Profibrotic transforming growth factor beta 1 and activin A are increased in nasal polyp tissue and induced in nasal polyp epithelium by cigarette smoke and Toll-like receptor 3 ligation.
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.


CONCLUSIONS
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.
Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Boston, MA.
Moshe
M
Yamin
Department of Otolaryngology, Massachusetts Eye & Ear Infirmary, Boston, MA.
Eric H
EH
Holbrook
Department of Otolaryngology, Massachusetts Eye & Ear Infirmary, Boston, MA.
Stacey T
ST
Gray
Department of Otolaryngology, Massachusetts Eye & Ear Infirmary, Boston, MA.
Nicolas Y
NY
Busaba
Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Boston, MA.
Brooke
B
Lovett
Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Boston, MA.
Daniel L
DL
Hamilos
D028341:Activins / Q000378:metabolism*; D000328:Adult; D000368:Aged; D056151:Airway Remodeling / Q000502:physiology*; D001706:Biopsy; D002908:Chronic Disease; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D009298:Nasal Polyps / Q000378:metabolism* / Q000473:pathology; D010256:Paranasal Sinuses / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D012220:Rhinitis / Q000378:metabolism* / Q000473:pathology; D012852:Sinusitis / Q000378:metabolism* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014420:Turbinates / Q000473:pathology; D055815:Young Adult
C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D053773:Transforming Growth Factor beta1; C422405:activin A; D028341:Activins
Activin A; TGF-β1; TLR 3; Toll-like receptor 3; airway remodeling; chronic rhinosinusitis; cigarette smoke; epithelium; inflammation; nasal polyposis; profibrotic; transforming growth factor beta 1