The extra domain A of fibronectin is essential for allergen-induced airway fibrosis and hyperresponsiveness in mice

Martin Kohan, Andres F. Muro, Reem Bader, Neville Berkman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Background: Asthma is characterized by airway inflammation, airway remodeling, and airway hyperresponsiveness (AHR). Myofibroblast differentiation and subepithelial fibrosis are key features of airway remodeling. Extra domain A (EDA)-containing fibronectin (EDA-FN), an alternatively spliced form of the extracellular matrix protein fibronectin, has been implicated in fibroblast differentiation during wound healing and tissue fibrosis. Objectives: We sought to investigate the role of EDA-FN in airway remodeling using a murine model of chronic allergen-induced experimental asthma. Methods: EDA-/- and wild-type (WT) mice were sensitized and exposed to inhaled ovalbumin (OVA) or saline for 5 weeks. EDA-FN expression was evaluated by means of PCR and immunostaining. Peribronchial fibrosis, smooth muscle area, mucus-producing cell numbers, bronchoalveolar cell counts, and lung function were assessed in WT and EDA-/- mice. Fibroblast activation and differentiation were evaluated ex vivo by using OVA-treated WT and EDA-/- lung fibroblasts. Results: Exposure to OVA increased EDA-FN expression in lung tissue and primary lung fibroblasts. OVA-treated EDA-/- mice showed reduced airway fibrosis and AHR and impaired expression of TGF-β1 and IL-13 without changes in airway inflammation or other aspects of remodeling. Lung fibroblasts from OVA-treated EDA-/- mice exhibited reduced proliferation, migration, α-smooth muscle actin expression, and collagen deposition and impaired TGF-β1 and IL-13 release compared with that seen in WT mice. Conclusions: EDA-FN is essential for the development of OVA-induced airway fibrosis and AHR. The effect of the EDA domain on airway fibrosis after OVA challenge is through activation and differentiation of fibroblasts. Fibroblast activation and airway fibrosis are necessary for the development of AHR.

Original languageAmerican English
Pages (from-to)439-446.e5
JournalJournal of Allergy and Clinical Immunology
Volume127
Issue number2
DOIs
StatePublished - Feb 2011

Bibliographical note

Funding Information:
Supported by grants from the Israel Science Foundation ( 1408/08 ) and the Chief Scientist Office of the Ministry of Health, Israel ( 4921 ) to N.B.

Keywords

  • Airway remodeling
  • EDA-containing fibronectin
  • asthma
  • fibroblast
  • fibrosis
  • myofibroblast

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