Urothelial Denudation Research Articles

Definition Change and Update of Clinical Guidelines for Interstitial Cystitis and Bladder Pain Syndrome.

The clinical guidelines for interstitial cystitis (IC) and bladder pain syndrome (BPS) have been revised by updating our previous guidelines. The symptoms of IC and BPS, collectively called as hypersensitive bladder (HSB) symptoms, are virtually indistinguishable between IC and BPS; however, IC and BPS should be considered as a separate entity of disorders. We define IC as a bladder disease with Hunner lesions, usually associated with HSB symptoms and bladder inflammation, and BPS as a condition with HSB symptoms in the absence of Hunner lesions and any confusable diseases. Pathophysiology totally differs between IC and BPS. IC involves immunological inflammation probably resulting from autoimmunity, while BPS is associated with the interaction of multiple factors such as neurogenic inflammation, exogenous substances, urothelial defects, psychological stress, and neural hyperactivity. Histopathology also differs between IC and BPS. IC is associated with severe inflammation of the whole bladder accompanied by plasma cell infiltration and urothelial denudation, while BPS shows little pathological changes. Management should begin with a differential diagnosis of IC or BPS, which would require cystoscopy to determine the presence or absence of Hunner lesions. The patients should be treated differently based on the diagnosis following the algorithm, although pain management would be common to IC and BPS. Clinical studies are also to be designed and analyzed separately for IC and BPS.

Intravesical Instillation of Hyaluronic Acid With Epidermal Growth Factor for Restoring Urothelial Denudation and Alleviating Oxidative Stress in Lipopolysaccharide-Induced Interstitial Cystitis of Rats.

To investigate the efficacy of an intravesical instillation of hyaluronic acid (HA) combined with epidermal growth factor (EGF) for the treatment of interstitial cystitis (IC) using a lipopolysaccharide (LPS)-induced IC animal model. A total of 24 female Sprague-Dawley rats were randomized to 4 groups: sham control, IC, HA, and treatment (HA/ EGF) groups. A polyethylene-50 tube was placed inside the bladder of each animal. IC was induced by twice-weekly instillations of LPS for 3 weeks, which resulted in chronic injury of the urothelium. Animals in the sham control group only received saline instillation. Treatment solutions of HA and HA/EGF were given on days 0, 7, and 14 after IC induction (400 μL of HA in a concentration of 0.4 mg/0.5 mL and 400 μL of NewEpi, a commercialized HA/EGF mixture containing 2 μg of EGF and 0.4 mg of sodium hyaluronate). Animals were sacrificed on day 21 for further examinations. The HA/EGF group showed visible improvement in hematuria with a significant reduction of red blood cells in the urine compared to the HA group. Histological examination revealed that HA/EGF treatment reversed the abnormalities developed in IC, including infiltration of inflammatory cells, irregular re-epithelialization, and fibrotic tissue. Moreover, HA/ EGF significantly reduced the levels of proinflammation cytokines (tumor necrosis factor-α, interleukin [IL]-6, and IL-1β) and substantially lowered the elevated oxidative stress biomarker malondialdehyde, yet restored the levels of antioxidant enzymes glutathione peroxidase and superoxide dismutase, with superior results than HA treatment. Cystometry studies indicated that HA/EGF significantly prolonged intercontraction interval and increased micturition volume. HA/EGF has been demonstrated as a more effective treatment for enhancing the urothelium lining and reducing inflammatory changes to alleviate clinical symptoms associated with IC in rats, compared to HA alone.

Therapeutic effects of axitinib, an anti-angiogenic tyrosine kinase inhibitor, on interstitial cystitis

To investigate the therapeutic effects of axitinib, a tyrosine kinase inhibitor, in an interstitial cystitis (IC) rat model. IC patients with or without Hunner lesion and non-IC controls were enrolled (n = 5/group). Bladder tissues were stained with vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), platelet-derived growth factor (PDGF), and PDGF receptor B (PDGFR-B). The IC group showed extensive VEGFR-2 and PDGFR-B staining compared with controls. Next, ten-week-old female Sprague Dawley rats were divided into three groups (n = 10/group): sham, hydrochloride (HCl), and axitinib groups. One week after HCl instillation (day 0), the axitinib group received oral axitinib (1 mg/kg) for five consecutive days and pain was evaluated daily. Bladder function, histology and genetics were evaluated on day 7. The pain threshold significantly improved 3 days after axitinib administration. Axitinib decreased non-voiding contraction and increased the micturition interval and micturition volume and alleviated urothelial denudation, angiogenesis, mast cell infiltration, and fibrosis. HCl instillation increased the expression of tyrosine kinase receptors, including VEGFR-2 and PDGFR-B; axitinib administration inhibited their expression. Oral administration of axitinib improved pain, voiding profiles, and urothelial integrity by inhibiting angiogenesis in IC rat model. Axitinib may have potential therapeutic efficacy in IC patients.

