Interstitial Cystitis Group Research Articles

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.

4-PBA inhibits endoplasmic reticulum stress to improve autophagic flux in the treatment of protamine/lipopolysaccharide-induced interstitial cystitis in rats

Interstitial cystitis (IC) has severe clinical symptoms with unclear mechanism. The continuous inflammatory response of the bladder is the basis of its pathogenesis. Endoplasmic reticulum stress (ERS) is involved in the regulation and development of various inflammatory diseases. And autophagy plays an important role in IC. In this study, we mainly focus on the therapeutic effect of endoplasmic reticulum stress and autophagy on protamine/lipopolysaccharide-induced interstitial cystitis. Female Sprague–Dawley rats were randomized into three experimental groups as follows: sham controls(N), IC alone, and IC+4-PBA.Rats in group IC received 10 mg/ml PS in the urinary bladder, followed by 2 mg/ml LPS instillation after 30 min, IC+4-PBA group SD rats received 4-PBA solution administered intragastrically once a day for 5 days. ERS biomarker (GRP78), autophagy-related proteins (LC3I/II, and Beclin1), autophagic flux biomarker (P62), inflammatory biomarkers (IL-6, TNF-a, NF-κB), apoptotic biomarkers (Caspase 3, Bax) were highest in the IC group compared to IC+4-PBA group and N group and the biomarkers expression in IC+4-PBA group were lower than in the IC group, anti-apoptotic biomarker (Bcl-2) was highest in the N group compared to the IC group and IC+4-PBA group and lower in the IC group than in the IC+4-PBA group, oxidative stress biomarkers (HO-1, NQO-1) were remarkably lower in the control group than in the IC and IC+4-PBA groups and notably lower in the IC group than in the IC+4-PBA group. The histological score and mast cell count demonstrated most severe in the IC group than those in the IC+4-PBA group. TUNEL assay examined the level of apoptosis in IC group was higher than in the IC+4-PBA group. The bladder micturition function was significantly improved with 4-PBA treatment. 4-PBA inhibits ERS to recover autophagic flux, and then to suppress the bladder oxidative stress, the inflammatory reaction and apoptosis, finally improve the bladder urinary function in Protamine/Lipopolysaccharide (PS/LPS) induced IC.

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.

Can montelukast sodium be an alternative treatment in the treatment of interstitial cystitis?

The leukotriene D4 receptors have been detected in human bladder detrusor myocytes, and they can play the role of interstitial cystitis etiology. Our study aims to explain the role of mast cells histologically and immunohistochemically in the pathogenesis and the effectiveness of montelukast that leukotriene D4 receptor antagonist in the treatment of interstitial cystitis. Twenty-four Wistar albino adult female rats were used. Group 1 (n = 8): control (sham) group, Group 2 (n = 8): interstitial cystitis group, and Group 3 (n = 8): treatment group. Groups 2 and 3 rats were administered 75 mg/kg cyclophosphamide four times every three days intraperitoneally. The rats in the treatment group were started on montelukast sodium as 10 mg/kg, 1 × 1/day per orally after the last administration of cyclophosphamide and were given for 14 days. Mast cells in the bladder tissues were examined histologically, and the presence of IL-6, 8, VEGF, and TNF alpha was examined immunohistochemically. Thin transitional epithelium, loose connective tissue, weak smooth muscle bundles, and signs of chronic inflammation were observed in the interstitial cystitis group. Regenerated transitional epithelium, intact basement membrane, compact lamina propia, thick smooth muscle bundles, and rare inflammatory cells were observed after the treatment with the montelukast. Mast cells were decreased in bladder tissue after treatment. IL-6, IL-8, VEGF, and TNF alpha levels were significantly decreased after treatment. We found that inflammatory mediators were significantly reduced after treatment with montelukast in the interstitial cystitis group. Montelukast can be used as an effective drug in the treatment of interstitial cystitis.

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.

