A rat model for studying effects of sacral neuromodulation on the contractile activity of a chronically inflamed bladder

OBJECTIVE: To develop an animal model in which the effects of electrical stimulation of the sacral nerves (sacral neuromodulation) on a chronic hyperactive urinary bladder can be studied. MATERIALS AND METHODS: In female rats the urinary bladder was instilled with mustard oil (0.4%); after 10 days the animals were anaesthetized with intraperitoneal urethane, the bladder catheterized and connected to a pressure transducer. Stimulating electrodes were placed into the sacral foramina bilaterally. The intensity and duration of sacral electrical stimulation was varied systematically to determine the effects of the sacral neuromodulation on bladder contractions. RESULTS: The main effect of the neuromodulation was an increase in the interval between contractions, i.e. during and for some time after the stimulation the contractions were completely abolished. The duration of the pause increased with the intensity and duration of stimulation. After the contractions had reappeared the frequency of contractions was reduced for a long period. In animals with chronic cystitis the effects of neuromodulation tended to be stronger (the pauses were longer) than in control animals with an intact bladder, but only in one test (increase of pause length with stimulus duration) was the difference statistically significant. CONCLUSIONS: The results show that this animal model is suitable for studying the effects and mechanisms of sacral neuromodulation on a chronic hyperactive urinary bladder.     

Neuromodulation of bladder activity by stimulation of feline pudendal nerve using a transdermal amplitude modulated signal (TAMS)

Aim: To develop a non‐invasive neuromodulation method to regulate bladder activity. Methods: Neuromodulation of bladder activity was investigated in felines with an intact spinal cord under α‐chloralose anesthesia using a transcutaneous stimulation method with surface electrodes attached to the skin area between the base of the tail and the sciatic notch. Results: The bladder could be either inhibited or excited depending on stimulation frequency and bladder volume. With the bladder distended to induce large amplitude rhythmic isovolumetric bladder contractions, stimulation at a frequency between 5 and 7 Hz significantly suppressed the contractions. Stimulation applied during a cystometrogram (CMG) also increased bladder capacity by 44.3 ± 10.8%. At a frequency between 20 and 40 Hz the inhibitory effect on rhythmic bladder contractions was weak and did not increase bladder capacity during CMG. At low bladder volumes ranging between 60% and 100% of the bladder capacity 20 Hz stimulation‐induced small amplitude (21.2 ± 14.6 cmH₂O) bladder contractions. However, stimulation at 20 Hz induced large amplitude (111.7 ± 22.2 cmH₂O) bladder contractions at a bladder volume about 100–110% of the bladder capacity after the rhythmic bladder contractions were completely inhibited by the inhibitory 5 Hz stimulation. Conclusions: Both inhibitory and excitatory effects on bladder activity can be obtained in cats using the non‐invasive neural stimulation approach. This pre‐clinical study warrants a further clinical trial to investigate the possibility of using this non‐invasive stimulation method to treat incontinence or urinary retention. Neurourol. Urodynam. 30: 1686–1694, 2011. © 2011 Wiley Periodicals, Inc.     

Experimental autoimmune cystitis in the Lewis rat: a potential animal model for interstitial cystitis

To develop an autoimmune animal model for interstitial cystitis (IC), we injected rats with Freund's adjuvant (CFA) containing bladder homogenate (experimentals) or CFA alone (shams). We observed a doubling of urinary frequency in the experimental animals over the shams (P=0.004) and histopathologic changes (venular congestion) consistent with IC. Statistically significant bladder capacity changes were not found. Mast cell (MC) number was not statistically different between experimentals and controls but the number of MCs from section to adjacent section within the same animal's bladder did vary markedly, indicating that MC counts are not a reliable measure of disease in the rat bladder. Splenocytes cultured from the experimental animals and transferred to naive syngeneic recipients were capable of transferring the urinary frequency changes and vascular congestion while splenocytes from animals which did not develop the condition were without effect. In summary, we have developed an autoimmune model for IC consistent with the clinical features of IC. The features of this model can be transferred to naive syngeneic recipients via adoptive splenocyte transfer. The model will permit us to ask and answer important questions about the pathogenesis and treatment of the human disease.     

