The Hedgehog target Gli1 is not required for bleomycin-induced lung fibrosis

Exp Lung Res. Feb-Mar 2019;45(1-2):22-29. doi: 10.1080/01902148.2019.1601795. Epub 2019 Apr 13.


Sonic Hedgehog (SHH) signaling, a developmental pathway promoting lung mesenchymal expansion and differentiation during embryogenesis, has been increasingly recognized as a profibrotic factor in mature lung, where it might contribute to the pathogenesis of lung fibrosis. Pathway inhibition at the level of the downstream Gli transcription factors Gli1 and Gli2 (by GANT61) ameliorates lung fibrosis in the bleomycin model, whereas inhibition proximally at the level of HH ligand (by anti Hh antibody 5E1) or Smo (by GDC-0449) of the canonical pathway does not, implicating Gli1 and/or Gli2 as a key target. The fact that both the Gli1-labelled cell lineage and Gli1 expressing cells expand during fibrosis formation and contribute significantly to the pool of myofibroblasts in the fibrosis scars suggests a fibrogenic role for Gli1. Therefore to further dissect the roles of Gli1 and Gli2 in lung fibrosis we evaluated Gli1 KO and control mice in the bleomycin model. Monitoring of Gli1+/+ (n = 12), Gli1lZ/+ (n = 37) and Gli1lZ/lZ (n = 18) mice did not reveal differences in weight loss or survival. Lung evaluation at the 21-day endpoint did not show differences in lung fibrosis formation (as judged by morphology and trichrome staining), Ashcroft score, lung collagen content, lung weight, BAL protein content or BAL cell differential count. Our data suggest that Gli1 is not required for bleomycin-induced lung fibrosis.

Keywords: Gli1; Hedgehog signaling; bleomycin; lung fibrosis; myofibroblast.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / adverse effects*
  • Cell Line
  • Hedgehog Proteins / physiology
  • Mice
  • Mice, Knockout
  • Myofibroblasts / metabolism
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / etiology*
  • Pyridines
  • Pyrimidines
  • Survival Rate
  • Weight Loss
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / physiology*
  • Zinc Finger Protein Gli2 / physiology


  • GANT 61
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Pyridines
  • Pyrimidines
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli2
  • Bleomycin