Cultured versus freshly isolated adipose-derived stem cells in improvement of the histopathological outcomes in HCL-induced cystitis in a rat model

Interstitial cystitis (IC) is an incurable chronic disease. The etiology of IC is unclear, and no effective therapies have been established. Here, using a hydrogen chloride (HCL)-induced IC in a rat model, the therapeutic potency of stromal vascular fraction (SVF) and Adipose-derived stem cells (ADSCs) was studied. Thirty-six female Sprague Dawley rats were divided into four groups: the sham, HCL, (HCL+SVF) group, and (HCL+ADSCs) group (9 for each). Cystitis was induced by transurethral instillation of HCL, while PBS was used for the sham group. A single dose of SVF or ADSCs was injected into the submucosa of the rat bladder in HCL-induced IC groups. The bladder tissues were analyzed for Toluidine Blue, Masson Trichrome, CD3, and CD34 to evaluate mast cell activation, fibrosis, inflammatory cells, and bladder regeneration, respectively. Compared to HCL-induced IC, SVF or ADSCs injection into IC bladder dramatically decreased mast cell infiltration, T-cell activation, and fibrosis. Taken together, administration of SVF cells or cultured ADSCs improves the histopathological outcomes of HCL-induced bladder injury in a time-dependent manner. Of note, SVF injection into the bladder submucosa was estimated to have the most potent therapeutic efficacy and may represent an essential component in future clinical applications.

Identification of diagnostic serum biomarkers for Hunner-type interstitial cystitis.

Diagnosis of Hunner-type interstitial cystitis (HIC) relies on the ability to identify Hunner lesions endoscopically, which can lead to storage symptom misdiagnosis. Here, we examined serum biomarkers for HIC and verified their utility. Based on the previous definition of the Japanese guidelines, which did not distinguish HIC and non-HIC diseases, we searched for serum biomarkers in 25 patients with interstitial cystitis (IC) and 25 control participants using metabolomics during 2013-2014. In 2019, we conducted a validation study in HIC and control groups. Serum samples were analyzed using liquid chromatography-tandem mass spectrometry, and candidate biomarker concentrations were compared between the groups using Mann-Whitney test. Metabolomics targeted 678 metabolites and revealed that the levels of 14 lysolipids, seven γ-glutamyl amino acids, and two monoacylglycerols were significantly different between the IC and control groups. The following metabolites were selected from each metabolite category as candidates: 1-linoleoylglycerophosphocholine (1-linoleloyl-GPC [18:2]), γ-glutamylisoleucine (γ-Glu-Ile), and 1-arachidonylglycerol (1-AG). The serum concentrations of 1-linoleoyl-GPC (18:2) in the HIC and control groups were 27 920 ± 6261 and 40 360 ± 1514 ng/mL (P=0.0003), respectively. The serum concentrations of γ-Glu-Ile and 1-AG were not significantly different between the groups. When the cut-off value of 1-linoleoyl-GPC (18:2) was set at 28 400 ng/mL, the sensitivity and specificity were 68% and 84%, respectively. Serum 1-linoleoyl-GPC (18:2) is a candidate diagnostic biomarker for HIC. Additional studies on whether this biomarker can distinguish HIC from other diseases with high urination frequency are required for its clinical use.

Effectiveness of hydrodistention procedure under local anesthesia in the treatment of bladder pain syndrome/interstitial cystitis