Systematic review and meta-analysis of ketamine-associated uropathy.

This systematic review and meta-analysis focused on the literature regarding ketamine-associated uropathy to summarise its clinical manifestations, the results of urological assessments, and current management. A literature search was conducted using keywords and MeSH terms related to ketamine abuse, urinary tracts, and urological examinations. Databases including Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched up to 26 June 2020. In total, 1365 articles were retrieved; 45 articles (4921 patients) were included in the analysis of patient demographics, clinical manifestations, examination results, and treatments. Frequency was the most common manifestation (pooled prevalence 77.1%, 95% confidence interval [CI]=56.9%-92.2%), followed by urgency (69.9%, 95% CI=48.8%-87.3%) and suprapubic pain (60.4%, 95% CI=35.3%-82.9%). Upper urinary tract involvement was less common; the pooled prevalence of hydronephrosis was 30.2% (95% CI=22.0%-39.2%). Further workup revealed a pooled functional bladder capacity of 95.23 mL (95% CI=63.57-126.88 mL), pooled voided volume of 113.31 mL (95% CI=59.44- 167.19 mL), and pooled maximum urine flow rate of 8.69 mL/s (95% CI=5.54-11.83 mL/s). Cystoscopic examinations and bladder biopsy revealed frequent urothelial denudation, inflammatory changes, and inflammatory cell infiltration. Treatments included oral medications for symptomatic relief, intravesical therapy, and surgery (eg, hydrodistension and bladder reconstruction), but ketamine abstinence was necessary for improvement. Ketamine-associated uropathy frequently involves frequency, urgency, and suprapubic pain; upper urinary tract involvement is less common. Affected patients showed reductions in bladder capacity and urine flow rate. Endoscopic and histological analyses often revealed cystitis. Despite variations in treatment, ketamine abstinence is important for all patients with ketamine-associated uropathy.

Dehydrated Human Amnion-Chorion Membrane Extracts Can Ameliorate Interstitial Cystitis in Rats by Down-Regulating Inflammatory Cytokines and Protein Coding Genes: A Preclinical Study.

The study aimed to investigate the therapeutic impact of intravesical instillation of dehydrated human amnion-chorion membrane (HACM) extracts based on the primary pathological feature of interstitial cystitis (IC). We divided 15 female Sprague-Dawley rats into three groups: sham control, IC, and treatment group. IC was induced by 400-µL lipopolysaccharide (1 µg/µL), and it was replaced with normal saline in the sham control group. After IC induction, 300 µL dehydrated HACM extracts (3 mg/kg) were instilled into rats' urinary bladder weekly for 3 weeks. General histology, inflammatory cytokines, NF-κB, oxidative markers, and western blots results were examined. The urothelial denudation, mast-cell infiltration, and tissues fibrosis were all ameliorated. The elevated TNF-α, IL-1β, IL-6, IL-8, and NF-κB were all down-regulated by dehydrated HACM extracts (p < 0.05). For reactive oxygen species, increased malondialdehyde, decreased superoxide dismutase, and decreased glutathione peroxidase were all reversed (p < 0.05). In apoptosis of IC, elevated Bax and suppressed Bcl-2 were improved (p < 0.05) after instillation. In fibrosis, dysregulated TGFβ/R-Smads/Snail was corrected by the instillation of dehydrated HACM (p < 0.05). In conclusion, dehydrated HACM extracts could be a powerful remedy in treating IC by reconstructing the damaged urothelium, reducing mast-cell infiltration and inflammatory reactions, and ameliorating fibrotic changes.