A spinal cord injured animal model of lower urinary tract function: observations using direct bladder and pelvic plexus stimulation with model microstimulators

BACKGROUND: Microstimulators are new devices that should be considered for management of lower urinary tract problems following spinal cord injury (SCI) such as urinary retention. These devices are small (less than 25 mm by 5 mm) with the electrodes located on the ends of the stimulator. However, it is not known whether the small electrodes on these devices would be effective in stimulating the plexus of nerves that innervate the bladder. The aim of the present study was to provide preliminary observations with model microstimulators (M-Micro) for inducing bladder contractions in an SCI animal model. Bladder wall and pelvic plexus stimulation sites were compared. Additional investigations evaluated parameters such as stimulation polarity, frequency, and period as well as bladder filling volume. METHODS: In an initial survival surgery, bilateral M-Micros were implanted on the bladder wall and the pelvic plexus along the urethra in 3 female cats. A second survival surgery was conducted 3 to 5 weeks later to produce a T1 0 SCI. Studies are reported following the second survival surgery. These studies included the effects of stimulation and bladder filling. RESULTS: The postmortem location of the implanted pelvic plexus M-Micro was previously described as near the bladder neck. Therefore, the pelvic plexus location is described in this report as "pelvic plexus (bladder neck)" stimulation. The observations showed effective stimulation with pelvic plexus (bladder neck) stimulation and voiding in some cases. Stimulation was limited by side effects of increased abdominal pressure and leg movement. Other factors also affected the response to stimulation, including the initial bladder volume and stimulating parameters. Fluoroscopy showed that when stimulation did not induce voiding the striated urethral sphincter was closed. CONCLUSIONS: This case series of 3 SCI animals showed that the small electrodes on the M-Micro could be used to stimulate the bladder with contractions and voiding in some cases. The pelvic plexus (bladder neck) location for the M-Micro may be a better location than higher on the bladder wall. Limiting side effects of stimulation included leg movement and increased abdominal pressure. Additional important factors included the stimulation parameters, initial bladder volume, and the function of the skeletal urethral sphincter.     

A Spinal Cord Injured Animal Model of Lower Urinary Tract Function: Observations Using Direct Bladder and Pelvic Plexus Stimulation With Model Microstimulators

Abstract

Background: Microstimulators are new devices that should be considered for managementof lower urinary tract problems following spinal cord injury (SCI) such as urinary retention. These devices are small(less than 25 mm by 5 mm) with the electrodes located on the ends of the stimulator. However, it is notknown whether the small electrodeson these devices would be effective in stimulating the plexus of nervesthat innervate thebladder. The aim of the present study was to provide preliminary observations with modelmicrostimulators (M-Micro) for inducing bladder contractions in an SCI animal model. Bladder wall andpelvic plexus stimulation sites were compared. Additional investigations evaluated parameters such asstimulation polarity, frequency, and period as well as bladder filling volume.

Methods: In an initial survival surgery, bilateral M-Micros were implanted on the bladderwall and the pelvic plexus along the urethra in 3 female cats. A second survival surgerywas conducted 3 to 5 weeks laterto produce a Tl 0 SCI. Studies are reportedfollowing the second survival surgery. These studies included the effects of stimulation and bladder filling.

Results: The postmortem location of the implanted pelvic plexus M-Micro was previouslydescribed asnear the bladder neck. Therefore, the pelvic plexus location is described in this reportas “pelvic plexus(bladder neck)”stimulation. The observations showed effective stimulation with pelvic plexus (bladder neck)stimulation andvoiding in some cases. Stimulation was limited byside effects of increased abdominalpressure and leg movement. Other factors also affected the response to stimulation, includingthe initial bladder volume and stimulating parameters. Fluoroscopy showed that when stimulation did not inducevoiding the striated urethral sphincter was closed.

Conclusions: This case series of 3 SCI animals showed that the small electrodes on the M-Micro could beused to stimulate the bladder with contractions and voidingin some cases. The pelvic plexus (bladder neck)location for the M-Micro may be a better location than higher on the bladder wall. Limiting side effects ofstimulation included legmovement and increased abdominal pressure. Additional important factors included the stimulation parameters, initial bladder volume, and the function of the skeletal urethral sphincter.     