Objective: We aimed to indicate the effectiveness of local anesthesia in the treatment of hydrodistention in women with Bladder Pain Syndrome/interstitial Cystitis (BPS/IC) in our study.
 Material and Method: The data of a total of 77 female patients who underwent hydrodistention treatment for BPS/IC in our clinic between January 2015 and July 2021 were analyzed retrospectively. The patients were divided into two groups as local anesthesia (LA, n=41) and spinal anesthesia (SA, n=36) groups according to the type of anesthesia applied. The groups were compared by determining the preoperative and postoperative O'Leary symptom index (SI) and problem index (PI), minimum voiding volume (MinVV), maximum voiding volume (MaxVV), average voiding volume (AvgVV) and daily frequency. 
 Results: The mean age of the patients was 48.97±11.09 years in the LA group and 45.19±14.35 years in the SA group (p=0.197). There was no significant difference between the groups in terms of the preoperative European Society for the Study of Interstitial Cystitis (ESSIC) group (p=0.999). During the postoperative period, a median (IQR) improvement of 11.0 (2.0) points was observed in the SI of the LA group, while a median improvement of 11.0 (2.0) points were observed in the SA group (p=0.437). The median improvement in PI score was 8.4 (4.0) points in the SA group, while it was 7.0 (3.0) points in the LA group (p=0.415). There was no significant difference between the groups in terms of improvements in minVV, maxVV, avgVV and daily frequency (p=0.480, p=0.460, p=0.614 and p=0.910, respectively).
 Conclusion: Hydrodistention treatment in women with BPS/IC can be performed safely and with high success rate under local anesthesia and it is well tolerated by the patients. Local anesthesia offers a minimally invasive treatment option as well as the advantage of avoiding possible complications of spinal, epidural or general anesthesia.

Anti-inflammatory iron chelator, DIBI, reduces leukocyte-endothelial adhesion and clinical symptoms of LPS-induced interstitial cystitis in mice.

Interstitial cystitis (IC) is a prevalent and debilitating chronic inflammatory disease of the urinary bladder. Currently there are no fully effective therapeutic agents available, in part due to the still obscure pathogenesis of IC. Lipopolysaccharide (LPS) also known as endotoxin from Gram negative bacteria elicits IC in mice and has formed the basis of model systems for investigation. Excess free iron plays an important role in inflammation through generation of reactive oxygen species (ROS). The novel iron chelator DIBI has been shown to sequester excess free iron and dampen excess inflammatory responses to systemic LPS administration and also to Gram negative bacterial infections. The overall objective of this study was to evaluate the effects of DIBI on LPS induced IC in mice. Leukocyte activation, endothelial adhesion and functional capillary density were assessed by intravital microscopy of the bladder microcirculation following a single intravesical LPS administration with or without intravesical DIBI treatment. Clinical IC symptoms were also assessed through behavioral and pain threshold force measurements. Four groups of female BALB/c mice (n = 5-6/group) were randomized in this study: control group, IC group without therapy, IC group with DIBI therapy and control group with DIBI therapy. The groups were examined using intravital microscopy (IVM) of the bladder for leukocyte-endothelial interactions (adherent leukocytes, temporarily interacting leukocytes) and functional capillary density (FCD). A modified behavioral score by Boucher et al. and Von-Frey-Aesthesiometry were used to evaluate key behavioral indices related to pain and visceral pain perception. LPS introduced intravesically induced an early (≤2h) inflammation of the bladder evidenced by leukocyte activation and adhesion to bladder capillary walls. Intravesical DIBI therapy of mice 30min following LPS administration and assessed after 1.5h treatment showed a significant decrease in the number of adherent leukocytes compared to IC animals without DIBI treatment. DIBI treated mice showed a significantly lowered increase in behavioral distress scores compared to IC mice without therapy. Untreated IC mice exhibited a significantly decreased threshold force value for evoked pain response and DIBI treatment improved the threshold pain response. A significant inverse correlation was found for the two pain and suffering evaluation methods results. DIBI reduced inflammatory endothelial leukocyte adhesion and key indices related to pain and suffering over those observed in untreated IC mice. Our findings suggest a potential therapeutic role for DIBI for IC treatment.

Combined Signature of the Urinary Microbiome and Metabolome in Patients With Interstitial Cystitis.

Interstitial cystitis (IC) is a clinical syndrome characterized by frequency, urgency, and bladder pain or pelvic pain; however, the underlying pathophysiological mechanisms and diagnostic markers are unknown. In this study, microbiome and metabolome analysis were used to explain the urine signatures of IC patients. Urine samples from 20 IC patients and 22 control groups were analyzed by using 16S rRNA sequence and liquid chromatography coupled with mass spectrometry. Four opportunistic pathogen genera, including Serratia, Brevibacterium, Porphyromonas, and Citrobacter, were significantly upregulated in IC group. The altered metabolite signatures of the metabolome may be related to sphingosine metabolism, amino acid metabolism, and fatty acid biosynthesis. Meanwhile, the associations were observed between different metabolites and microbiomes of IC. The present study suggests that the combined signatures of IC in urine microbiome and metabolome may become its prospective diagnostic markers.

