Painful Bladder Disease Research Articles

Antiproliferative factor (APF) binds specifically to sites within the cytoskeleton-associated protein 4 (CKAP4) extracellular domain

BackgroundAntiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis—a chronic, painful bladder disease. APF inhibits the proliferation of normal bladder epithelial cells and cancer cells in vitro, presumably by binding to its cellular receptor, cytoskeleton associated-protein 4 (CKAP4); however, the biophysical interaction of APF with CKAP4 has not been characterized previously. In this study, we used surface plasmon resonance (SPR) to explore the binding kinetics of the interaction of APF and as-APF (a desialylated APF analogue with full activity) to CKAP4.ResultsWe immobilized non-glycosylated APF (TVPAAVVVA) to the Fc1 channel as the control and as-APF to Fc2 channel as the ligand in order to measure the binding of CKAP4 recombinant proteins encompassing only the extracellular domain (Aa 127–602) or the extracellular domain plus the transmembrane domain (Aa 106–602). Positive binding was detected to both CKAP4126–602 and CKAP4106–602, suggesting that as-APF can bind specifically to CKAP4 and that the potential binding site(s) are located within the extracellular domain. To identify the primary APF binding site(s) within the CKAP4 extracellular domain, deletion mutants were designed according to structural predictions, and the purified recombinant proteins were immobilized on a CM5 chip through amine-coupling to measure as-APF binding activity. Importantly, both CKAP4127–360 and CKAP4361–524 exhibited a fast association rate (kon) and a slow dissociation rate (koff), thus generating high binding affinity and suggesting that both regions contribute relatively equally to overall as-APF binding. Therefore, two or more as-APF binding sites may exist within the Aa 127–524 region of the CKAP4 extracellular domain.ConclusionsWe determined that the CKAP4127–360 and CKAP4361–524 mutants exhibit improved binding activity to as-APF as compared to the full-length extracellular domain, making it possible to detect low concentrations of as-APF in urine, thereby establishing a foundation for a non-invasive diagnostic assay for IC. Further, these data have revealed novel APF binding site(s) suggesting that targeting this region of CKAP4 to inhibit APF binding may be a useful strategy for treating IC-related bladder pathology.

MP42-18 ENDOCANNABINOID 2-ARACHIDONOYL GLYCEROL DECREASES VISCERAL PAIN ASSOCIATED WITH EXPERIMENTAL CYSTITIS

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology I1 Apr 2017MP42-18 ENDOCANNABINOID 2-ARACHIDONOYL GLYCEROL DECREASES VISCERAL PAIN ASSOCIATED WITH EXPERIMENTAL CYSTITIS Zunyi Wang, Peiqing Wang, and Dale Bjorling Zunyi WangZunyi Wang More articles by this author , Peiqing WangPeiqing Wang More articles by this author , and Dale BjorlingDale Bjorling More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1307AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Endocannabinoids exert potent analgesic and anti-inflammatory effects and may suppress clinical symptoms of painful inflammatory bladder diseases. 2-arachidonoyl glycerol (2-AG) is the most abundant endocannabinoid and the activity of 2-AG in the bladder has not been previously described. We investigated whether 2-AG has the potential to prevent visceral pain associated with experimental cystitis in mice. METHODS Expression of diacylglycerol lipase-α and -β (DAGL-α and -β, primary enzymes of 2-AG synthesis) and monoacylglycerol lipase (MAGL, primary enzyme of 2-AG degradation) in urothelium was examined by real-time RT-PCR and immunohistochemistry. Cystitis was induced by intraperitoneal injection of cyclophosphamide (CYP, 150 mg/kg), and mechanical sensitivity of hind paws was determined. Effects of 2-AG were also evaluated in cultured human urothelial cells. RESULTS DAGL-α, -β and MAGL were present in the mouse urothelium. CYP (3 hours) induced cystitis in mice characterized by submucosal edema. Pretreatment with a specific MAGL inhibitor JZL 184 (8 mg/kg/day, sc, 6 days) prior to CYP treatment did not appear to affect bladder inflammation. Mechanical sensitivity threshold was significantly reduced after CYP treatment in mice that received vehicle (basal: 2.9 ± 0.1 g; vehicle: 0.6 ± 0.1 g; n =6; p<0.01 vs basal). However, the increase of mechanical sensitivity was attenuated in JZL184-treated mice (basal: 2.8±0.1 g; JZL 184: 1.4±0.6 g; n =6, p<0.05 vs basal and vehicle-treated animals). CYP augmented expression of IL-6 mRNA in urothelium (151.8±34.1 fold increase compared to control animals, n=6, p<0.01 vs control) and JZL 184 inhibited increased IL-6 expression (79.5±23.4, p<0.05 vs control and vehicle-treated animals). In cultured human urothelial cells, 2-AG attenuated LPS-induced increased TNF-α mRNA expression in a concentration-dependent manner. CONCLUSIONS We demonstrated the presence of the 2-AG pathway in the bladder, and this is the first available evidence that treatment with a MAGL inhibitor decreased visceral pain associated with cystitis. Urothelial cells play an important role in the activity of 2-AG in bladder. Manipulation of 2-AG may provide a novel therapeutic option for treatment of bladder pain. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e551 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Zunyi Wang More articles by this author Peiqing Wang More articles by this author Dale Bjorling More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Attenuation of cystitis and pain sensation in mice lacking fatty acid amide hydrolase.

