transforming-growth-factor-beta and Cystitis--Interstitial

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic disease for which no effective treatment is available. Transforming growth factor-β (TGF-β) is thought to be involved in the pathogenesis of IC/PBS, and previous studies have suggested that administrations of a TGF-β inhibitor significantly ameliorated IC/PBS in a mouse model. However, the molecular mechanisms underlying the therapeutic effect of a TGF-b inhibitor on IC/PBS has not been comprehensively analyzed. TGF-β has a variety of actions, such as regulation of immune cells and fibrosis. In our study, we induced IC/PBS-like disease in mice by an intravesical administration of hydrogen peroxide (H₂O₂) and examined the effects of three TGF-β inhibitors, Repsox, SB431542, and SB505124, on the urinary functions as well as histological and gene expression profiles in the bladder. TGF-β inhibitor treatment improved urinary function and histological changes in the IC/PBS mouse model, and SB431542 was most effective among the TGF-β inhibitors. In our present study, TGF-β inhibitor treatment improved abnormal enhancement of nociceptive mechanisms, immunity and inflammation, fibrosis, and dysfunction of bladder urothelium. These results show that multiple mechanisms are involved in the improvement of urinary function by TGF-β inhibitor.

Topics: Animals; Cystitis, Interstitial; Disease Models, Animal; Fibrosis; Humans; Hydrogen Peroxide; Mice; Transforming Growth Factor beta

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.

Topics: Animals; Anti-Inflammatory Agents; Cystitis, Interstitial; Extracellular Vesicles; Mesenchymal Stem Cells; Transforming Growth Factor beta

This study assessed the functional role of WNT genes and the association between WNT signalling cascades and fibrosis in interstitial cystitis/bladder pain syndrome (IC/BPS) patients. Twenty-five patients (3 males, 22 females; mean age 59.7 ± 10.9 years), included 7 non-Hunner-type IC (NHIC), 18 Hunner-type IC (HIC), and 5 non-IC (control) groups. The expression of sonic hedgehog, WNT gene family, and genes previously reported as biomarkers for IC/BPS were examined using RT-PCR in biopsy specimens from the mucosa and submucosa layer of the bladder. WNT2B, WNT5A, WNT10A, and WNT11 functions in the urothelium were evaluated by silencing in an HBlEpC cell line. Pelvic Pain and Urgency/Frequency Patient Symptom Scale scores, O'Leary-Sant Symptom and Problem Index scores, and Visual Analogue Scores did not differ between the NHIC and HIC groups. However, HIC patients had significantly shorter symptom duration (30.9 vs 70.8 months, p = 0.046), higher daily urinary frequency (16.1 versus 8.5 times, p = 0.006), and smaller bladder capacity (208.6 versus 361.4 ml, p = 0.006) than NHIC patients. Overall WNT gene expression was lower in NHIC than HIC patients. Bladder epithelial tissues from HIC patients were characterised by the downregulation of WNT11. Silencing of WNT11, WNT2B, WNT5A, and WNT10A in HBlEpCs resulted in fibrotic changes, indicated by fibrotic morphology, increased fibrosis-related gene expression, and nuclear localisation of phosphorylated SMAD2, and increased vimentin and fibronectin levels. Downregulation of WNT11 results in fibrotic changes of bladder epithelial cells and is associated with the pathogenesis and differential diagnosis of NHIC. Decreased expression of WNT11 is a potential biomarker for predicting NHIC.

Topics: Aged; Cell Nucleus; Cystitis, Interstitial; Down-Regulation; Epithelial Cells; Female; Fibronectins; Fibrosis; Humans; Male; Middle Aged; Phosphorylation; Smad2 Protein; Transforming Growth Factor beta; Up-Regulation; Urinary Bladder; Vimentin; Wnt Proteins

Topics: Animals; Cystitis, Interstitial; Female; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Urinary Bladder; Urothelium

Numerous proinflammatory cytokines have been implicated in the reorganization of lower urinary tract function following cyclophosphamide (CYP)-induced cystitis. The present study investigated the functional profile of three pleiotropic transforming growth factor-β (TGF-β) isoforms and receptor (TβR) variants in the normal and inflamed (CYP-induced cystitis) rat urinary bladder. Our findings indicate that TGF-β (1, 2, and 3) and TβR (1, 2, and 3) transcript and protein expression were regulated to varying degrees in the urothelium or detrusor smooth muscle following intermediate (48 h; 150 mg/kg ip) or chronic (75 mg/kg ip; once every 3 days for 10 days), but not acute (4 h; 150 mg/kg ip), CYP-induced cystitis. Conscious, open-outlet cystometry was performed to determine whether aberrant TGF-β signaling contributes to urinary bladder dysfunction following intermediate (48 h) CYP-induced cystitis. TβR-1 inhibition with SB505124 (5 μM) significantly (p ≤ 0.001) decreased voiding frequency and increased bladder capacity (2.5-fold), void volume (2.6-fold), and intercontraction intervals (2.5-fold) in CYP-treated (48 h) rats. Taken together, these results provide evidence for 1) the involvement of TGF-β in lower urinary tract neuroplasticity following urinary bladder inflammation, 2) a functional role of TGF-β signaling in the afferent limb of the micturition reflex, and 3) urinary bladder TβR-1 as a viable target to reduce voiding frequency with cystitis.

