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

Int Forum Allergy Rhinol. 2015 Jul;5(7):573-82. doi: 10.1002/alr.21516. Epub 2015 Apr 25.

Abstract

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.

Keywords: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism*
  • Adult
  • Aged
  • Airway Remodeling / physiology*
  • Biopsy
  • Chronic Disease
  • Female
  • Humans
  • Male
  • Middle Aged
  • Nasal Mucosa / drug effects*
  • Nasal Mucosa / metabolism
  • Nasal Polyps / metabolism*
  • Nasal Polyps / pathology
  • Paranasal Sinuses / pathology
  • Real-Time Polymerase Chain Reaction
  • Rhinitis / metabolism*
  • Rhinitis / pathology
  • Sinusitis / metabolism*
  • Sinusitis / pathology
  • Smoking / adverse effects*
  • Toll-Like Receptor 3 / metabolism*
  • Transforming Growth Factor beta1 / metabolism*
  • Turbinates / pathology
  • Young Adult

Substances

  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Transforming Growth Factor beta1
  • activin A
  • Activins