Chlorogenic acid attenuates cyclophosphamide-induced rat interstitial cystitis

AimsThis study aimed to investigate the therapeutic effect and molecular mechanism of chlorogenic acid (CGA) on cyclophosphamide (CYP)-induced rat interstitial cystitis (IC). Materials and methodsAn animal model of IC was established by intraperitoneal injection of CYP in female Sprague-Dawley rats. Eighty rats were randomly assigned to four groups: negative control (NC), NC treated with CGA (NC + CGA), IC, and IC treated with CGA (IC + CGA). Bladder urination function was assessed by analyzing urodynamic parameters. The expression of apoptosis-related proteins and inflammatory biomarkers in bladder specimens was detected using western blot and immunohistochemistry analysis. Key findingsCompared with the IC group, bladder urinary function was significantly improved in the IC + CGA group. CGA treatment reduced inflammatory damage in the bladder tissue of IC rats. Caspase3 and Bax expression was higher while Bcl-2 expression was lower in the IC group compared to the IC + CGA group. In addition, there were significant differences between the groups in the expression levels of inflammatory biomarkers in the bladder tissue. Furthermore, CGA could inhibit CYP-induced MAPK/NF-κB phosphorylation in the rat bladder tissue. SignificanceIn a CYP-induced rat model of IC, CGA could reduce inflammation and apoptosis, thus partially restoring bladder function, and the MAPK/NF-κB pathway was probably involved in it.

Comparison of urodynamic results and quality of life between women with interstitial cystitis and overactive bladder

ObjectivesSome symptoms of overactive bladder overlap with those of interstitial cystitis. This study was conducted to compare the urodynamic results and quality of life of patients with the two conditions. Materials and MethodsUrodynamic data were retrospectively analyzed in 55 females with interstitial cystitis and 171 females with overactive bladder between 2012 and 2016. Females with overactive bladder were divided into detrusor overactivity group and non-detursor overactivity group based on urodynamic results. All recruited patients completed validated questionnaires including incontinence impact questionnaire (IIQ-7), urogenital distress inventory (UDI-6), and short form 12 health survey (SF-12). Patient demographics, total scores of questionnaires, and urodynamic results were compared among interstitial cystitis, detrusor overactivity, and non-detrusor overactivity groups. ResultsThe age and body mass index of interstitial cystitis patients were significantly lower than that of overactive bladder patients. The severity of urinary symptoms was higher in interstitial cystitis group than in non-detrusor overactivity group from questionnaire, but similar as detrusor overactivity group. Interstitial cystitis group had lower maximum flow rate, lower residual urine volume, lower maximum cystometric capacity, and higher maximal urethral closure pressure compared with non-detrusor overactivity group. However, there was no significant difference in urodynamic parameters between interstitial cystitis and detrusor overactivity groups. ConclusionInterstitial cystitis and overactive bladder have a negative impact on quality of life, but urodynamic studies are not effective in distinguishing between interstitial cystitis and detrusor overactivity.

Effectiveness of transcutaneous electrical stimulation for refractory lower urinary tract symptoms in elderly female patients