Effects of sensitization on female guinea pig urinary bladder function: in vivo and in vitro studies

Although bladder inflammation is known clinically to produce a variety of symptoms including urgency, frequency, and pain, there are only a few experimental studies that directly relate bladder inflammation with urodynamic and functional alterations. We have used the sensitized guinea pig model to study the effects of inflammation on micturition parameters, cystometry, and in vitro bladder contractility. This model depends on the allergic response of the bladder mucosa to ovalbumin, an otherwise non-irritative agent, as an antigen. In vivo exposure of the bladder to ovalbumin via urethral catheterization induced a prompt and marked increase in the number of micturitions in antigen-sensitized guinea pigs. Ovalbumin had no effects on the micturition parameters in the control group. Using in vivo cystometry, intravesical exposure to ovalbumin induced a significant decrease in both the pressure at which micturition was induced, and the volume at which micturition was induced. Ovalbumin had no effect on cystometric parameters of the control animals. In vitro exposure of whole-bladder preparations to ovalbumin induced a significant contractile response only in the bladders isolated from the sensitized guinea pigs. The responses of the isolated bladders to field stimulation and bethanechol were identical for bladders from both sensitized and control animals. In conclusion, exposure of the bladder to ovalbumin in the sensitized animal induced an increase in the frequency of micturitions and a decrease in the pressure and volume at which micturition was induced. Thus, intravesical exposure of the bladder mucosa to a substance that the bladder has been sensitized to can induce alterations in micturition that are consistent with the clinical symptoms of "urgency and frequency".     

Substance P induced changes in CD74 and CD44 in the rat bladder

PURPOSE: Substance P (SP) induces rat bladder inflammation along with release of the proinflammatory cytokine, macrophage migration inhibitory factor (MIF). To describe the mechanism of MIF action we examined changes in the amount of CD74 (membrane receptor for MIF), CD44 and phospho-(p-ERK)1/2 in the bladder. MATERIALS AND METHODS: In anesthetized rats the bladder was isolated by cutting the ureters and urine was replaced by saline as intraluminal fluid (ILF). One hour after subcutaneous SP (40 mug/kg) or saline administration the ILF and bladder were collected. Bladder tissue was analyzed for CD74 and CD44 by immunohistochemistry. Western blot analysis determined the relative amounts of bladder tissue MIF, CD74, CD44 and p-ERK1/2. ILF immunoprecipitation followed by Western blot analysis was performed to identify an association of MIF with CD74 and/or CD44. RESULTS: SP induced significant MIF release from the bladder and increased CD74 and CD44 bladder immunostaining. SP treatment increased the total amount of bladder CD74 protein and mRNA, intracellular domain CD44, p-ERK1/2 and soluble CD44 in the ILF. Finally, MIF was found to be associated with soluble CD44 in the ILF. CONCLUSIONS: CD74 is present in the rat urothelium. SP increases CD74 and intracellular domain CD44 in the bladder, while stimulating the release of soluble CD44 and MIF into the ILF. MIF interacts with soluble CD44 in the ILF and it is available to bind with CD74 in the bladder to exert proinflammatory effects. Therefore, a mechanistic model is emerging to explain the proinflammatory effects of MIF in this acute model of bladder inflammation. Possible clinical implications are discussed.     

Inflammation of the rat urinary bladder is associated with a referred thermal hyperalgesia which is nerve growth factor dependent

We have assessed whether a referred somatic hyperalgesia to thermal stimulation of the hind limb of rats occurs after inflammation of the urinary bladder. Furthermore, we evaluated whether any such viscero- somatic hyperalgesia (VSH) is dependent on the neurotrophin nerve growth factor (NGF). Limb withdrawal thresholds from thermal stimulation of both fore and hind limbs were assessed simultaneously at baseline and at fixed times for 24 h after various interventions. After plotting curves for the difference in withdrawal time of fore and hind limbs against time, the area under the curve (AUC) was calculated to provide a single measure over the 24-h period. A negative value indicated relative hyperalgesia of the hind limb. With simple catheterization, although there was a trend towards hind limb hyperalgesia, there was no significant difference in this AUC (mean - 100.5) compared with naive control animals (mean AUC +53.6). However, inflammation with 50% turpentine oil was associated with a significant change in AUC (mean -676.8), indicative of relative hyperalgesia of the hind limb. This hyperalgesia was mimicked by intra-vesical instillation of NGF (in place of turpentine) (mean AUC -1418.3 while mean AUC in naive animals was +439.4). Furthermore, prior administration of an NGF sequestering molecule, trkA-IgG, attenuated turpentine-induced VSH. These findings increase our knowledge of the nature of visceral and referred pain and further implicate NGF in the hyperalgesic response to inflammation of the urinary bladder.      

