Interstitial Cystitis: Pathogenesis, Urinary Markers, and Experimental Models

摘要

Interstitial Cystitis (IC) is a chronic and painful inflammation of the bladder wall that most often causes frequency and urgency to urinate. Interstitial cystitis (IC) affects at least 20,000 to 90,000 women in the United States (1) and one tenth as many men. Patients with IC usually present with pelvic pain, urgency and frequency of urination, and tend to follow a waxing and waning course. The diagnosis of IC remains one of exclusion, based entirely on clinical and cystoscopic criteria. The cause of IC is unknown and to date, there is no effective treatment to cure this disease; however, the treatments that are available may help relieve the symptoms, which include oral and intravesical therapies and surgery as a last resort. The lack of effective research models has hindered the development and understanding of this debilitating disease. Herein we review the pathogenisis, markers, and possible in vitro models of interstitial cystitis. Introduction The NIH-NIDDK established a set of inclusion and exclusion criteria, originally meant to be for research protocols (2). These have evolved into the defacto criteria for clinical diagnosis (3). These guidelines include a history of pain or urgency, as well as cystoscopic evidence of petechial hemorrhages (glomerulations) or ulcers that extend into the lamina propria (Hunner’s ulcers). Several etiologies of IC have been proposed, including changes in neuronal function, autoimmune reactivity, mast cell activation, defects in urothelium and infection. Although no one specific etiology for IC has yet been identified, the use of in vitro models has helped to demonstrate specific pathologies that may contribute to symptoms. The syndrome may have multiple etiologies, and may involve a number of pathologic processes, all of which result in a similar clinical picture. Thus, the most realistic models will likely be those that incorporate data from a variety of sources to form a multifactorial model of the disease. This article reviews the current theories of pathogenesis, and describes in vitro models used to study IC, and how they have been used to refine etiologic hypotheses. Methods A periodical search was performed using PubMed to identify references pertaining to etiologies of IC, with a focus on the use of in vitro models. Search terms included cystitis, in vitro, model, interstitial cystitis and etiology. Articles published from 1980 to August of 2003 were included, with an emphasis placed on the more recent literature. The leading etiological hypotheses were identified as urine toxicity, occult infection, defective urothelium, neurogenic inflammation, mast cell activation and autoimmunity. These theories of pathogenesis are detailed below.THEORIES OF PATHOGENESISToxic Substances in the UrineOne of the leading theories of pathogenesis is that the urine of IC patients is itself carrying a toxic substance accounting for the disorder. This may be an abnormal substance, uniquely present in the urine of IC patients, or a normal constituent present at an abnormal concentration. This hypothesis is usually tested by exposing normal adult urothelial cells to samples of urine from IC and control patients. The proliferation of the cells is then assessed by measuring the uptake of 3H-thymidine. Studies of this type have yielded conflicting results. In one report, inhibition of colony formation by urine from healthy volunteers or women with IC was not significantly different (4). However, a limitation of this study was that fibroblasts were used rather than urothelium. Other studies have found no difference in urine toxicity, (5) or lymphocytic response (6) between interstitial cystitis patients and healthy controls. This study was unique in that it measured the release of intracellular bound 51Cr to assess cell death. The use of cell death as an outcome makes it possible to miss a sub lethal effect of IC urine on normal epithelial cells. For this reason, the effect on cell proliferation is more c