Superior therapeutic activity of TGF-β-induced extracellular vesicles against interstitial cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by incapacitating pelvic pain. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are considered key mediators of the paracrine action of MSCs and show better biological activities than the parent MSCs, especially in the bladder tissue, which may be unfavorable for MSC survival. Here, we produced MSC-EVs using advanced three-dimensional (a3D) culture with exogenous transforming growth factor-β3 (TGF-β3) (T-a3D-EVs). Treatment with T-a3D-EVs led to significantly enhanced wound healing and anti-inflammatory capacities. Moreover, submucosal layer injection of T-a3D-EVs in chronic IC/BPS animal model resulted in restoration of bladder function, superior anti-inflammatory activity, and recovery of damaged urothelium compared to MSCs. Interestingly, we detected increased TGF-β1 level in T-a3D-EVs, which might be involved in the anti-inflammatory activity of these EVs. Taken together, we demonstrate the excellent immune-modulatory and regenerative abilities of T-a3D-EVs as observed by recovery from urothelial denudation and dysfunction, which could be a promising therapeutic strategy for IC/BPS.

Simvastatin Toxicity Induces Alteration of Bladder Thickness in Interstitial Cystitis Rat Model

Background: Interstitial cystitis (IC) is a chronic inflammatory of the bladder, while statin can increase its risk.Recently, the exact mechanism is yet known. We hypothesizedsimvastatin can induce alteration of bladderthickness.Methods: Twenty-four female Wistar rats were aged 6-8 weeks old were divided into two groups and weretreated with simvastatin 50 mg/kg BW or carboxymethylcellulose 0.5% by oral gavage for 30 days. Each groupwas then equally subdivided into three groups: control, Interstitial Cystitis (IC) day-0, and IC day-3. Either ICor control rat group was induced by intravesical instillation of protamine sulfate or buffered saline respectively.All animals in the control and IC day-0 group were sacrificed and collected for the bladder tissue in less thanthree hours following intravesical treatment, while animals in the IC day-3 group three days after. All collectedtissue was prepared in hematoxylin-eosin staining and measured for the bladder thickness, namely the urothelial,suburothelial, and detrusor layer by image analyzer application.Results: There was no significant difference between the groups receiving simvastatin and placebo in thethickness of the urothelium, suburothelium, and detrusor layers in all rat models, both control, IC0, and IC3 rats(all p values > 0.05). However, the thickness of the urothelium layer was consistently lower in the simvastatingroup than in the placebo group in all rat models.Conclusion: Mechanism of simvastatin toxicity on bladder tissue through urothelial denudation thus may alterthe urothelial barrier function.

Functional and histologic imaging of urinary bladder wall after exposure to psychological stress and protamine sulfate

To quantify the urinary bladder wall T1 relaxation time (T1) before and after the instillation contrast mixture in rats previously subjected to water avoidance stress (WAS) and/or acute exposure to protamine sulfate (PS). Female Wistar rats were randomized to receive either sham (control) or 1 h of WAS for ten consecutive days before the evaluation of nocturnal urination pattern in metabolic cages. T1 mapping of urinary bladder wall at 9.4 T was performed pre- and post- instillation of 4 mM Gadobutrol in a mixture with 5 mM Ferumoxytol. Subsequently, either T1 mapping was repeated after brief intravesical PS exposure or the animals were sacrificed for histology and analyzing the mucosal levels of mRNA. Compared to the control group, WAS exposure decreased the single void urine volume and shortened the post-contrast T1 relaxation time of mucosa- used to compute relatively higher ingress of instilled Gadobutrol. Compromised permeability in WAS group was corroborated by the urothelial denudation, edema and ZO-1 downregulation. PS exposure doubled the baseline ingress of Gadobutrol in both groups. These findings confirm that psychological stress compromises the paracellular permeability of bladder mucosa and its non-invasive assay with MRI was validated by PS exposure.

