title: An essential role for fibronectin extra type III domain A in pulmonary fibrosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors: Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, 6301 MSRB III/0642, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0642, USA.
authors: Andrés F
authors: AF
authors: Muro
authors: Federico A
authors: FA
authors: Moretti
authors: Bethany B
authors: BB
authors: Moore
authors: Mei
authors: M
authors: Yan
authors: Rachelle G
authors: RG
authors: Atrasz
authors: Carol A
authors: CA
authors: Wilke
authors: Kevin R
authors: KR
authors: Flaherty
authors: Fernando J
authors: FJ
authors: Martinez
authors: Jessica L
authors: JL
authors: Tsui
authors: Dean
authors: D
authors: Sheppard
authors: Francisco E
authors: FE
authors: Baralle
authors: Galen B
authors: GB
authors: Toews
authors: Eric S
authors: ES
authors: White
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000503:physiopathology*; D014945:Wound Healing / Q000502:physiology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D005353:Fibronectins; C501364:fibronectin type III like peptide, human