Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling

Robert D. Guzy, Ling Li, Craig Smith, Samuel J. Dorry, Hyun Young Koo, Lin Chen, David M. Ornitz

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive pulmonary scarring, decline in lung function, and often results in death within 3–5 five years after diagnosis. Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of IPF; however, the mechanism through which FGF signaling contributes to pulmonary fibrosis remains unclear. We hypothesized that FGF receptor (FGFR) signaling in fibroblasts is required for the fibrotic response to bleomycin. To test this, mice with mesenchyme-specific tamoxifen-inducible inactivation of FGF receptors 1, 2, and 3 (Col12-CreER; TCKO mice) were lineage labeled and administered intratracheal bleomycin. Lungs were collected for histologic analysis, whole lung RNA and protein, and dissociated for flow cytometry and FACS. Bleo-mycin-treated Col12-CreER; TCKO mice have decreased pulmonary fibrosis, collagen production, and fewer -smooth muscle actin-positive (SMA) myofibroblasts compared with controls. Freshly isolated Col12-CreER; TCKO mesenchymal cells from bleomycin-treated mice have decreased collagen expression compared with wild type mesenchymal cells. Furthermore, lineage labeled FGFR-deficient fibroblasts have decreased enrichment in fibrotic areas and decreased proliferation. These data identify a cell autonomous requirement for mesenchymal FGFR signaling in the development of pulmonary fibrosis, and for the enrichment of the Col12-CreER-positive (Col12) mesenchymal lineage in fibrotic tissue following bleomycin exposure. We conclude that mesenchymal FGF signaling is required for the development of pulmonary fibrosis, and that therapeutic strategies aimed directly at mesenchymal FGF signaling could be beneficial in the treatment of IPF.

Original languageEnglish
Pages (from-to)10364-10378
Number of pages15
JournalJournal of Biological Chemistry
Volume292
Issue number25
DOIs
StatePublished - Jun 23 2017

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