An essential role for fibronectin extra type III domain A in pulmonary fibrosis

Am J Respir Crit Care Med. 2008 Mar 15;177(6):638-45. doi: 10.1164/rccm.200708-1291OC. Epub 2007 Dec 20.


Rationale: Tissue fibrosis is considered a dysregulated wound-healing response. Fibronectin containing extra type III domain A (EDA) is implicated in the regulation of wound healing. EDA-containing fibronectin is deposited during wound repair, and its presence precedes that of collagen.

Objectives: To investigate the role of EDA-containing fibronectin in lung fibrogenesis.

Methods: Primary lung fibroblasts from patients with idiopathic pulmonary fibrosis or from patients undergoing resection for lung cancer were assessed for EDA-containing fibronectin and alpha-smooth muscle actin (alpha-SMA) expression. Mice lacking the EDA domain of fibronectin and their wild-type littermates were challenged with the bleomycin model of lung fibrosis. Primary lung fibroblasts from these mice were assayed in vitro to determine the contribution of EDA-containing fibronectin to fibroblast phenotypes.

Measurements and main results: Idiopathic pulmonary fibrosis lung fibroblasts produced markedly more EDA-containing fibronectin and alpha-SMA than control fibroblasts. EDA-null mice failed to develop significant fibrosis 21 days after bleomycin challenge, whereas wild-type controls developed the expected increase in total lung collagen. Histologic analysis of EDA-null lungs after bleomycin showed less collagen and fewer alpha-SMA-expressing myofibroblasts compared with that observed in wild-type mice. Failure to develop lung fibrosis in EDA-null mice correlated with diminished activation of latent transforming growth factor (TGF)-beta and decreased lung fibroblast responsiveness to active TGF-beta in vitro.

Conclusions: The data show that EDA-containing fibronectin is essential for the fibrotic resolution of lung injury through TGF-beta activation and responsiveness, and suggest that EDA-containing fibronectin plays a critical role in tissue fibrogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Fibroblasts
  • Fibronectins / chemistry
  • Fibronectins / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Pulmonary Fibrosis / physiopathology*
  • Wound Healing / physiology


  • ACTA2 protein, human
  • Actins
  • Fibronectins
  • fibronectin type III like peptide, human