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  • Targeting the hedgehog-glioma-associated oncogene homolog pathway inhibits bleomycin-induced lung fibrosis in mice.

Targeting the hedgehog-glioma-associated oncogene homolog pathway inhibits bleomycin-induced lung fibrosis in mice.

American journal of respiratory cell and molecular biology (2014-01-24)
Elika Farrokhi Moshai, Lidwine Wémeau-Stervinou, Natacha Cigna, Stephanie Brayer, Joëlle Marchal Sommé, Bruno Crestani, Arnaud A Mailleux
ABSTRACT

Idiopathic pulmonary fibrosis has been associated with the reactivation of developmental pathways, notably the Hedgehog-Glioma-associated oncogene homolog (GLI) pathway. In this study, we determined whether the Hedgehog pathway was activated in bleomycin-induced lung injury in mice, and whether targeting the Hedgehog-Gli pathway could decrease bleomycin-induced lung fibrosis. After intratracheal injection of bleomycin on Day 0, C57Bl6 mice received GDC-0449 (an inhibitor of Smoothened, the transducer of the pathway), or 2,2'-[[Dihydro-2-(4-pyridinyl)-1,3(2H,4H)-pyrimidinediyl]bis(methylene)]bis[N,N dimethylbenzenamine (GANT61; an inhibitor of GLI transcription factors in the nucleus), from Day 7 to Day 13. At Day 14, whole-lung homogenates were obtained for morphological analysis, assessment of cell apoptosis and proliferation, collagen quantification, and evaluation of profibrotic (transforming growth factor-β, connective tissue growth factor, plasminogen activator inhibitor 1, vascular endothelial growth factor-A) and proinflammatory mediators (IL-1β) expression. We showed that the Hedgehog pathway was activated in bleomycin-induced lung fibrosis on Day 14 after injury, with an increased lung expression of the ligand, Sonic Hedgehog, and with increased messenger RNA expression and nuclear localization of GLI1 and GLI2. Inhibition of Smoothened with GDC-0449 did not influence the development of bleomycin-induced lung fibrosis. By contrast, the inhibition of GLI activity with GANT61 decreased lung fibrosis and lung collagen accumulation, and promoted an antifibrotic and anti-inflammatory environment. Our results identify the hedgehog-Gli pathway as a profibrotic pathway in experimental fibrosis. Inhibition of the Hedgehog-Gli pathway at the level of GLI transcriptional activity could be a therapeutic option in fibrotic lung diseases.

MATERIALS
Product Number
Brand
Product Description

Bleomycin sulfate, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Bleomycin sulfate from Streptomyces verticillus, 1.5-2.0 units/mg solid, BioReagent, suitable for cell culture
Sigma-Aldrich
Bleomycin sulfate from Streptomyces verticillus, BioXtra, crystalline
Sigma-Aldrich
Bleomycin sulfate from Streptomyces verticillus, for fluorescence, mixture of bleomycin sulfate salts, lyophilized, powder or crystals, white to off-white
Sigma-Aldrich
Bleomycin sulfate from Streptomyces verticillus, crystalline, 1.5-2.0 U/mg