Topics: Animals; Cyclophosphamide; Cystitis, Interstitial; Disease Models, Animal; Female; Muscle, Smooth; Protein Isoforms; Rats; Rats, Wistar; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Urinary Bladder; Urothelium

The aim of the study was to investigate the molecular signatures underlying bladder pain syndrome/interstitial cystitis (BPS/IC) using cDNA microarray.. Microarray gene expression profiles were [corrected] studied in a matched case-control study [corrected] by using a system of conditional regression modeling.. The main [corrected] findings are summarized as follows: Firstly, a "139-gene" model was discovered to contain high expressions of bladder epithelium, which feature in BPS/IC. Secondly, complex metabolic reactions, including carbohydrate, lipid, cofactors, vitamins, xenobiotics, nucleotide, and amino acid metabolisms, were [corrected] found to have a strong relationship with bladder smooth muscle contraction through IC status. Thirdly, we [corrected] found the transcriptional regulations of IC-induced bladder smooth muscle contraction status, including the level of contractile force, tissue homeostasis, energy homeostasis, and the development of the [corrected] nervous system. In addition, our study suggested the mast-cell activation mediated by the high-affinity receptor of Fc epsilon [corrected] RI triggering allergic inflammation through IC status. Such genetic changes, jointly termed "bladder remodeling," [corrected] can constitute an important long-term consequence of BPS/IC. [corrected].. The success of this innovation has supported the use of microarray-based expression profiling as a single standardized platform for diagnosis of PBS/IC and offers [corrected] drug discovery.

Topics: Actins; Adipokines; Amino Acids; Apoptosis; Carbohydrate Metabolism; Case-Control Studies; Cells, Cultured; Cystitis, Interstitial; Cytokines; DNA, Complementary; Epithelial Cells; Female; Gene Expression Profiling; Homeostasis; Humans; Lipid Metabolism; Logistic Models; MAP Kinase Signaling System; Muscle Contraction; Muscle, Smooth; Oligonucleotide Array Sequence Analysis; Peroxisome Proliferator-Activated Receptors; Transcriptome; Transforming Growth Factor beta; Urothelium

We examined whether the expression of angiogenic factors, such as platelet-derived endothelial cell growth factor/thymidine phosphorylase (PDEGF/TP) and transforming growth factor-beta, in bladder tissue correlates with the severity of symptoms, such as urinary urgency and bladder pain, in patients with bladder carcinoma and interstitial cystitis.. Bladder biopsy was performed in 32 patients with bladder carcinoma, including 19 with interstitial cystitis and 3 controls. Immunohistological staining for PDEGF/TP, transforming growth factor-beta and CD44 was performed in bladder specimens. PDEGF/TP in bladder tissues was also measured by enzyme-linked immunosorbent assay to examine the correlation of the expression of this factor with painful symptoms in patients with bladder carcinoma or interstitial cystitis.. Immunohistochemical staining showed that PDEGF/TP stained in the submucosal layer beneath the basement membrane in bladder tissues of patients with interstitial cystitis and peritumoral areas of those with bladder carcinoma. In addition, PDEGF/TP, transforming growth factor-beta and CD44 stained in the same submucosal region and staining was observed at deeper submucosal levels in interstitial cystitis cases with severe rather than mild bladder pain. Quantitative analyses revealed that mean PDEGF/TP expression plus or minus standard deviation in tumor tissues of 10 patients with bladder carcinoma and pain was significantly higher than in tumor tissues of 22 with asymptomatic bladder carcinoma (129.3 +/- 70.7 versus 37.6 +/- 29.2 units per mg. protein). The mean expression of PDEGF/TP in peritumoral mucosa of patients with bladder carcinoma and pain was also significantly higher than in those with asymptomatic bladder carcinoma (75.5 +/- 42.1 versus 12.6 +/- 5.4 units per mg. protein). For interstitial cystitis mean expression in 6 patients with severe bladder pain was significantly higher than in 13 with moderate pain (79.2 +/- 59.2 versus 16.6 +/- 17.5 units per mg. protein). Mean expression in bladder tissues of controls was less than 2.3 units per mg. protein.. These results suggest that angiogenic factors, such as PDEGF/TP and transforming growth factor-beta, may be involved in the inflammatory process to induce painful symptoms in patients with interstitial cystitis or bladder carcinoma. Proteoglycans such as CD44 may contribute to the presentation of these soluble angiogenic factors at the inflammation site.

Topics: Aged; Aged, 80 and over; Cystitis, Interstitial; Female; Humans; Hyaluronan Receptors; Male; Middle Aged; Severity of Illness Index; Thymidine Phosphorylase; Transforming Growth Factor beta; Urinary Bladder; Urinary Bladder Neoplasms