Endocannabinoids, such as N-arachidonoylethanolamine (AEA, also called anandamide), exert potent analgesic and anti-inflammatory effects. Fatty acid amide hydrolase (FAAH) is primarily responsible for degradation of AEA, and deletion of FAAH increases AEA content in various tissues. Since FAAH has been shown to be present in the bladder of various species, we compared bladder function, severity of experimental cystitis, and cystitis-associated referred hyperalgesia in male wild-type (WT) and FAAH knock-out (KO) mice. Basal concentrations of AEA were greater, and the severity of cyclophosphamide (CYP)-induced cystitis was reduced in bladders from FAAH KO compared to WT mice. Cystitis-associated increased peripheral sensitivity to mechanical stimuli and enhanced bladder activity (as reflected by increased voiding frequency) were attenuated in FAAH KO compared to WT mice. Further, abundances of mRNA for several pro-inflammatory compounds were increased in the bladder mucosa after CYP treatment of WT mice, and this increase was inhibited in FAAH KO mice. These data indicate that endogenous substrates of FAAH, including the cannabinoid AEA, play an inhibitory role in bladder inflammation and subsequent changes in pain perception. Therefore, FAAH could be a therapeutic target to treat clinical symptoms of painful inflammatory bladder diseases.

Treatment with a Cannabinoid Receptor 2 Agonist Decreases Severity of Established Cystitis

We investigated whether treatment with the selective cannabinoid receptor 2 agonist GP1a would ameliorate the severity of experimental cystitis. We determined the association of referred hyperalgesia and increased urinary frequency after establishing cystitis in mice by intravesical instillation of acrolein. Cystitis was induced by intravesical instillation of acrolein in female C57BL/6NH mice. Mice were treated with GP1a (10 mg/kg intraperitoneally) or vehicle 3.5, 22 and 30 hours after instillation of acrolein. Mice were tested for mechanical sensitivity of hind paws. Short-term voluntary voiding was assessed by quantifying urine spots of freely moving mice. Bladders were collected, weighed and processed for immunohistochemical, histological and immunoblotting analysis. At 48 hours after acrolein instillation the bladder of all mice showed histological evidence of inflammation. The severity of edema and increase in bladder weight were inhibited in cannabinoid receptor 2 agonist treated animals (p <0.05). Neither cystitis nor treatment with GP1a or AM630 (selective cannabinoid receptor 2 antagonist) plus GP1a appeared to alter cannabinoid receptor 2-like immunoreactivity abundance in urothelium. Mechanical sensitivity was significantly increased after acrolein and the increase was attenuated in cannabinoid receptor 2 agonist treated mice (p <0.05). The number of small diameter urine spots was significantly increased after acrolein and treatment with GP1a attenuated this increase (p <0.05). GP1a effects were prevented by AM630. Treatment with a selective cannabinoid receptor 2 agonist decreased severity of established acrolein induced cystitis and inhibited bladder inflammation associated increased referred mechanical sensitivity and increased bladder urinary frequency. Our data indicate that cannabinoid receptor 2 is a potential therapeutic target for treatment of painful inflammatory bladder diseases.