Therapeutic effect of modulating the NLRP3-regulated transforming growth factor-β signaling pathway on interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder with complex pathogenesis and lacks effective treatment. Chronic inflammation is the main pathogenesis of Hunner-type IC/BPS. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome-related transforming growth factor-β (TGF-β)/Smad signaling pathway plays a crucial role in inflammation-related tissue fibrosis. Lipopolysaccharide (LPS) and protamine sulfate (LPS/PS) were instilled into the mouse bladder twice a week for 5 consecutive weeks to establish a chronic inflammation-induced IC/BPS model (LPS/PS model). Following LPS/PS treatment, curcumin (oral, 100 mg/kg; a potent NLRP3 modulator) was administered for 2 weeks in the curcumin treatment group, and normal saline was used for the sham group. Bladder function was evaluated by performing the voiding spot assay and examining the status of urothelial denudation and fibrosis in bladder tissues. The expression of NLRP3 inflammasome, interleukin-1β, TGF-β, Smad, vimentin, and E-cadherin in bladder tissues was evaluated through immunohistochemistry staining. Results revealed that the repeated instillation of LPS/PS leads to voiding dysfunction, bladder urothelium denudation, and detrusor muscle fibrosis through the upregulation of the NLRP3 inflammasome/IL-1β-related TGF-β/Smad pathway and the increased epithelial–mesenchymal transition process in bladder tissues. The downregulation of the NLRP3 inflammasome/IL-1β-related TGF-β/Smad pathway in bladder tissues through curcumin effectively mitigated bladder injury in the LPS/PS model. In conclusion, the NLRP3 inflammasome/IL-1β-related TGF-β/Smad pathway plays a crucial role in bladder injury in the LPS/PS model, and modulation of this pathway, such as by using curcumin, can effectively mitigate the sequelae of chronic inflammation-induced IC/BPS.

Clinical guidelines for interstitial cystitis/bladder pain syndrome

The clinical guidelines for interstitial cystitis and related symptomatic conditions were revised by updating our previous guidelines. The current guidelines define interstitial cystitis/bladder pain syndrome as a condition with chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder accompanied by other urinary symptoms, such as persistent urge to void or urinary frequency in the absence of confusable diseases. The characteristic symptom complex is collectively referred as hypersensitive bladder symptoms. Interstitial cystitis/bladder pain syndrome is divided into Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis and bladder pain syndrome represent interstitial cystitis/bladder pain syndrome with Hunner lesions and interstitial cystitis/bladder pain syndrome without Hunner lesions, respectively. So-called non-Hunner-type interstitial cystitis featured by glomerulations or bladder bleeding after distension is included in bladder pain syndrome. The symptoms are virtually indistinguishable between Hunner-type interstitial cystitis and bladder pain syndrome; however, Hunner-type interstitial cystitis and bladder pain syndrome should be considered as a separate entity of disorder. Histopathology totally differs between Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis is associated with severe inflammation of the urinary bladder accompanied by lymphoplasmacytic infiltration and urothelial denudation, whereas bladder pain syndrome shows little pathological changes in the bladder. Pathophysiology would also differ between Hunner-type interstitial cystitis and bladder pain syndrome, involving interaction of multiple factors, such as inflammation, autoimmunity, infection, exogenous substances, urothelial dysfunction, neural hyperactivity and extrabladder disorders. The patients should be treated differently based on the diagnosis of Hunner-type interstitial cystitis or bladder pain syndrome, which requires cystoscopy to determine the presence or absence Hunner lesions. Clinical studies are to be designed to analyze outcomes separately for Hunner-type interstitial cystitis and bladder pain syndrome.

Editorial Comment to Angiogenesis in bladder tissues is strongly correlated with urinary frequency and bladder pain in patients with interstitial cystitis/bladder pain syndrome

The authors collected bladder biopsies from 12 Hunner lesion patients, 12 non-Hunner interstitial cystitis/bladder pain syndrome (IC/BPS) patients, and 12 controls. A variety of immunohistochemical testing was performed on the specimens to correlate among bladder inflammation, angiogenesis, fibrosis, and urothelial denudation in bladder tissues among immunohistochemistry, and symptom scores. Results suggest that bladder angiogenesis evident as the increased expression of CD31 is strongly correlated with urinary frequency and bladder pain in patients with non Hunner and Hunner positive IC. The study is quite interesting and suggests that angiogenesis might be a therapeutic target. There are a couple of questions that came to my mind reading the research. Could the bladder distention performed on all patients but not on controls prior to biopsy have affected the results? Why was there not a group of hypersensitive bladder patients (those with no mucosal bleeding or glomerulations under distention) included? These missing group would comprise patients considered to have IC/BPS in Europe and North America but not in East Asia where they would be classified as having hypersensitive bladder syndrome. Certainly, there is more work to be done, but the authors have provided much to think about as we try to unravel this disorder. None declared.