Experimental autoimmune cystitis: further characterization and serum autoantibodies

Previously, we described an animal model for interstitial cystitis (IC), experimental autoimmune cystitis (EAC) [Luber-Narod et al. Urol Res 24:367]. Further characterization of animals with EAC indicates that peak and mean urinary frequency are elevated compared with sham-injected controls and that the disease progresses with at least two cycles of exacerbations and remissions. We had shown evidence suggesting EAC to be autoimmune in nature. In this paper, we identify serum autoantibodies from 9/10 EAC animals which bind to a protein specific to rat bladder with a relative molecular weight of 12-kDa. Such autoantibodies are absent in 12/13 normal and sham-injected animals as well as animals which fail to develop EAC despite disease induction. These findings suggest that EAC is a reproducible model of cyclical increases of urinary frequency, and that a 12-kDa antigen is the target of autoantibodies which correlate with those elevations. Identification of this target antigen may explain the pathogenesis of increased urinary frequency in these animals and potentially in IC as well. Received: 28 July 1998 / Accepted: 7 December 1998     

Potentiation by Bradykinin and Substance P of Purinergic Neurotransmission in Urinary Bladder

Purpose

The higher than normal levels of substance P (SP) and the kinins in patients suffering from interstitial cystitis suggest that they may contribute to the complex symptoms of the condition. The purpose of our experiments was to determine whether SP and bradykinin (BK) influence the excitatory motor innervation of the urinary bladder.

Materials and Methods

Strips of guinea pig urinary bladder were placed in isolated tissue baths, and the influence of SP and BK on contractions induced by transmural electrical stimulation and cholinergic and purinergic agonists was evaluated.

Results

Substance P and BK potentiated responses to the purinergic component of the neurogenic stimulation (that part of the contractile response that remains after treatment with atropine) and potentiated responses to exogenously applied adenosine triphosphate (ATP). The peptides did not potentiate the response to the cholinergic component of the nerve-induced contraction (that part of the neurogenic response that remains after desensitization of purinoceptors with alpha, beta-methylene ATP) nor responses to carbachol. The potentiating actions of SP and BK were reduced but not abolished by treatment with meclofenamic acid.

Conclusions

Substance P and BK potentiate the neurogenic response of the bladder by influencing the purinergic component of the excitatory motor innervation, apparently at a postjunctional site. Prostaglandins may be involved in mediating some of the actions of these peptides.     

Micturition by functional magnetic stimulation in dogs: A preliminary report

The effectiveness of functional magnetic stimulation (FMS) technology on bladder contraction and bladder emptying was evaluated in ten normal neurologically intact male dogs. In seven animals, FMS of the bladder was performed by using a commercially available magnetic coil (non-water-cooled) for stimulating the sacral nerves or over the suprapubic region. With sacral stimulation, the mean change in bladder pressure (Pves) was 68.0 ± 12.96 cm H₂O; with suprapubic stimulation, the mean change in Pves was 40.7 ± 8.08 cm H₂O. This change in Pves by sacral stimulation was higher than suprapubic stimulation (P < 0.01). In three additional animals, voiding was demonstrated by using a specialized water-cooled magnetic coil and by stimulating the sacral nerves with an intermittent stimulation sequence. Voiding occurred in all three animals and was reproducible. In summary, FMS of the bladder has the potential to be a useful non-invasive technology for bladder emptying and bladder training in patients with neurogenic bladder. Neurourol. Urodynam. 16:305–314, 1997. © 1997 Wiley-Liss, Inc.     

Modulating bladder neuro-inflammation: RDP58, a novel anti-inflammatory peptide, decreases inflammation and nerve growth factor production in experimental cystitis