Antiproliferative Factor Regulates Connective Tissue Growth Factor (CTGF/CCN2) Expression in T24 Bladder Carcinoma Cells

Antiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis—a chronic, painful bladder disease. APF inhibits the proliferation of normal bladder epithelial and T24 bladder carcinoma cells in vitro by binding to cytoskeleton associated protein 4 (CKAP4) and altering the transcription of genes involved in proliferation, adhesion, and tumorigenesis; however, specific molecular mechanisms and effector genes that control APF's antiproliferative effects are unknown. In this study, we found that there was a 7.5‐fold upregulation of connective tissue growth factor (CTGF/CCN2) expression in T24 bladder carcinoma cells treated with APF, and Western blot revealed a dose‐dependent increase in CCN2 protein levels with secretion into the culture medium following APF treatment. CCN2 overexpression enhanced APF's antiproliferative activity while CCN2 knockdown by siRNA diminished it. Using a luciferase reporter construct, we found that APF treatment resulted in a 5‐fold activation of the CCN2 proximal promoter and that siRNA‐mediated knockdown of CKAP4 inhibited CCN2 upregulation. Additionally, we show that CKAP4 translocates to the nucleus and binds to the CCN2 proximal promoter in an APF‐dependent manner, providing evidence that CCN2 regulation by APF involves CKAP4 nuclear translocation and binding to the CCN2 promoter. NIH 1R03AR057193‐01; KIZ grant

Antiproliferative factor regulates connective tissue growth factor (CTGF/CCN2) expression in T24 bladder carcinoma cells

Antiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis (IC)-a chronic, painful bladder disease of unknown etiology. APF inhibits the proliferation of normal bladder epithelial and T24 bladder carcinoma cells in vitro by binding to cytoskeleton-associated protein 4 (CKAP4) and altering the transcription of genes involved in proliferation, cellular adhesion, and tumorigenesis; however, specific molecular mechanisms and effector genes that control APF's antiproliferative effects are unknown. In this study, we found that there was a 7.5-fold up-regulation of connective tissue growth factor (CTGF/CCN2) expression in T24 bladder carcinoma cells treated with APF. Western blot revealed a dose-dependent increase in CCN2 protein levels, with secretion into the culture medium after APF treatment. CCN2 overexpression enhanced APF's antiproliferative activity, whereas CCN2 knockdown diminished APF-induced p53 expression. Using a luciferase reporter construct, we found that APF treatment resulted in fivefold activation of the CCN2 proximal promoter and, of importance, that small interfering RNA-mediated knockdown of CKAP4 inhibited CCN2 upregulation. In addition, we demonstrate that CKAP4 translocates to the nucleus and binds to the CCN2 proximal promoter in an APF-dependent manner, providing evidence that CCN2 regulation by APF involves CKAP4 nuclear translocation and binding to the CCN2 promoter.

Potential Use of Antiproliferative Factor as a Targeting Therapy in Painful Bladder Syndrome/Interstitial Cystitis

syndrome/interstitial cystitis (PBS/IC) encompasses a major portion of the painful bladder disease complex. Painful comprise a large group of patients with and/or urethral and/or pelvic pain, irritative voiding symptoms (urgency, frequency, nocturia, and dysuria), and sterile urine cultures. conditions with well-established causes include radiation cystitis, cystitis caused by microorganisms that are not detected by routine culture methodologies, and systemic disorders that affect the bladder. In addition, many gynecologic disorders can mimic PBS/IC [1]. PBS/IC has no easily discernible etiology. There are no pathognomonic findings on pathologic examination, and even the detection of petechial hemorrhages on the mucosa during cystoscopy after hydrodistention under anesthesia is no longer considered the sine qua non of PBS/IC that it had been until a decade ago [2]. PBS/IC is truly a diagnosis by exclusion. It may have multiple causes and represent a final common reaction of the to different types of insult. There are numerous theories regarding its pathogenesis, but confirmatory evidence found in clinical practice has proven sparse. Among numerous proposals that have been further studied are leaky epithelium, mast cell activation, neurogenic inflammation, inhibition of uroepithelial cell proliferation: antiproliferative factor (APF), nitric oxide metabolism, urine abnormality and the role of genetics or some combination of these and other factors leading to a self-perpetuating process resulting in chronic pain and voiding dysfunction [3]. Among the various possible evidences, APF has recently been the subject of much attention. The finding that cells from the lining of normal controls grow significantly more rapidly in culture than cells from PBS/IC patients led Keay et al. [4] at the University of Maryland to the discovery of an APF produced by the urothelium of IC patients. Studies are ongoing to confirm the hypotheses related to APF and expand on its significance in diagnosis and development of a rational targeting treatment approach. Especially, the article by Kim and Freeman [5] in this issue of the journal will be recognized as a valuable update on signal transduction pathways and networks that are responsive to APF to learning more about potential therapeutic pathways.