Objective To assess the clinical effects of percutaneous electrical stimulation on refractory lower urinary tract symptoms in elderly female patients. Methods Elderly female patients with refractory lower urinary tract symptoms from July 2016 to December 2017 were recruited.According to cystoscopy results, patients were divided into an interstitial cystitis group, a suspected interstitial cystitis group and an overactive bladder group.All patients received 3 courses of transcutaneous low-frequency electrical stimulation treatment in the suprapubic bladder area, with 40 min per time, 4 times per day, 7 days per course.Bladder diaries, pain scores and overactive bladder symptom scores were recorded before and after treatment. Results A total of 27 patients with a mean age of 74.3 years were enrolled.Under the cystoscope with water dilatation, 9 cases were found to have mucosal bleeding, with mast cells detected in mucosal specimens examined via electron microscopy(in the interstitial cystitis group), 5 cases had superficial mucosal congestion(in the suspected interstitial cystitis group)and 13 cases showed normal imaging(in the overactive bladder group). In the interstitial cystitis group, the 24-h urinary frequency improved from 15.4±2.5 times before treatment to 11.9±2.0 times after treatment(P 0.05]. In the suspected interstitial cystitis group, the 24-h urinary frequency improved from (11.8±1.5) times before treatment to (8.4±1.1) times after treatment, and pain scores decreased from (6.4±1.1) to (4.2±1.1)(P<0.05). In the overactive bladder group, the 24-h urinary frequency improved from (19.2±2.0) times before treatment to (15.9±1.3) times after treatment(P<0.05), and the overactive bladder symptom score(OABSS)decreased from (8.9±1.6) to (5.9±1.6)(P<0.05). Conclusions Percutaneous electrical stimulation is an easy, safe and effective treatment in elderly females with refractory lower urinary tract symptoms, and should be encouraged in clinical practice. Key words: Urinary, incontinence; Electrical stimulation therapy

N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model

Therapeutic options for non-Hunner type interstitial cystitis (IC), which is histologically characterized by fibrosis and mast cell infiltration, are limited. We developed a rat model that replicates chronic inflammation and fibrosis and evaluated the therapeutic effect of N-acetylcysteine (NAC), a well-known anti-fibrotic agent, on the model. Intravesical instillation of lipopolysaccharide (LPS, 750 μg) after protamine sulfate (10 mg) was conducted twice per week for five consecutive weeks. One week after final instillation, 200 mg/kg NAC (n = 10, IC + NAC group) or phosphate-buffered saline (n = 10, IC group) was daily injected intraperitoneally once daily for 5 days. LPS instillation induced bladder fibrosis, mast cell infiltration, and apoptotic tissue damage. Functionally, LPS insult led to irregular micturition, decreased inter-contraction intervals, and decreased micturition volume. NAC significantly improved most of the voiding parameters and reversed histological damages including fibrosis. NAC inhibited the induction and nuclear localization of phospho-Smad2 protein in bladder tissues and the upregulation of genes related to fibrosis, such as Tgfb2, Tgfb3, Smad2, Smad3, Cxcl10, and Card10. This is the first study to demonstrate the beneficial effects on NAC in restoring voiding function, relieving tissue fibrosis and related bladder injuries, in the LPS-induced cystitis rat model.

Retracted: Microrna‐139‐5p inhibits epithelial‐mesenchymal transition and fibrosis in post‐menopausal women with interstitial cystitis by targeting LPAR4 via the PI3K/Akt signaling pathway

The study explores whether miR-139-5p targeting LPAR4 affects epithelial-mesenchymal transition (EMT) and fibrosis in post-menopausal women with interstitial cystitis (IC) via the PI3K/Akt signaling pathway. Bladder tissues of IC and normal bladder tissues were collected. The pathology of bladder tissues was observed by HE, Masson and Picrosirius red staining. LPAR4 positive expression rate were determined by IHC. ELISA was performed to detect the levels of IL-6, IL-8, IL-10, and TNF-α. Rat IC models were randomized into seven different groups. miR-139-5p, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, P13K, Akt, E-cadherin, N-cadherin, Vimentin, TGF-β1, and CTGF expression were determined by RT-qPCR and Western blotting. Dual luciferase reporter gene assay verified that LPAR4 is a target gene of miR-139-5p. Fibrosis was a pathological manifestation of IC. The IC group showed higher LPAR4, PI3K, Akt, p-PI3K, p-Akt, N-cadherin, Vimentin, TGF-β1, and CTGF expression but lower miR-139-5p and E-cadherin expression than the normal group. The levels of IL-6, IL-8, IL-10, and TNF-α expression decreased while HB-EGF increased in the IC group in comparison of the normal group. Compared with the blank and NC groups, E-cadherin expression was increased in the miR-139-5p mimic and siRNA-LPAR4 groups, while LPAR4, PI3K, Akt, p-P13K, p-Akt, N-cadherin, Vimentin, TGF-β1, and CTGF expression were decreased. An opposite trend was found in the miR-139-5p inhibitor group. The miR-139-5p decreased in the miR-139-5p inhibitor + siRNA-LPAR4 and miR-139-5p inhibitor + wortmannin groups. Conclusively, miR-139-5p targeting LPAR4 inhibits EMT and fibrosis in post-menopausal IC women through the PI3K/Akt signaling pathway.

