Deficient repair response of IPF fibroblasts in a co-culture model of epithelial injury and repair.
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive disorder marked by relentless fibrosis and damage of the lung architecture. A growing body of evidence now suggests that IPF progresses as a result of aberrant epithelial-fibroblast crosstalk. Injured epithelia are a major source of growth factors such as PDGF which guide resident fibroblasts to injury sites.


RESULTS
In this study, we utilized a novel co-culture system to investigate the effect of fibroblast phenotype on their response to epithelial injury. Fibroblasts from normal lungs (NHLF) responded to epithelial injury and populated the wound site forming a fibroblast plug/mechanical barrier which prevented epithelial wound closure. IPF fibroblasts were impaired in their response to epithelial injury. They also expressed reduced PDGFRα compared to NHLFs and were defective towards PDGF-AA mediated directional movement. Neutralization of PDGF-AA and pan-PDGF but not PDGF-BB reduced the injury response of NHLFs thereby preventing the formation of the mechanical barrier and promoting epithelial wound closure. Co-culture of epithelial cells with IPF fibroblasts led to marked increase in the levels of pro-fibrotic growth factors - bFGF and PDGF and significant depletion of anti-fibrotic HGF in the culture medium. Furthermore, IPF fibroblasts but not NHLFs induced a transient increase in mesenchymal marker expression in the wound lining epithelial cells. This was accompanied by increased migration and faster wound closure in co-cultures with IPF fibroblasts.


CONCLUSIONS
Our data demonstrate that the IPF fibroblasts have an aberrant repair response to epithelial injury.
Novartis Institutes of Biomedical Research, Respiratory Disease Area, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK.
Sony
S
Prasad
Department of Medicine, Cedars Sinai Medical Center, AHSP Room A9108, 127 S. San Vicente Blvd, Los Angeles, CA 90048-3311, USA.
Cory M
CM
Hogaboam
Novartis Institutes of Biomedical Research, Respiratory Disease Area, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK.
Gabor
G
Jarai
Co-culture; HGF; IPF; Idiopathic pulmonary fibrosis; PDGF; PDGFR; Wound healing; bFGF