Angiogenesis in bladder tissues is strongly correlated with urinary frequency and bladder pain in patients with interstitial cystitis/bladder pain syndrome.

To examine the correlation among bladder inflammation, angiogenesis, fibrosis and urothelial denudation in biopsied bladder specimens, and O'Leary-Sant symptom indexes, O'Leary-Sant problem indexes and visual analog scale pain scores in interstitial cystitis/bladder pain syndrome patients with or without Hunner lesions (Hunner type interstitial cystitis or non-Hunner type interstitial cystitis). Bladder biopsied tissues were collected from 12 Hunner type interstitial cystitis female patients, 12 non-Hunner type interstitial cystitis female patients and 12 age-matched non-interstitial cystitis female patients (controls). Immunohistochemical stainings of tissue necrotic factor-α, mast cell tryptase, vascular endothelial growth factor, CD31, transforming growth factor-β, SLUG associated with epithelial mesenchymal transition and E-cadherin as well as Masson trichrome staining were evaluated. The significant correlation between the expression of tissue necrotic factor-α, mast cell tryptase, vascular endothelial growth factor, CD31, transforming growth factor-β, collagen, SLUG or E-cadherin, and O'Leary-Sant symptom indexes, O'Leary-Sant problem indexes or visual analog scale pain scores was then examined. The expression of tissue necrotic factor-α, vascular endothelial growth factor, CD31, transforming growth factor-β and SLUG was significantly increased in non-Hunner type interstitial cystitis and Hunner type interstitial cystitis patients compared with controls whereas the significant increases in the expression of mast cell tryptase and collagen were observed in Hunner type interstitial cystitis patients compared with controls and non-Hunner type interstitial cystitis patients. On the other hand, the expression of E-cadherin was significantly decreased in Hunner type interstitial cystitis patients compared with controls and non-Hunner type interstitial cystitis patients. In addition, the increased expression of CD31 in bladder tissues was strongly correlated with O'Leary-Sant symptom indexes, O'Leary-Sant problem indexes and visual analog scale pain scores. These results suggest that bladder angiogenesis evident as the increased expression of CD31 is strongly correlated with urinary frequency and bladder pain in patients with non-Hunner type interstitial cystitis and Hunner type interstitial cystitis.

Implantable orthotopic bladder cancer model in Wistar rats: A pilot and feasibility study

Abstract Purpose: The implantable bladder cancer (BC) models allow the researchers to perform rapid and useful experiments for BC. We investigated the implantation success of BC cells obtained from Wistar rats (grown in vitro), into bladders of syngeneic Wistar rats, which are commonly used in the laboratories. Methods: The Nara Bladder Tumor No.2 (NBT-II) BC cells induced with 4-hydroxybutylnitrosamine were grown with passages in Kocaeli University Center for Stem-Cell and Gene-Therapies. After urothelial denudation, 2x106 NBT-II cells were then implanted into bladders of 24 female Wistar rats (aged 7-8 weeks). The rats were randomly divided into four experimental groups; three instillation groups (8 per group) and one sham-operated control group consisting of 6 rats. First, second and third instillation groups were sacrificed at days 7, 14, and 21, respectively, and, bladders were histopathologically evaluated for BC according to WHO / International Society of Urological Pathology. Results: All tumors were pT1 (including 1 rat that prematurely died at 5th day), except one rat that died prematurely at 8th day had pT2 tumor. Implantation rates were 28.58% (2/7) in the first group, and 42.85% (3/7) in the second, for a cumulative rate of 35.71% (5/14) in these two-groups (until 14th day). Interestingly, there was no tumor in the third group, but there was an inflammatory granulation tissue. Conclusion: Seeding NBT-II cells into bladders of Wistar rats was described, successfully tested and demonstrated in this study. This implantable BC model of Wistar rats may be improved to increase the success rate of BC cell implantation in new studies with higher number of animals.

Effects of caveolae depletion and urothelial denudation on purinergic and cholinergic signaling in healthy and cyclophosphamide-induced cystitis in the rat bladder.

