Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1β.
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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.
Disease Models, Animal
Urinary Bladder Neck Obstruction
Interleukin 1 Receptor Antagonist Protein
NLR Family, Pyrin Domain-Containing 3 Protein
Published Version (Please cite this version)10.1152/ajprenal.00128.2017
Publication InfoPurves, Todd; Hughes, Francis; Sexton, Stephanie J; Jin, Huixia; & Govada, Vihasa (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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