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

Abstract

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), Gli1^lZ/+ (n = 37) and Gli1^lZ/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:

• Hedgehog signaling
• Gli1
• bleomycin
• myofibroblast
• lung fibrosis

Acknowledgments

We would like to thank the following funding entities for their support: the NIH/NHLBI (K08-HL128842)(M.C.K) and (5R21-HL104455)(J.S.M.), NIH/NCI (P30-CA016087) (C.A.L.), the Stony Wold-Herbert Foundation NYC (M.C.K), the NYU Weissmann Scholarship program (M.C.K), and the Will Rogers Foundation (M.C.K, J.S.M). We also thank the members of the Experimental Pathology Research laboratory, which is partially supported by the Cancer Center Support Grant P30CA016087.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Additional information

Funding

National Heart, Lung, and Blood Institute; Stony Wold-Herbert Fund; National Cancer Institute.