Intravesical Suplatast Tosilate (IPD-1151T) Inhibits Experimental Bladder Inflammation

Interstitial cystitis is a painful bladder disease characterized by urgency, frequency and variable inflammation but there is no curative therapy. Suplatast tosilate (IPD-1151T) is an immunoregulatory compound that decreases interstitial cystitis symptoms but to our knowledge its mechanism of action is unknown. We investigated the effect of intravesical IPD-1151T on mediator release from bladder explants in experimental cystitis. A catheter was inserted into the bladder of female mice. After urine was emptied normal saline, carbachol (100 nM) or lipopolysaccharide (10 mg/ml) was introduced with or without 10-minute pretreatment with IPD-1151T. Urine was removed after 45 minutes for histamine and tumor necrosis factor-alpha assays. The bladder was removed after 4 hours, minced into 1 mm2 pieces and cultured with or without triggers overnight for mediator release. The effect of IPD-1151T was also tested on rat skin vascular permeability as well as on purified rat peritoneal mast cells and human cord blood derived mast cells. Carbachol significantly increased histamine release in urine (61.3% in 8 preparations, p<0.05) but not in explant medium. IPD-1151T inhibited this effect by 77%. Lipopolysaccharide induced a 350% urine histamine increase in 9 preparations (p<0.05) and a 300% tumor necrosis factor-alpha increase in explant medium. IPD-1151T inhibited the lipopolysaccharide induced medium tumor necrosis factor-alpha increase by 95% in 5 preparations (p<0.05). IPD-1151T did not inhibit rat skin vascular permeability or purified rat peritoneal mast cell activation by compound 48/80 or human cord blood derived mast cells by anti-IgE. IPD-1151T inhibits bladder release of histamine and tumor necrosis factor-alpha through a mechanism that does not appear to involve direct mast cell inhibition. These findings may justify a beneficial effect of IPD-1151T in interstitial cystitis.

Semelhanças entre a doença idiopática do trato urinário inferior dos felinos e a cistite intersticial humana

A doença idiopática do trato urinário inferior dos felinos (DITUIF) continua sendo um grande desafio para o clínico veterinário uma vez que, apesar dos avanços nas técnicas diagnósticas, sua etiologia continua por ser determinada. O objetivo do presente trabalho é demonstrar as principais semelhanças entre a doença urinária felina e a cistite intersticial humana (CI), principalmente no que se refere à comprovação do caráter neurogênico da inflamação vesical, o papel do estresse na gênese e/ou exacerbação dos sinais clínicos da doença, e os principais achados cistoscópicos e histopatológicos em ambas as síndromes urinárias. Conclui-se, portanto, que além da dieta comercial, podem existir outros fatores com participação na inflamação vesical de felinos com DITUI.

Oral cimetidine gives effective symptom relief in painful bladder disease: a prospective, randomized, double‐blind placebo‐controlled trial