Cholesterol rich membrane invaginations, caveolae, have important roles in various cellular activities, one of them being signal transduction. This signaling pathway seems to be affected during various bladder disorders and the current study aimed to elucidate the plausible involvement of caveolae mediated signal transduction during cyclophosphamide induced cystitis. Furthermore, the urothelial cholinergic part of ATP-evoked contractions and its possible link to caveolae were investigated. Cholinergic, as well as purinergic, contractile responses in rat urinary bladders were examined using a classic organ bath set-up with full-thickness strip preparations or a whole bladder model that enabled luminal administration of substances. Furthermore, sub groups with and without urothelium were examined. The expression of caveolin-1 was also tested using western blot and immunofluorescence. Caveolae cholesterol depletion by methyl-β-cyclodextrin entailed a significant decrease of ATP-evoked bladder contractility. Interestingly, after muscarinic blockade the ATP induced contractions were significantly reduced in the same manner. Furthermore, this atropine-sensitive part of ATP-evoked responses was absent in denuded as well as inflamed bladders. A tendency towards a reduced expression of caveolin-1 was observed in rats with experimental cystitis. The cholinergic part of ATP-induced contractile responses seemed to be affected by urothelium denudation as well as caveolae depletion. Removing one of these structures nullifies the effect of the other, suggesting an important interaction between the urothelium and the caveolar structures. These effects are absent in inflamed animals and might be one pathophysiological aspect behind BPS/IC.

MP39-02 WHOLE-TRANSCRIPTOME PROFILING IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS BY NEXT-GENERATION SEQUENCING: A DISTINCT GENOMIC LANDSCAPE BY THE PHENOTYPES

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Interstitial Cystitis1 Apr 2018MP39-02 WHOLE-TRANSCRIPTOME PROFILING IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS BY NEXT-GENERATION SEQUENCING: A DISTINCT GENOMIC LANDSCAPE BY THE PHENOTYPES Akiyama Yoshiyuki, Daichi Maeda, Hiroto Katoh, Aya Niimi, Akira Nomiya, Tetsuya Fujimura, Hiroshi Fukuhara, Haruki Kume, Yasuhiko Igawa, and Yukio Homma Akiyama YoshiyukiAkiyama Yoshiyuki More articles by this author , Daichi MaedaDaichi Maeda More articles by this author , Hiroto KatohHiroto Katoh More articles by this author , Aya NiimiAya Niimi More articles by this author , Akira NomiyaAkira Nomiya More articles by this author , Tetsuya FujimuraTetsuya Fujimura More articles by this author , Hiroshi FukuharaHiroshi Fukuhara More articles by this author , Haruki KumeHaruki Kume More articles by this author , Yasuhiko IgawaYasuhiko Igawa More articles by this author , and Yukio HommaYukio Homma More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1249AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Bladder pain syndrome/interstitial cystitis (BPS/IC) comprises a diverse variety of clinical phenotypes. Among them, BPS/IC with Hunner lesions has been implied to be a distinct entity, histologically characterized by inflammatory infiltrates and urothelial denudation. In this study, we performed high-throughput sequencing-based whole transcriptome analysis to identify differentially expressed genes (DEGs) and characterize the genomic landscape in BPS/IC. METHODS A total of 54 urinary bladder biopsy samples were taken from 33 patients with BPS/IC with (12) (one each from the lesion and a non-lesion area; n = 24 in total) or without (21) Hunner lesions, and 9 non-IC patients without bladder symptoms and pathology, and subjected to whole RNA-sequencing. Hierarchical clustering and KEGG pathway analysis were performed for DEGs. RESULTS A total of 17,363 DEGs were identified among the groups (false discovery rate≤0.05). Hierarchical clustering analysis segregated samples into 2 distinct clusters. Cluster 1: BPS/IC with Hunner lesions. Cluster 2: BPS/IC without Hunner lesions and non-IC control (Fig. 1). KEGG pathway analysis revealed that DEGs upregulated in BPS/IC with Hunner lesions were significantly enriched in the T/B cell receptor signaling, chemokine signaling, Th17 cell differentiation, VEGF signaling, NF-κB signaling, NOD-like receptor signaling, Toll-like receptor signaling, inflammatory mediator regulation of TRP channels, and GAG degradation pathways, while those downregulated in BPS/IC with Hunner lesions were significantly related to the adherence/tight junction and estrogen signaling pathways (all P<0.05). On the other hand, DEGs in BPS without Hunner lesions were only 104 genes, for which KEGG pathway analysis could not find any significant biological pathways. CONCLUSIONS The results demonstrated a distinct genomic profile of BPS/IC with Hunner lesions. Urothelial deficiency, inflammatory/immune responses, aberrant vascularization, and abnormal estrogen signaling pathway may be involved in the pathophysiology of BPS/IC with Hunner lesions. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e510 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Akiyama Yoshiyuki More articles by this author Daichi Maeda More articles by this author Hiroto Katoh More articles by this author Aya Niimi More articles by this author Akira Nomiya More articles by this author Tetsuya Fujimura More articles by this author Hiroshi Fukuhara More articles by this author Haruki Kume More articles by this author Yasuhiko Igawa More articles by this author Yukio Homma More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Clinical and histological findings in bladder pain syndrome/interstitial cystitis: The implication of time of symptoms