PURPOSE: In interstitial cystitis (IC) inflammation induces and perpetuates neurotrophic changes in the bladder, resulting in the symptoms of frequency, urgency and pain. RDP58 (NH2-arg-norleucine (nle)-nle-arg-nle-nle-nle-gly-tyr-CONH2) (Sangstat Corp., Fremont, California) is a novel synthetic peptide that inhibits early signal transduction pathways for the expression of inflammatory cytokines. In this study we evaluated the effects of intravesical RDP58 on an established model of cystitis. MATERIALS AND METHODS: Mice were catheterized and equal volumes of Escherichia coli lipopolysaccharide (LPS) or saline were instilled into the bladder. After 45 minutes the bladders were drained and distilled water or RDP58 (1 mg/ml) was instilled for 30 minutes. At 24 hours later the bladders were excised and cultured for analysis of tumor necrosis factor-alpha (TNF-alpha), substance P (SP) and nerve growth factor (NGF) production, as quantified by enzyme-linked immunosorbent assay. RESULTS: LPS caused severe inflammation in mouse bladders compared with controls. Exposure to LPS increased the levels of TNF-alpha, SP and NGF production compared with controls (each p <0.05). In LPS exposed mice RDP58 significantly decreased inflammatory parameters by 82% 24 hours after treatment (p <0.05). Within 4 hours RDP58 abolished TNF-alpha production and at 24 hours TNF-alpha remained undetectable. RDP58 also significantly decreased SP and NGF production in LPS exposed bladders by more than 40% and 85%, respectively (each p <0.05). CONCLUSIONS: Inflammatory models of cystitis result in increased levels of TNF-alpha, SP and NGF production in the bladder, paralleling the hypothesized neuro-inflammatory etiology of IC. RDP58 decreases inflammation and neurotrophic factors in vivo and it may potentially treat bladder disorders with an inflammatory component, such as IC.     

Local high-frequency hyperthermia of the Brown-Pearce carcinoma in the urinary bladder of rabbits (author's transl)

The effect of a conductive high-frequency hyperthermia on a model tumor in the urinary bladder of rabbits (Brown-Pearce Carcinoma) was studied at a temperature of 43 degrees C, and with an application time of 30 min. The frequency used was 500 kHz, wattage 30-300 and wavelength 600 m. This resulted in the homogeneous warming of the urinary bladder tissue, in contrast to the results obtained when warm water was injected. Essential test results included: (1) a temperature gradient of max. 6.7 degrees C from the tumor center to the lumen of the urinary bladder, the tumor favoring the higher temperatures; (2) a prolongation of the survival time for animals with heat-treated tumors as opposed to the control animals. After transplantation heat-treated tumors evolved to receptor animals considerably less often than did untreated tumors.     

Location and concentration of estrogen,progesterone, and androgen receptors in the bladder and urethra of the rabbit

The objective of this study was to determine location and concentration of estrogen, androgen and progesterone receptors in the bladder and urethra of the rabbit. Two urethral and two bladder specimens were obtained from four 12-week-old female New Zealand white rabbits. Rat monoclonal antibody (AN 1–15) to human androgcn receptor and (H222) to human estrogen receptor and mouse monoclonal antibody (PR6) to chicken progesterone receptor were used. Immunocytochemical staining was performed and specimens were evaluated lor presence and location of steroid receptors. Androgen receptors were found in the highest concentrations in urethral and bladder epithelium. Low to low/moderate concentration were found in smooth muscle. Estrogen receptors were found in moderate to moderate/high concentrations in urethral epithelium and bladder and urethral smooth muscle. Progesterone receptors were not found in appreciable concentrations from any location, though the animals were not pretreated with estrogen. The rabbit model suggests a mechanism by which estrogen therapy can be effective in treating postmenopausal lower urinary tract symptoms. Progesterone receptors were not found in appreciable concentrations, suggesting progesterone therapy may not diminish the effectiveness of estrogen therapy by acting on urethral progesterone receptors. The effect of androgcns on the lower urinary tract needs further investigation to determine if androgen therapy can alleviate lower urinary tract symptoms. © 1995 Wiley-Liss, Inc.     

Effects of foreign bodies on development of urinary bladder tumors in rats treated with N-butyl-N-(4-hydroxybutyl) nitrosamine

Summary The effects of chronic mechanical stimulation induced by glass balls or paraffin balls on precursor lesions of the urinary bladder of male Wistar strain rats induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in the drinking water were studied.When foreign bodies were present in the bladder, proliferative lesions of the urinary bladder epithelium were found even without administration of carcinogen. When the foreign bodies were implanted into the urinary bladder and then rats were given BBN in the drinking water for the first 4 weeks of the experimental period, a high incidence of tumors of the urinary bladder was observed. The incidence of tumors induced by BBN was increased by the presence of glass balls or paraffin balls in the urinary bladder.These results clearly show that foreign bodies in the urinary bladder have a significant effect in promoting carcinogenesis of the urinary bladder in rats.     