Protective Effect of Intravesical Platelet-Rich Plasma on Cyclophosphamide-Induced Hemorrhagic Cystitis

Hemorrhagic cystitis (HC) is the most common urotoxic side effect of cyclophosphamide (CYP). Platelet rich plasma (PRP) plays an important role in wound healing and inflammatory responses. The aim of this study was to investigate the efficacy of intravesical PRP at treatment of interstitial cystitis (IC). Female rats (n=24) were used. IC was induced by intraperitoneal injection of cyclophosphamide (CYP). Rats were randomly allocated to one of four groups (n = 6 per group): a control group; a sham group with saline (75 mg/kg; i.p.) instead of CYP on day 1; a IC group, which was injected with CYP (150 mg/kg; i.p.) on day 1; and, a intravesical PRP‑treated group which was injected with CYP (150 mg/kg; i.p.) on day 1. On day 2, the rats in each group were sacrificed under anesthesia. Histological evaluation showed that bladder inflammation in CYP‑treated rats was not suppressed by PRP. CYP administration induced severe IC with marked edema, hemorrhage and inflammation in CYP and CYP+PRP groups, but PRP was not found to be effective to decrease these effects. The application of PRP could not reverse the histopathological changes in rats that had interstitial cystitis due to the cyclophosphamide injection.

Protective Effect of Intravesical Platelet-Rich Plasma on Cyclophosphamide-Induced Hemorrhagic Cystitis

Purpose: Hemorrhagic cystitis (HC) is the most common urotoxic side effect of cyclophosphamide (CYP). Platelet rich plasma (PRP) plays an important role in wound healing and inflammatory responses. The aim of this study was to investigate the efficacy of intravesical PRP at treatment of interstitial cystitis (IC). Material-Methods: Female rats (n=24) were used. IC was induced by intraperitoneal injection of cyclophosphamide (CYP). Rats were randomly allocated to one of four groups (n = 6 per group): a control group; a sham group with saline (75 mg/kg; i.p.) instead of CYP on day 1; a IC group, which was injected with CYP (150 mg/kg; i.p.) on day 1; and, a intravesical PRP‑treated group which was injected with CYP (150 mg/kg; i.p.) on day 1. On day 2, the rats in each group were sacrificed under anesthesia. Results: Histological evaluation showed that bladder inflammation in CYP‑treated rats was not suppressed by PRP. CYP administration induced severe IC with marked edema, hemorrhage and inflammation in CYP and CYP+PRP groups, but PRP was not found to be effective to decrease these effects. Conclusion: The application of PRP could not reverse the histopathological changes in rats that had interstitial cystitis due to the cyclophosphamide injection.

Measurement of oxyhemoglobin concentration changes in interstitial cystitis female patients: A near-infrared spectroscopy study.

