin 1 (no mention of hydrodistention for BPS/IC patients or controls) [35], vascular endothelial growth factor (only BPS/IC patients hydrodistended prior to biopsy) [36], human chorionic gonadotropin beta (no mention of hydrodistention for BPS/IC patients or controls) [37], claudin 2, and a variety of cell signaling receptors including bradykinin B(1) receptor, cannabinoid receptor CB1, muscarinic receptors M3–M5 [10], and transient receptor potential vanilloid 2 (TRPV2) [32]. Increased activated (nuclear) NF κ B was also evident in BPS/IC bladder urothelial cells [38].…”