Targeting the hedgehog/GLI pathway decreases bleomycin-induced lung fibrosis

Introduction. Idiopathic Pulmonary Fibrosis (IPF) has been associated with aberrant reactivation of developmental pathways, namely the Hedgehog (HH) pathway, which is involved in epithelial cells-fibroblasts interaction. We reported that the activation of the HH pathway, from Smoothened (SMO, the mandatory transducer of the pathway) to the transcription factors GLI in the nucleus is required for the TGF-β1 induced myofibroblastic differentiation in human lung fibroblasts (Cigna et al. Am J Pathol 2012;181:2126). Aims. We hypothesized that inhibition of the HH pathway could decrease bleomycin-induced fibrosis in mice. Methods. After intratracheal injection of bleomycin, C57Bl6 mice were treated either with cyclopamine (CYC, an inhibitor of SMO) or with GANT-61 (an inhibitor of GLI transcription factors in the nucleus). At day 14, whole lung homogenates were obtained for morphological analysis, collagen quantification and evaluation of profibrotic (TGF-β1, CTGF, PAI-1, VEGF) and inflammatory mediators (IL-1β). Results. We showed that the HH pathway was activated in bleomycin-induced lung fibrosis, with increased mRNA expression and nuclear localization of GLI1 and GLI2 on day 14. Inhibition of SMO with CYC increased lung fibrosis and induced a profibrotic and proinflammatory environment. By contrast, the inhibition of GLI activity with GANT-61 decreased fibrosis histological score, collagen content, collagen expression and promoted an anti-fibrotic and anti-inflammatory environment. Conclusions. Inhibition of the HH pathway targeting GLI transcriptional activity may be seen as a potential therapeutic target in IPF.