Myofibroblast differentiation and enhanced TGF-B signaling in cystic fibrosis lung disease.
BACKGROUND
TGF-β, a mediator of pulmonary fibrosis, is a genetic modifier of CF respiratory deterioration. The mechanistic relationship between TGF-β signaling and CF lung disease has not been determined.


OBJECTIVE
To investigate myofibroblast differentiation in CF lung tissue as a novel pathway by which TGF-β signaling may contribute to pulmonary decline, airway remodeling and tissue fibrosis.


METHODS
Lung samples from CF and non-CF subjects were analyzed morphometrically for total TGF-β1, TGF-β signaling (Smad2 phosphorylation), myofibroblast differentiation (α-smooth muscle actin), and collagen deposition (Masson trichrome stain).


RESULTS
TGF-β signaling and fibrosis are markedly increased in CF (p<0.01), and the presence of myofibroblasts is four-fold higher in CF vs. normal lung tissue (p<0.005). In lung tissue with prominent TGF-β signaling, both myofibroblast differentiation and tissue fibrosis are significantly augmented (p<0.005).


CONCLUSIONS
These studies establish for the first time that a pathogenic mechanism described previously in pulmonary fibrosis is also prominent in cystic fibrosis lung disease. The presence of TGF-β dependent signaling in areas of prominent myofibroblast proliferation and fibrosis in CF suggests that strategies under development for other pro-fibrotic lung conditions may also be evaluated for use in CF.
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA. tharris@peds.uab.edu
William T
WT
Harris
David R
DR
Kelly
Yong
Y
Zhou
Dezhi
D
Wang
Mark
M
MacEwen
Mark
M
Macewen
James S
JS
Hagood
J P
JP
Clancy
Namasivayam
N
Ambalavanan
Eric J
EJ
Sorscher
D000328:Adult; D002454:Cell Differentiation; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1