BACKGROUND: The 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-β1) 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. METHODS: Frozen tissue from CRSwNP patients, healthy control (HC) middle turbinates, and sinus tissue from CRS without NP (CRSsNP) patients were immunostained for TGF-β1, 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). RESULTS: CRSwNP patients showed increased TGF-β1 and activin A in the stroma, increased TGF-β1 signaling (phosphorylated Smad2/3) in the stroma and epithelium, and increased Smad3-dependent Snail1 in the stroma. Immunostaining for TGF-β1, 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-β1 and activin A and more strongly induced by dsRNA in terms of chemokines. CONCLUSION: Increased TGF-β1 and activin A and increased downstream TGF-β1 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-β1 and activin A by CSE and dsRNA, suggesting that cigarette smoke and viral infection might also contribute to airway remodeling.
BACKGROUND: The 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-β1) 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. METHODS: Frozen tissue from CRSwNP patients, healthy control (HC) middle turbinates, and sinus tissue from CRS without NP (CRSsNP) patients were immunostained for TGF-β1, 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). RESULTS: CRSwNP patients showed increased TGF-β1 and activin A in the stroma, increased TGF-β1 signaling (phosphorylated Smad2/3) in the stroma and epithelium, and increased Smad3-dependent Snail1 in the stroma. Immunostaining for TGF-β1, 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-β1 and activin A and more strongly induced by dsRNA in terms of chemokines. CONCLUSION: Increased TGF-β1 and activin A and increased downstream TGF-β1 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-β1 and activin A by CSE and dsRNA, suggesting that cigarette smoke and viral infection might also contribute to airway remodeling.