Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice.
BACKGROUND
Fibroblast growth factor-10 (FGF10) controls survival, proliferation, and differentiation of distal-alveolar epithelial progenitor cells during lung development.


OBJECTIVE
To test for the protective and regenerative effect of Fgf10 overexpression in a bleomycin-induced mouse model of pulmonary inflammation and fibrosis.


METHODS
In SP-C-rtTA; tet(O)Fgf10 double-transgenic mice, lung fibrosis was induced in 2-month-old transgenic mice by subcutaneous delivery of bleomycin (BLM), using an osmotic minipump for 1 week. Exogenous Fgf10 expression in the alveolar epithelium was induced for 7 days with doxycycline during the first, second, and third weeks after bleomycin pump implantation, and lungs were examined at 28 days.


RESULTS
Fgf10 overexpression during Week 1 (inflammatory phase) resulted in increased survival and attenuated lung fibrosis score and collagen deposition. In these Fgf10-overexpressing mice, an increase in regulatory T cells and a reduction in both transforming growth factor-beta(1) and matrix metalloproteinase-2 activity were observed in bronchoalveolar lavage fluids whereas the number of surfactant protein C (SP-C)-positive, alveolar epithelial type II cells (AEC2) was markedly elevated. Analysis of SP-C and TUNEL (terminal deoxynucleotidyltransferase dUTP nick end labeling) double-positive cells and isolation of AEC2 from lungs overexpressing Fgf10 demonstrated increased AEC2 survival. Expression of Fgf10 during Weeks 2 and 3 (fibrotic phase) showed significant attenuation of the lung fibrosis score and collagen deposition.


CONCLUSIONS
In the bleomycin model of lung inflammation and fibrosis, Fgf10 overexpression during both the inflammatory and fibrotic phases results in a greatly reduced extent of lung fibrosis, suggesting that FGF10 may be useful as a novel approach to the treatment of pulmonary fibrosis.
Gupte
Varsha V
VV
Division of Surgery, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, CA 90027, USA.
Ramasamy
Suresh K
SK
Reddy
Raghava
R
Lee
Jooeun
J
Weinreb
Paul H
PH
Violette
Shelia M
SM
Guenther
Andreas
A
Warburton
David
D
Driscoll
Barbara
B
Minoo
Parviz
P
Bellusci
Saverio
S
D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D004195:Disease Models, Animal; D004318:Doxycycline; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D012016:Reference Values; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D004318:Doxycycline