Journal
INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY
Volume 5, Issue 7, Pages 573-582Publisher
WILEY
DOI: 10.1002/alr.21516
Keywords
nasal polyposis; chronic rhinosinusitis; epithelium; inflammation; profibrotic; transforming growth factor beta 1; TGF-beta 1; Activin A; cigarette smoke; Toll-like receptor 3; TLR 3; airway remodeling
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Funding
- Flight Attendants Medical Research Institute (FAMRI)
- Merck
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BackgroundThe mechanism of airway remodeling in chronic rhinosinusitis with nasal polyposis (CRSwNP) remains unknown. We wished to determine whether profibrotic transforming growth factor beta 1 (TGF-1) and activin A and their downstream signaling proteins are increased in CRSwNP and if they are regulated in epithelial cells by noxious or inflammatory stimuli. MethodsFrozen tissue from CRSwNP patients, healthy control (HC) middle turbinates, and sinus tissue from CRS without NP (CRSsNP) patients were immunostained for TGF-1, activin A, and downstream signaling proteins. Primary nasal epithelial cells (PNECs) from HCs and CRSwNP patients were cultured in media, cigarette smoke extract (CSE), or double-stranded RNA (dsRNA) (a ligand for Toll-like receptor-3) and examined for inflammatory and profibrotic genes using real-time polymerase chain reaction (PCR). ResultsCRSwNP patients showed increased TGF-1 and activin A in the stroma, increased TGF-1 signaling (phosphorylated Smad2/3) in the stroma and epithelium, and increased Smad3-dependent Snail1 in the stroma. Immunostaining for TGF-1, pSmad2/3, and Snail1 in CRSwNP patients was highly correlated. Immunostaining for pSmad2/3 and Snail1 was similar in CRSwNP and CRSsNP patients. Compared to HCs, PNECs from CRSwNP patients were more responsive to CSE and dsRNA in terms of TGF-1 and activin A and more strongly induced by dsRNA in terms of chemokines. ConclusionIncreased TGF-1 and activin A and increased downstream TGF-1 signaling is present in CRSwNP patients, primarily in the stroma. This may contribute to features of airway remodeling previously described. PNECs from CRSwNP patients are induced to produce TGF-1 and activin A by CSE and dsRNA, suggesting that cigarette smoke and viral infection might also contribute to airway remodeling. (C) 2015 ARS-AAOA, LLC.
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