Objective To evaluate the efficacy of oral cimetidine as a treatment for painful bladder disease (PBD, variously described as a ‘symptom complex’ of suprapubic pain, frequency, dysuria and nocturia in the absence of overt urine infection) by assessing symptom relief and histological changes in the bladder wall tissue components, compared with placebo. Patients and methods The study comprised 36 patients with PBD enrolled into a double-blind clinical study with two treatment arms, i.e. oral cimetidine or placebo, for a 3-month trial. Patients were asked to complete a symptom questionnaire (maximum score 35), and underwent cystoscopy and bladder biopsy before treatment allocation. On completing treatment the patients were re-evaluated by the questionnaire and biopsy. The symptom scores and bladder mucosal histology were compared before and after treatment, and the results analysed statistically to assess the efficacy of cimetidine. Results Of the 36 patients recruited, 34 (94%) completed the study. Those receiving cimetidine had a significant improvement in symptoms, with median symptom scores decreasing from 19 to 11 (P 0.3 and > 0.2, respectively). Angiogenesis remained relatively unchanged. The incidence of mast cells and B cells was sporadic in both groups. Conclusions Oral cimetidine is very effective in relieving symptoms in patients with PBD but there is no apparent histological change in the bladder mucosa after treatment; the mechanism of symptom relief remains to be elucidated.

COMPARISON OF CYSTOSCOPIC AND HISTOLOGICAL FINDINGS IN PATIENTS WITH SUSPECTED INTERSTITIAL CYSTITIS

Although the exact etiology of interstitial cystitis remains elusive, bladder inflammation appears to be common in many patients. The National Institutes of Health (NIH) have established diagnostic criteria for interstitial cystitis based on the presence of irritative voiding symptoms in the absence of other identifiable pathology. Cystoscopic examination with hydrodistention performed in patients under anesthesia is part of the NIH diagnostic criteria. We determine if the severity of cystoscopic findings correlated with histological evidence of inflammation in patients with suspected interstitial cystitis. A total of 69 patients who met NIH symptom criteria for interstitial cystitis and underwent cystoscopy, hydrodistention and bladder biopsy under anesthesia were reviewed. There were 2 investigators blinded to the histological data who independently reviewed operative reports. A urological pathologist blinded to the clinical data reviewed biopsies for inflammation severity. Cystoscopic and histological findings were then converted to a numeric scale. Numeric data were analyzed using the Pearson correlation coefficient. Cystoscopic examination revealed no evidence of interstitial cystitis in 6 patients (9%), mild changes in 27 (39%), moderate changes in 23 (33%) and severe changes in 13 (19%). Histological examination revealed no inflammation in 21 patients (30%), mild inflammation in 28 (41%), moderate inflammation in 11 (16%) and severe inflammation in 9 (13%). Histological scores correlated poorly with total and scaled cystoscopic severity scores (r = 0.295 and 0.349, respectively). Severity of cystoscopic findings observed during hydrodistention with anesthesia does not appear to correlate with the degree of inflammation identified histologically in patients with suspected interstitial cystitis.

A RANDOMIZED DOUBLE-BLIND TRIAL OF ORAL L-ARGININE FOR TREATMENT OF INTERSTITIAL CYSTITIS

Nitric oxide synthase activity is decreased in the urine of patients with interstitial cystitis compared to the urine of controls. In a preliminary trial oral L-arginine, the substrate for nitric oxide synthase, increased urinary nitric oxide synthase activity and improved interstitial cystitis symptoms. This randomized, double-blind, placebo controlled study further investigates the efficacy of L-arginine treatment for interstitial cystitis. A total of 53 interstitial cystitis patients were assigned to receive daily 1,500 mg. L-arginine or placebo orally for 3 months. Interstitial cystitis symptoms were assessed by interviews at 2 weeks, and 1, 2 and 3 months. The trial was completed by 21 of 27 patients in the L-arginine group and 25 of 26 in the placebo group. Using per protocol analysis 29% (6 of 21 patients) in the L-arginine group and 8% (2 of 25) in the placebo group were clinically improved by the end of the trial (p = 0.07). A Likert scale showed greater global improvement in the L-arginine group (48%, 10 of 21) compared to the placebo group (24%, 6 of 25) at 3 months (p = 0.05) with a decrease in pain intensity (p = 0.04), and tendency toward improvement in urgency (p = 0.06) and frequency of pain (p = 0.09). Using an intention to treat approach to analysis there were no differences between groups. Oral L-arginine (1,500 mg. daily) may decrease pain and urgency in a subset of interstitial cystitis patients.

