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ICS2015 : 膀胱内TLR7(TLR= Toll Like Receptor: Toll様受容体)の活性化により膀胱炎を誘発、マウスにおける研究

30 Nov 2015

膀胱内TLR7(TLR= Toll Like Receptor: Toll様受容体)の活性化が、膀胱炎を誘発し、膀胱痛と機械受容体を促進することが、第45回国際禁制学会(ICS 2015)にて発表された。

[Original article by MNCS reporter Toni Rizzo]

Toll Like Receptor 7 Activation in the Urinary Bladder Induces Cystitis in Mice

Clinical Newswire – Activation of toll like receptor 7 (TLR7) in the urinary bladder induces cystitis and facilitates bladder nociception and mechanosensory pathways in mice, according to the results of a study presented at the 2015 Annual Meeting of the International Continence Society (ICS).*

Toll like receptors (TLRs) alert the innate immune system to the presence of pathogenic microorganisms. TLRs are primarily expressed in neural and inflammatory cells but are also present in human and mouse bladder urothelium. When activated, TLRs induce pain and inflammation. TLR7 plays a role in some autoimmune diseases, including systemic lupus erythematosus (SLE) and Sjogren’s syndrome, which are associated with interstitial cystitis (IC). Although there have been no reports linking TLR7 with lower urinary tract function, the authors of this study hypothesized that TLR7 might be involved in the pathophysiology of bladder pain and IC.

The aim of this study was to investigate the effects of TLR7 activation on nociception, mechanosensation, and bladder histology in mice. The TLR7 agonist loxoribine (1.5 or 4.5 mL) or its vehicle (control) was administered by intravesical instillation in female C57/BL6N mice. Bladder pain was assessed by quantification of licking near the bladder for 30 minutes prior to and at several time-points after intravesical instillation. Voiding frequency and volume were monitored for 24 hours before instillation (baseline) and for 3 days after instillation. Baseline cystometry measurements were obtained with saline instillation at baseline and then repeated with loxoribine or vehicle.

At baseline, afferent measurement of mechanosensitive pelvic nerve activity was analyzed with saline instillation to classify the single unit response to bladder distension. The measurements were repeated 3 times with loxoribine or vehicle instillation. Finally, histologic evaluation of the bladder was performed. TLR7 mRNA expression in the bladder and urethra was evaluated by real time polymerase chain reaction (PCR).

The results showed that licking behavior increased from baseline after instillation of loxoribine 1.5 mM, loxoribine 4.5 mM, and vehicle (P <0.01 for all). Licking increased after loxoribine instillation compared with vehicle instillation at 2 hours (1.5 mM, P <0.05; 4.5 mM, P <0.01) and day 2 (1.5 and 4.5 mM, P <0.01). After loxoribine instillation, voiding frequency increased from baseline in a dose-dependent manner at days 1, 2, and 3. At day 3, voiding frequency was significantly increased with loxoribine 4.5 mM versus vehicle (P <0.05). Mean voided volume gradually decreased from baseline after instillation with loxoribine 4.5 mM at days 2 and 3 (P <0.01) and increased after vehicle instillation at day 2 (P <0.05). Mean voided volume decreased with loxoribine 4.5 mM versus vehicle instillation at day 2 (P <0.01) and day 3 (P <0.05). Cystometry showed that loxoribine instillation reduced the intercontraction interval from baseline (1.5 and 4.5 mM, P <0.01) but there was no significant difference with vehicle instillation. Loxoribine 1.5 mM versus vehicle instillation significantly facilitated afferent nerve activity in response to bladder distension after each of 3 instillations (P <0.01, average of 3 instillations). Histologic evaluation demonstrated inflammatory cell infiltration, edema, and capillary congestion in the suburothelial layer with loxoribine 1.5 and 4.5 mM during the subacute phase (day 3). These results showed that intravesical instillation of loxoribine induced pain-like behavior and urinary frequency, suggesting that TLR7 activation in the bladder facilitates nociceptive and mechanosensitive afferent pathways innervating the bladder. TLR7 activation also induced bladder inflammation leading to bladder pain and mechanosensation during the subacute phase. The authors concluded that TLR7 activation in the bladder can induce cystitis and facilitate bladder nociception and mechanosensory pathways in mice. *Ichihara K, Aizawa N, Sugiyama R, et al. Activation of toll like receptor 7 induces cystitis and facilitation of bladder pain and mechanosensation in mice. ICS 2015, Abstract #442.

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