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Am J Respir Crit Care Med. 2009 Sep 1;180(5):424-36. doi: 10.1164/rccm.200811-1794OC. Epub 2009 Jun 4.

Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice.

Author information

1
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.

Abstract

RATIONALE:

Fibroblast growth factor-10 (FGF10) controls survival, proliferation, and differentiation of distal-alveolar epithelial progenitor cells during lung development.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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.

PMID:
19498056
PMCID:
PMC2742760
DOI:
10.1164/rccm.200811-1794OC
[Indexed for MEDLINE]
Free PMC Article

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