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Overexpression of Fibroblast Growth Factor-10 during Both Inflammatory and Fibrotic Phases Attenuates Bleomycin-induced Pulmonary Fibrosis in Mice

¹ Developmental Biology Program, Division of Surgery, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California; ² Biogen Idec, Inc., and ³ Stromedix, Inc., Cambridge, Massachusetts; ⁴ University of Giessen Lung Center, Department of Internal Medicine II, University of Giessen, Giessen, Germany; and ⁵ Department of Pediatrics, Women's and Children's Hospital, University of Southern California Keck School of Medicine, Los Angeles, California

Correspondence and requests for reprints should be addressed to Saverio Bellusci, Ph.D., Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA 90027. E-mail: sbellusci{at}chla.usc.edu; and to Parviz Minoo, Ph.D., Women's and Children's Hospital, Los Angeles, CA 90033. E-mail: minoo{at}usc.edu

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-β₁ 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.

Key Words: bleomycin • fibrosis • Fgf10 • transforming growth factor-β₁ • alveolar epithelial progenitors

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Fibroblast growth factor-10 (FGF10) plays a crucial role in lung development. It is also up-regulated during hyperoxia–induced injury in adult mice. Whether FGF10 has a role in repair in lung fibrosis has not been studied. What This Study Adds to the Field This study shows that 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.