An essential role for fibronectin extra type III domain A in pulmonary fibrosis.
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.
Muro
Andrés F
AF
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.
Moretti
Federico A
FA
Moore
Bethany B
BB
Yan
Mei
M
Atrasz
Rachelle G
RG
Wilke
Carol A
CA
Flaherty
Kevin R
KR
Martinez
Fernando J
FJ
Tsui
Jessica L
JL
Sheppard
Dean
D
Baralle
Francisco E
FE
Toews
Galen B
GB
White
Eric S
ES
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
C541116:ACTA2 protein, human; D000199:Actins; D005353:Fibronectins; C501364:fibronectin type III like peptide, human