Effects of Stretch on IC and Normal Urothelia

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DESCRIPTION (Adapted from the Applicant's Abstract): Interstitial cystitis (IC) patients typically present with extreme urinary frequency, urgency and pelvic pain. It has a 10:1 female:male predominance. Since the pathophysiologic picture of IC is unclear, cure remains elusive and treatment options are largely ineffectual. Even the diagnosis of IC is controversial. An objective diagnostic criterion is the cystoscopic appearance of glomerulations after bladder hydrodistention (stretch) under anesthesia. Recent data disputed the diagnostic specificity of this procedure because hydrodistention of control bladders resulted in glomerulations. Based on the investigators' preliminary data which showed that IC urothelia responded to stretch significantly differently than controls in cystoscopic appearance, levels of urinary heparin binding epidermal growth factor-like growth factor (HB-EGF), antiproliferative activity (APF), and adenosine triphosphate (ATP), they propose to test these hypotheses: 1. Bladder glomerulations, which appear after hydrodistention, are specific for NIH-IC symptoms criteria (NISC). 2. Male patients with chronic non-bacterial prostatitis (prostatitis class III or chronic pelvic pain syndrome, CPPS) and NISC have post-hydrodistention glomerulations whereas males with CPPS and no NISC do not. This observation would further strengthen the association of glomerulations with NISC. 3. Some NISC patients improve symptomatically after hydrodistention and degree of improvement correlates with changes in urinary markers (APF, HB-EGF and ATP). 4. In vitro stretch of IC urothelial cells results in increased ATP, HBEGF and decreased APF activity compared to stretch of control cells. 5. There is increased expression of P2X1 and P2X3 ATP receptors in IC compared to control bladder urothelium and suburothelium. This project is unique because it links clinical and laboratory data to test the central hypothesis that IC urothelia respond differently to stretch. Only human samples will be used to provide optimal clinical relevance. Findings from this study will clarify the current diagnostic dilemma regarding specificity of glomerulations for diagnosing IC and determine the therapeutic efficacy of hydrodistention. Furthermore, this study will explore the exciting new discovery that ATP released by stretched IC cells is significantly higher compared to controls. ATP may mediate nociception in the bladder. Urothelial stretch thus appears to be an important consideration in diagnosis, treatment and pathophysiology of IC.