AUTHORS REPLY

International Journal of UrologyVolume 5, Issue 4 p. 336-336 Free Access AUTHORS REPLY Tetsuo Yamada, Tetsuo Yamada MD Department of Urology National Sagamihara Hospital Sagamihara, JapanSearch for more papers by this author Tetsuo Yamada, Tetsuo Yamada MD Department of Urology National Sagamihara Hospital Sagamihara, JapanSearch for more papers by this author First published: 02 July 2007 https://doi.org/10.1111/j.1442-2042.1998.tb00362.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Kzol JA, Clark DC, Gittes RF, Tan EM. The natural history of interstitial cystitis. J Urol 1993; 149: 465– 469. 2 Alagiri M, Chottiner S, Ratner V, Slade D, Hanno P. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology 1993; 49: 52– 57. 3 Johansson SL, Fall M. Clinical featurs and spectrum of light microscopic changes in interstitial cystitis. J Urol. 1990; 143: 1118– 1124. 4 Holm-Bentzen M. Pathology and pathophysiology of painful bladder diseases. Urol Int 1989; 44: 327– 331. 5 Messing EM. Interstitial cystitis. In: PC Walsh, AB Retik, TA Stamey, ED Vaughan (eds) Campbell's urology. 6th ed. Philadelphia : Saunders , 1991; 985– 986. Volume5, Issue4July 1998Pages 336-336 ReferencesRelatedInformation

The effect of acute distension on vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY) and substance P (SP) immunoreactive nerves in the female rat urinary bladder.

The effect of acute distension on vasoactive polypeptide (VIP)-, neuropeptide Y (NPY)- and substance P (SP)-immunoreactive nerves in the wall of the urinary bladder was investigated. At the age of 3 months, 25 female albino rats underwent forced diuresis combined with balloon obstruction to achieve maximal distension for 3 h. A modified, indirect immunofluorescence detection method was applied 2 days, 7 days and 21 days after distension. A marked, extensive depletion of VIP, NPY- and SP-immunoreactive nerves was observed after distension. This disturbance was reversible, and increased fluorescence of VIP-, NPY- and SP-immunoreactive nerve fibres compared with control specimens was seen in bladder specimens taken even as soon as 21 days after distension. This transient depletion of peptidergic innervation may partly explain the prolonged voiding problems that often occur after acute urinary retention. The depletion of sensory nerves containing SP shortly after distension may explain the transient benefit obtained from distension therapy in patients with painful bladder disease. It is suggested that the increased SP activity during the recovery phase may be related to neurogenic inflammation.

Pathology and pathophysiology of painful bladder diseases.

Painful bladder disease is an ill-defined disease presenting with chronic cystitis symptoms, despite sterile urine. This report includes only patients with painful bladder diseases of unknown etiology and pathogenesis. We have chosen to classify these patients pathoanatomically as follows: interstitial cystitis, detrusor myopathy, chronic unspecific cystitis and eosinophilic cystitis. The pathoanatomical appearance of the four groups of patients are described in details and certain clinical differences appear between the groups. The etiology and pathogenesis to the inflammatory reactions and muscle changes found in the detrusor biopsies are unknown, but many theories exist. It is suggested that something in the urine gains access to the bladder wall and initiates the pathoanatomical changes through a defective urothelium and glycosaminoglycans layer. In the interstitial cystitis patients, the inflammatory process and mast cell degranulation might be monitored by the urinary excretion of 1,4-methyl-imidazole-acetic acid and eosinophil cationic protein. It is concluded that no specific therapy for the disease exists, since etiology and pathogenesis are still unknown and therefore future research in this field is very important.

Pathology, pathophysiology, and pathogenesis of painful bladder diseases.

Many unresolved questions remain regarding painful bladder disease. The etiology, pathogenesis and pathophysiology are not precisely known and therefore no rational therapy exist. One have to keep in mind that the lack of efficient therapy is the main problem for these, often very disabled and handicapped patients [64]. The goal for all future research regarding painful bladder patients has to be to find an efficient and rational therapy.

PAINFUL BLADDER DISEASES: INTERSTITIAL OR ABACTERIAL CYSTITIS?

PAINFUL BLADDER DISEASES: INTERSTITIAL OR ABACTERIAL CYSTITIS?