Transcutaneous electrical stimulation of urinary bladder in patients with spinal cord injuries

Introduction  The treatment of neurogenic dysfunctions of micturition, both surgical and conservative, aims primarily to protect upper urinary tract function. This goal can be achieved by lowering intravesical pressure and increasing urinary bladder capacity in the urine collection phase or by facilitating bladder emptying. Objective  The objective of this paper was to assess the outcome of transcutaneous stimulation of the urinary bladder in the treatment of neurogenic disorders of micturition. Materials and methods  The effect of urinary bladder stimulation was assessed in 22 patients (4 females, 18 males) with spinal injuries (19 with injuries to the lumbo-sacral spine and 3 with cervical spine injuries) treated at the Department of Rehabilitation of the Military Hospital in Bydgoszcz, Poland, in 2006 and 2007. The treatment consisted of 30 procedures of transcutaneous electrical stimulation of the urinary bladder. A pulsed sinusoid current was used with a pulse duration of 200 ms, break duration of 1,000 ms, intensity of 15–20 mA, frequency of 50 Hz, and duration of stimulation of 15 min. A urodynamic study was carried out in each patient at baseline and on completion of the electrical stimulation therapy (immediately and after 2 months). Results  Electrical stimulation of the neurogenic urinary bladder produced increases in the cystometric bladder capacity and reduction in the amount of residual urine (72% of patients), with reduction of intravesical pressure at peak urine flow (59% of the patients). The dynamic aspects of micturition also improved with increased peak voiding velocity in 77.3% of the patients. More than half of the patients (57%) still had elevated intravesical pressures during micturition that posed a risk to the function of the upper urinary tract despite significant decreases following the stimulation therapy. Micturition, which was absent at baseline, was restored in three patients. No local complications were observed. Conclusions  Transcutaneous electrical stimulation of the urinary bladder in patients with neurogenic bladder dysfunction improves lower urinary tract function. Urodynamic studies executed 2 months after finishing TES show persistent results.     

Inhibiting the hyperreflexic bladder with electrical stimulation in a spinal animal model

Uninhibited bladder contractions are a problem in spinal cord injured patients. Accordingly, methods using electrical stimulation to inhibit the bladder were investigated in chronic spinal cord injured (C6-T1) male cats. In unanesthetized, restrained animals, spontaneous bladder contractions were observed after the bladder was filled above the micturition threshold. In 3 of the 5 cats studied, this bladder activity could be inhibited with stimulation of either sacral nerves or pudendal nerves. Pudendal nerve stimulation, however, was more selective than sacral nerve stimulation for inhibition with fewer side effects such as leg spasms. Tibial nerve stimulation was ineffective and caused leg spasms and increased bladder activity. Finally, high-frequency stimulation (1,000 Hz) of the sacral nerves was shown to block bladder contractions in 2 of 3 cats investigated. However, this method had adverse side effects such as leg flexion and secondary bladder contractions. We conclude that pudendal nerve/pelvic floor stimulation at low frequency is a relatively effective method in this model.     

Regulation von Interleukin-6 durch Lipopolysaccharid-Stimulation in kultivierten humanen Detrusormyozyten

BACKGROUND: Interleukin-6 (IL-6) is a pleiotropic cytokine which shows elevated plasma and urine levels in cancer and inflammatory diseases of the urinary tract. The aim of the study is to define IL-6 target gene regulation in cultivated human detrusor smooth muscle cells. PATIENTS AND METHODS: The expression of IL-6 and IL-6R (gp80, gp130) was studied by confocal immunofluorescence, rtPCR and Western blotting. Lipopolysaccharide (LPS) stimulation experiments were conducted in smooth muscle cell cultures derived from bladder biopsies of four male tumor patients. RESULTS: IL-6 and IL-6R expression was found in urothelium, lamina propria and detrusor cells. LPS stimulation evoked a time-dependent synthesis and/or release of IL-6, IL-6R and STAT3. CONCLUSIONS: Our results favor the notion that IL-6 can stimulate various cells of the human urinary bladder. Both detrusor cells and urothelium can serve as a source of elevated IL-6 levels. Finding genes regulated by IL-6 could be of great value for new therapeutical approaches in cancer and chronic inflammation of the lower urinary tract.