To investigate brain activity related to bladder sensation in interstitial cystitis patients. A total of 10 interstitial cystitis patients (all women; mean age 68 years) and 10 healthy controls (all women; mean age 64 years) participated in the present study. Frontal lobe blood flow was measured non-invasively by using multichannel near-infrared spectroscopy with large and small bladder volumes (created by infusing water) up to the first desire to void. The frontal cortex of the right and left hemisphere was activated, and the activation was detected as an increase in oxyhemoglobin concentration. The increase during the first desire to void in the interstitial cystitis group was greater than that in the control group. In addition, this difference was particularly observed in Brodmann's areas 9, 44, 45 and 46, reportedly associated with micturition and sensory modulation. The present study shows that the frontal area is largely activated during bladder filling in interstitial cystitis patients. Our findings suggest that the major change in cerebral blood flow is related to the characteristic urinary symptoms of interstitial cystitis patients.

Mesenchymal Stem Cell Therapy Alleviates Interstitial Cystitis by Activating Wnt Signaling Pathway.

Interstitial cystitis (IC) is a syndrome characterized by urinary urgency, frequency, pelvic pain, and nocturia in the absence of bacterial infection or identifiable pathology. IC is a devastating disease that certainly decreases quality of life. However, the causes of IC remain unknown and no effective treatments or cures have been developed. This study evaluated the therapeutic potency of using human umbilical cord-blood-derived mesenchymal stem cells (UCB-MSCs) to treat IC in a rat model and to investigate its responsible molecular mechanism. IC was induced in 10-week-old female Sprague-Dawley rats via the instillation of 0.1 M HCl or phosphate-buffered saline (PBS; sham). After 1 week, human UCB-MSC (IC+MSC) or PBS (IC) was directly injected into the submucosal layer of the bladder. A single injection of human UCB-MSCs significantly attenuated the irregular and decreased voiding interval in the IC group. Accordingly, denudation of the epithelium and increased inflammatory responses, mast cell infiltration, neurofilament production, and angiogenesis observed in the IC bladders were prevented in the IC+MSC group. The injected UCB-MSCs successfully engrafted to the stromal and epithelial tissues and activated Wnt signaling cascade. Interference with Wnt and epidermal growth factor receptor activity by small molecules abrogated the benefits of MSC therapy. This is the first report that provides an experimental evidence of the therapeutic effects and molecular mechanisms of MSC therapy to IC using an orthodox rat animal model. Our findings not only provide the basis for clinical trials of MSC therapy to IC but also advance our understanding of IC pathophysiology.

Phloroglucinol protects the urinary bladder via inhibition of oxidative stress and inflammation in a rat model of cyclophosphamide-induced interstitial cystitis.

Background:Phloroglucinol plays an important role in oxidative stress and inflammatory responses. The effects of phloroglucinol have been proven in various disease models. The aim of the present study was to investigate the efficacy and possible mechanisms of phloroglucinol in the treatment of interstitial cystitis (IC).Methods:Thirty-two female Sprague-Dawley (SD) rats were used in this study. IC was induced by intraperitoneal injection of cyclophosphamide (CYP). Rats were randomly allocated to one of four groups (n = 8 per group): A control group, which was injected with saline (75 mg/kg; i.p.) instead of CYP on days 1, 4, and 7; a chronic IC group, which was injected with CYP (75 mg/kg; i.p.) on days 1, 4, and 7; a high-dose (30 mg/kg) phloroglucinol-treated group; and a low-dose (15 mg/kg) phloroglucinol-treated group. On day 8, the rats in each group underwent cystometrography (CMG), and the bladders were examined for evidence of oxidative stress and inflammation. Statistical analysis was performed by analysis of variance (ANOVA) followed by least square difference multiple comparison post-hoc test.Results:Histological evaluation showed that bladder inflammation in CYP-treated rats was suppressed by phloroglucinol. CMG revealed that the CYP treatment induced overactive bladder in rats that was reversed by phloroglucinol. Up-regulated tumor necrosis factor-α and interleukin-6 expression in the CYP-treated rats were also suppressed in the phloroglucinol treated rats. CYP treatment significantly increased myeloperoxidase activity as well as the decreased activities of catalase of the bladder, which was reversed by treatment with phloroglucinol.Conclusions:The application of phloroglucinol suppressed oxidative stress, inflammation, and overactivity in the bladder. This may provide a new treatment strategy for IC.