The NLRP3 Inflammasome Mediates Inflammation Produced by Bladder Outlet Obstruction

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• 作者：Francis M. Hughes Jr.^a ; ^c ; ^&lowast ; ; Hayden M. Hill^c ; ^&dagger ; ; Case M. Wood^c ; ^&dagger ; ; Andrew T. Edmondson^c ; ^&dagger ; ; Aliya Dumas^c ; ^&dagger ; ; Wen-Chi Foo^b ; ^&dagger ; ; James M. Oelsen^c ; ^&dagger ; ; Goran Rac^c ; ^&dagger ; ; J. Todd Purves^a ; ^c ; ^&lowast ; ; ^{todd.purves@duke.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：urinary bladder neck obstruction ; inflammasomes ; inflammation ; cystitis ; immunity ; innate
• 刊名：The Journal of Urology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：195
• 期：5
• 页码：1598-1605
• 全文大小：2022 K

文摘

While bladder outlet obstruction is well established to elicit an inflammatory reaction in the bladder that leads to overactive bladder and fibrosis, little is known about the mechanism by which this is initiated. NLRs (NOD-like receptors) and the structures that they form (inflammasomes) have been identified as sensors of cellular damage, including pressure induced damage, and triggers of inflammation. Recently we identified these structures in the urothelium. In this study we assessed the role of the NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome in bladder dysfunction resulting from bladder outlet obstruction.

Materials and Methods

Bladder outlet obstruction was created in female rats by inserting a 1 mm outer diameter transurethral catheter, tying a silk ligature around the urethra and removing the catheter. Untreated and sham operated rats served as controls. Rats with bladder outlet obstruction were given vehicle (10% ethanol) or 10 mg/kg glyburide (a NLRP3 inhibitor) orally daily for 12 days. Inflammasome activity, bladder hypertrophy, inflammation and bladder function (urodynamics) were assessed.

Results

Bladder outlet obstruction increased urothelial inflammasome activity, bladder hypertrophy and inflammation, and decreased voided volume. Glyburide blocked inflammasome activation, reduced hypertrophy and prevented inflammation. The decrease in voided volume was also attenuated by glyburide mechanistically as an increase in detrusor contraction duration and voiding period.

Conclusion

Results suggest the importance of the NLRP3 inflammasome in the induction of inflammation and bladder dysfunction secondary to bladder outlet obstruction. Arresting these processes with NLRP3 inhibitors may prove useful to treat the symptoms that they produce.