Objective: To find out whether a correlation exists between denudation of urothelium and time of symptom onset in patients with bladder pain syndrome/interstitial cystitis (BPS/IC), and to search for a correlation between the impact of symptoms. Patients and methods: Fifty-seven consecutive patients underwent cystoscopy under anaesthesia to classify those cases suspected of being affected with BPS/IC. The time elapsed between onset of symptoms and diagnosis at the time of bladder biopsy was also defined as BPS/IC duration. Bladder biopsies were taken including detrusor muscle, three deep cold biopsies of posterior, anterior and lateral bladder wall. Results: Statistical analysis showed significant correlation between BPS/IC duration and the presence of Hunner’s lesions ( P&lt;0.023). Hunner’s lesion with cystoscopy and histological evidence of urothelial denudation with bladder biopsy appear to be related to BPS/IC duration. Thus an early diagnosis allows an appropriate therapeutic approach to be started to prevent a more severe evolution of this multifaceted painful syndrome. Conclusions: Our study shows a correlation between the time of symptom onset and evidence of urothelial denudation and with detrusor mast cell count in the whole group of patients. BPS/IC duration did not seem to correlate with the severity of symptoms, but rather with the presence of associated diseases. Level of evidence: Not applicable for this multicentre audit.

Time of symptom onset and histologic findings in bladder pain syndrome/interstitial cystitis: new findings on useful correlations

The aim was to find out whether a correlation exists between denudation of urothelium and time of symptom onset in patients with bladder pain syndrome/interstitial cystitis (BPS/IC), and to search a correlation between impact of symptoms evaluated with ICSI-ICPI and the presence of comorbid conditions associated with BPS/IC. Ninety-seven consecutive patients underwent cystoscopy under general anesthesia to classify those cases suspected of being affected from BPS/IC. Three cold bladder biopsies were taken including detrusor muscle. Statistical analysis showed significant correlation between IC/BPS duration and the presence of Hunner’s lesions (P&lt;0.023). Hunner’s lesion with cystoscopy and histological evidence of urothelial denudation with bladder biopsy appear to be items related to IC/BPS duration. Thus an early diagnosis allows to start an appropriate therapeutic approach and prevent a more severe evolution of this multifaceted painful syndrome. Our study shows a correlation between time of symptom onset and evidence of urothelial denudation and with detrusor mast cell count in the whole group of patients. IC/BPS duration seem to correlate with the presence of associated diseases.

Histopathological characteristics of interstitial cystitis/bladder pain syndrome without Hunner lesion.

To assess the distinct histopathological characteristics and their clinical significance between non-Hunner-type and Hunner-type interstitial cystitis (IC)/bladder pain syndrome (BPS). We prospectively enrolled and classified IC/BPS patients, on the basis of cystoscopic findings, as having non-Hunner-type IC and Hunner-type IC. Specimens obtained from the posterior wall in non-Hunner-type IC cases during hydrodistension or from Hunner/non-Hunner lesions in Hunner-type IC cases during transurethral resection were evaluated. Stress urinary incontinence patients with microscopic haematuria were selected as controls. Biopsy specimens were obtained from 15 non-Hunner-type IC, 15 Hunner-type IC and 5 non-IC patients. Severe and moderate fibrosis was more frequently observed in non-Hunner-type IC than in Hunner-type IC and non-IC cases. However, severe and moderate inflammation was more frequently observed in Hunner-type IC than in non-Hunner-type IC cases. The remnant urothelium was significantly decreased in Hunner-type IC cases as compared with non-Hunner-type IC and non-IC cases (P<0.05), and non-Hunner-type IC cases showed a higher number of mast cells than Hunner-type IC and non-IC cases (P=0.035). Accordingly, several fibrosis-promoting genes were highly expressed in bladder tissues of non-Hunner-type IC, as compared with Hunner-type IC. Patients with severe fibrosis showed significantly higher urinary frequency and smaller bladder capacity than those with moderate and mild fibrosis (all P<0.05). Non-Hunner-type IC is characterized by severe fibrosis and increased mast cell infiltration, whereas Hunner-type IC is characterized by severe inflammation and urothelial denudation in the entire bladder. Fibrosis in the bladder of IC/BPS patients was correlated with increased urinary frequency and decreased bladder capacity.

