Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1β.

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2017-09

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Abstract

Bladder outlet obstruction (BOO) triggers inflammation in the bladder through the NLRP3 inflammasome. BOO also activates fibrosis, which is largely responsible for the decompensation of the bladder in the chronic state. Because fibrosis can be driven by inflammation, we have explored a role for NLRP3 (and IL-1β produced by NLRP3) in the activation and progression of BOO-induced fibrosis. Female rats were divided into five groups: 1) control, 2) sham, 3) BOO + vehicle, 4) BOO + the NLRP3 inhibitor glyburide, or 5) BOO + the IL-1β receptor antagonist anakinra. Fibrosis was assessed by Masson's trichrome stain, collagen secretion via Sirius Red, and protein localization by immunofluorescence. BOO increased collagen production in the bladder, which was blocked by glyburide and anakinra, clearly implicating the NLRP3/IL-1β pathway in fibrosis. The collagen was primarily found in the lamina propria and the smooth muscle, while IL-1 receptor 1 and prolyl 4-hydroylase (an enzyme involved in the intracellular modification of collagen) both localized to the urothelium and the smooth muscle. Lysyl oxidase, the enzyme involved in the final extracellular assembly of mature collagen fibrils, was found to some extent in the lamina propria where its expression was greatly enhanced during BOO. In vitro studies demonstrated isolated urothelial cells from BOO rats secreted substantially more collagen than controls, and collagen expression in control cultures could be directly stimulated by IL-1β. In summary, NLRP3-derived-IL-1β triggers fibrosis during BOO, most likely through an autocrine loop in which IL-1β acts on urothelia to drive collagen production.

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10.1152/ajprenal.00128.2017

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Hughes, Francis M, Stephanie J Sexton, Huixia Jin, Vihasa Govada and J Todd Purves (2017). Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1β. American journal of physiology. Renal physiology, 313(3). pp. F603–F610. 10.1152/ajprenal.00128.2017 Retrieved from https://hdl.handle.net/10161/17176.

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Scholars@Duke

Hughes

Monty Hughes

Assistant Professor in Urology

 Dr. Hughes received his Ph.D. from the Medical University of South Carolina and was a post doc at both the University of North Carolina at Chapel Hill and NIH. He then joined the faculty of the University of North Carolina at Charlotte where he rose to the rank of Associate Professor (with tenure). Following a brief stint as the director of the biology division of a start-up pharmaceutical company, he joined forces with Dr. Purves at the Medical University of South Carolina to begin this lab focused on benign urinary disorders. Dr. Hughes has been at Duke since 2015. He is currently an Assistant Professor working within the Department of Surgery and Division of Urology. He serves as the Director of the Urinary Dysfunction Laboratory which studies the role of inflammation in disorders such as bladder outlet obstruction and diabetic bladder dysfunction. In association with Dr. J Todd Purves, this lab has been instrumental in demonstrating the central importance of the NLRP3 inflammasome in sensing the biochemical stressors associated with these disorders and translating them into an inflammatory signal. This signal is ultimately responsible for changes in voiding function, denervation and fibrosis.

Purves

J Todd Purves

Professor of Urology

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