Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic illness characterized by bladder epithelial thinning or ulceration, pain, urinary frequency and urgency [1–3]. The etiology of IC/PBS remains unknown, and no treatment is reliably effective. Therefore, a greater understanding of the pathogenesis of this debilitating chronic painful bladder syndrome, along with the development of animal models based on that pathogenesis, may be necessary for the development of more effective therapy(ies).
Epithelial abnormalities are indeed a cardinal finding in bladder biopsies from IC patients, with predominant histologic findings including denudation and tears in the bladder epithelium (Hunner's ulcers or glomerulations) and/or thinning of the bladder epithelium to 1–2 cell layers thick [1–5]. Although tissue from patients with Hunner's ulcers typically contains inflammatory cell infiltrates in the epithelium (or lamina propria) that often consists of T lymphocytes with or without mast cells [1, 3], little inflammation is usually seen in the epithelium or submucosal interstitial tissue from the much larger number of patients without ulcers , indicating that inflammation in tissue superficial to the detrusor muscle is not a consistent finding in nonulcerative IC/PBS patients. However, epithelial cell proliferation and gene expression consistently appear to be abnormal in bladder tissue from IC/PBS patients in vivo[6–12], and abnormalities in cell proliferation and expression of most of the same genes have also been demonstrated in isolated explanted IC/PBS cells in vitro[13–20] with altered levels of specific cell proteins [including increased E-cadherin, inducible nitric oxide synthase (iNOS), plus P2X2 and P2X3 receptors; but decreased uroplakin III (UPIII), zonula occludens type 1 (ZO-1), occludin, and vimentin]. Taken together, these findings suggest an intrinsic bladder epithelial cell defect with specifically altered epithelial cell gene expression in IC/PBS patients.
To date, over 20 existing animal models of IC/PBS have been described. With the exceptions of the naturally occurring feline interstitial cystitis model and a model involving spontaneous cystitis in estrogen receptor beta-deficient mice, the other models generally involve the induction of bladder inflammation and/or epithelial damage via intravesical instillation of chemical irritants, systemic instillation of self or foreign antigens to induce an immune cell infiltrate in the bladder, or systemic viral infection to induce bladder epithelial damage [21–35]. While some of these models have been shown to express altered bladder or immune cell expression of inflammatory cytokines, only a few have been shown to exhibit abnormal expression of some of the epithelial cell proteins found to be abnormally expressed in IC/PBS patient biopsies (to date these have been limited to decreased ZO-1 in feline IC, decreased UPIII in acrolein-induced and CYP-induced cystitis, and increased iNOS in feline IC and CYP-induced cystitis); therefore, the relationship of these models to the human illness, or their utility for testing therapeutic or preventive agents for this syndrome, remains unknown.
In addition to the gene expression abnormalities noted above, we discovered that the same IC/PBS cell explants that express abnormal quantities of certain epithelial cell proteins similar to those found in IC/PBS cell biopsies also secrete a novel Frizzled 8-related glycopeptide “antiproliferative factor” (APF) [16, 36, 37] whose activity is also found in urine of 94-97% of patients who fulfill the symptomatic, exclusionary, and cystoscopic NIDDK criteria for ulcerative or non-ulcerative IC and 93% of patients who fulfill symptomatic and exclusionary criteria alone [38–43]. This small sialoglycopeptide (Neu5Acα2-3Galβ1-3GalNAcα-O-TVPAAVVVA) causes abnormalities in normal bladder epithelial cells and bladder cancer cell lines that mimic changes seen in explanted IC/PBS cells, including profoundly inhibited cell proliferation [13, 16, 44], increased p53 and p21 expression [44, 45], altered epithelial growth factor production [16, 46], and a specifically altered gene expression pattern including increased E-cadherin with decreased ZO-1, occludin, and vimentin [14, 15]. APF may therefore play a role in the pathogenesis of IC/PBS by inducing these abnormalities in vivo.
Prior patient studies indicate that the onset of IC/PBS symptoms may be preceded by clinical evidence for a urinary tract infection , and previous animal studies indicate frequent shedding of the bladder epithelium as part of a response to bacterial pathogens . We therefore postulated that IC/PBS may occur following bladder epithelial damage (as from bacterial cystitis or other cause) in patients who have impaired bladder epithelial repair because their epithelial cells secrete the APF toxin. With this hypothesis in mind, we performed pilot studies of a mouse model of IC/PBS based on inhibition of bladder epithelial repair by synthetic as-APF, using acetic acid to induce epithelial damage as previously described for a rabbit model of cystitis as well as a rat model of colitis [49, 50], and determining bladder epithelial area, UPIII and ZO-1 gene expression (all previously shown to be abnormally decreased in IC/PBS patient biopsy specimens).