Autorosette Inhibition Factor: A Positive Acute Phase Reactant in Interstitial Cystitis

Autorosette inhibition factor (AIF), complement C3d and eosinophil cationic protein (ECP) in urine were determined in 28 patients with painful bladder disease. In patients with interstitial cystitis (IC), diagnosed by the demonstration of detrusor mastocytosis, a positive correlation (r = 0.73, p less than 0.01) between AIF and C3d was found, whereas no reliable correlation was found in the remaining patients. The median concentration of urinary ECP was significantly elevated in the group of patients with IC whereas the median concentration of C3d was significantly elevated in both groups. AIF seems to behave as a positive acute phase reactant in IC. It is hypothesized that AIF may play a role in the pathogenesis of IC by influencing the normal barrier function of the epithelium of the bladder.

A Prospective Double-Blind Clinically Controlled Multicenter Trial of Sodium Pentosanpolysulfate in the Treatment of Interstitial Cystitis and Related Painful Bladder Disease

Painful bladder disease, sensory bladder disease, chronic abacterial cystitis and interstitial cystitis are ill-defined conditions of unknown etiology and pathogenesis, and, therefore, they are without any rational therapy. Pathogenetic theories concerning defects in the epithelium and/or mucous surface coat (including glycosaminoglycans) of the bladder, and theories concerning immunological disturbances predominate.Sodium pentosanpolysulfate (Elmiron) acts by substituting a defective glycosaminoglycan layer and inhibits complement reactions in inflammatory processes. We compared sodium pentosan polysulfate versus placebo in a prospective double-blind, clinically controlled multicenter trial of 115 patients with painful bladder disease. Two protocols were used. Protocol A included 43 patients with clinically and pathologically anatomically verified interstitial cystitis (28 or more mast cells per mm.2), and protocol B included 72 patients with a painful bladder and unspecific histological findings. The patients were randomized to receive either sodium pentosanpolysulfate (200mg. twice daily) or placebo capsules for 4 months. Before and after the trial the patients were evaluated with symptom grading, urodynamics and cystoscopy with distension and deep bladder biopsies.The results showed no difference between the pre-trial and post-trial values in the sodium pentosanpolysulfate and placebo groups in both protocols in regard to symptoms, urodynamic parameters, cystoscopic appearance and mast cell counts. A significant increase in the cystoscopi-cally determined bladder capacity in the sodium pentosanpolysulfate group in protocol A was found. We conclude that no statistically or clinically significant effect of sodium pentosanpolysulfate was found compared to placebo in patients with painful bladder disease. (J. Urol., 138: 503–507, 1987)

Painful Bladder Disease: Clinical and Pathoanatomical Differences in 115 Patients

The diagnostic criteria for interstitial cystitis considered as a subgroup of painful bladder disease (that is sensory bladder disease and chronic abacterial cystitis) are not well established. Some urologists rely on symptoms, while others rely on cystoscopic appearance or pathological findings. Among 115 patients with painful bladder disease we compared symptoms, and cystoscopic and urodynamic findings in those with and without detrusor mastocytosis (28 or more mast cells per mm.2) and attempted to elucidate possible differences between the groups. We chose the pathological anatomical criterion of detrusor mastocytosis to be diagnostic for interstitial cystitis.A total of 43 patients had detrusor mastocytosis and other pathological anatomical signs of interstitial cystitis, and 72 had no mastocytosis but the pathological diagnoses of chronic unspecific cystitis, fibrosis of the bladder, detrusor myopathy, intestinal metaplasia and normal findings. When the 2 groups of patients were compared we found no differences in regard to symptoms (pain, dysuria, frequency, nocturia and urgency), frequency of allergy and hysterectomy, duration of symptoms, petechial bleeding during cystoscopy with bladder distension and cystometric findings. The patients with mastocytosis differed from those without mastocytosis in that they were older, and had a higher frequency of hematuria, a higher frequency of a red, scarred and richly vascularized bladder at cystoscopy before distension, and a smaller cystoscopic bladder capacity.We conclude that by dividing patients with painful bladder into 2 groups according to the mast cell counts in the detrusor, certain differences in the clinical findings in the groups can be ruled out. However, in individual patients one cannot note with certainty to which pathological anatomical group the patient belongs, since great overlapping between the groups exists. Whether only patients with detrusor mastocytosis have interstitial cystitis depends on definitions and still remains an open question. (J. Urol., 138: 500–502, 1987)