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Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1β.
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.
Type
Journal articleSubject
Cells, CulturedAnimals
Rats, Sprague-Dawley
Disease Models, Animal
Fibrosis
Glyburide
Fibrillar Collagens
Protein-Lysine 6-Oxidase
Receptors, Interleukin-1
Autocrine Communication
Signal Transduction
Female
Urinary Bladder
Urinary Bladder Neck Obstruction
Interleukin 1 Receptor Antagonist Protein
Interleukin-1beta
Inflammasomes
Prolyl Hydroxylases
NLR Family, Pyrin Domain-Containing 3 Protein
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https://hdl.handle.net/10161/17176Published Version (Please cite this version)
10.1152/ajprenal.00128.2017Publication Info
Hughes, Francis M; Sexton, Stephanie J; Jin, Huixia; Govada, Vihasa; & Purves, J Todd (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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Monty Hughes Jr.
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 l
J Todd Purves
Professor of Urology
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