A rat long-lasting cystitis model induced by intravesical injection of hydrogen peroxide.

Novel longer lasting inflammatory bladder animal models are needed to better understand the pathophysiology of chronic cystitis. We previously developed a relatively long‐lasting mouse cystitis model by intravesical injection of hydrogen peroxide (H2O2). To further evaluate its pathophysiology, in this study, we established and analyzed a rat cystitis model. Under anesthesia, 1.5% H2O2 solution was introduced transurethrally into the bladder of female rats, and kept for 30 min. The H2O2 injection significantly increased the number of micturition events up to day 14 and decreased urine volume per micturition, with the smallest volumes on day 3, compared with the vehicle‐treated group. Cystometric analysis on day 7 revealed that intercontraction intervals were significantly shortened without affecting the baseline, threshold, or maximum pressures. Intravesical resiniferatoxin‐evoked nociceptive behaviors, such as freezing, were significantly enhanced on days 7 and 14. Furthermore, histopathology revealed hemorrhage, edema, infiltration of neutrophils into the lamina propria, and urothelial denudation in the early phase (day 1). These damages were gradually repaired, while hyperplasia of the urothelium, vascularization, increases in fibroblast counts, and infiltration of mast cells and eosinophils were observed through the later phase (days 7 and 14). These results suggest that intravesical H2O2 injection induces relatively long‐lasting cystitis with enhanced bladder activity and pain sensation in rats. This approach thus provides a novel rat long‐lasting cystitis model that allows us to analyze detailed symptoms and pathophysiology of H2O2‐induced cystitis model than the mouse model and may be used to investigate the pathophysiology and treatment of chronic bladder hypersensitive disorders, such as bladder pain syndrome/interstitial cystitis.

Past, Present and Future of Chemodenervation with Botulinum Toxin in the Treatment of Overactive Bladder

We systematically reviewed preclinical and clinical studies on bladder chemodenervation with onabotulinumtoxin A to highlight current limitations and future drug delivery approaches. We identified peer reviewed basic and clinical research studies of onabotulinumtoxin A in the treatment of neurogenic bladder and refractory idiopathic overactive bladder published between March 2000 and March 2016. Paired investigators independently screened 125 English language articles to identify controlled studies on onabotulinumtoxin A administration in the MEDLINE® database and abstracts presented at annual American Urological Association meetings. The review yielded an evidence base of more than 50 articles relevant to the approach of injection-free onabotulinumtoxin A chemodenervation. The efficacy and safety of intradetrusor injection of onabotulinumtoxin A for the treatment of overactive bladder are sensitive to injection volume and depth, and this issue has motivated researchers to study injection-free modes of drug delivery into the bladder. Urothelial denudation with protamine sulfate or dimethyl sulfoxide, liposome encapsulated onabotulinumtoxin A and other physical approaches are being studied to increase toxin permeability and avoid intradetrusor injections. Liposome encapsulated onabotulinumtoxin A enhances toxin activity while reducing its toxin degradation. The safety and efficacy of liposome encapsulated onabotulinumtoxin A were tested in a multicenter, placebo controlled study. Although this treatment successfully reduced urinary frequency and urgency, it did not significantly reduce urgency urinary incontinence episodes. Intradetrusor injection of onabotulinumtoxin A is a safe and effective treatment as reported in several large multicenter, randomized controlled trials. Injection of the toxin into the bladder wall impairs afferent and efferent nerves, but injection-free drug delivery approaches only impair the bladder afferent nerves. Further studies are needed todevelop better drug delivery platforms that overcome the drawbacks of intradetrusor injection, increase patient acceptance and reduce treatment costs.