Involvement Of The Sonic Hedgehog Signaling Pathway In Idiopathic Pulmonary Fibrosis

Abstract

Identification of new therapeutic targets in idiopathic pulmonary fibrosis (IPF) is required. We hypothesized that, in the adult lung, SHH pathway plays a critical role during the alveolar repair process and lung fibrogenesis. Methods: We determined the expression pattern of several members of the SHH pathway in lung biopsies and primary cultured fibroblasts from controls and IPF patients. We also examined the expression profile of SHH pathway after TGF-β stimulation in fibroblasts. We characterized the action of recombinant SHH and cyclopamine, an inhibitor of SHH pathway, on the effect of TGF-β on fibroblast differentiation markers. Results: In lung biopsies, the ligand SHH, the receptor Patched (PTC), the transmembrane protein Smoothened (SMO) and the transcription factors GLI 1-2-3 were detected in both control and IPF tissues. Compared to controls, PTC was decreased in IPF, both in epithelial cells and fibroblasts. SMO was maintained and GLI2 was localized in the nuclei in IPF. In vitro, there was no difference between control and IPF fibroblasts in the expression of HH signalling components. After TGF-β stimulation, PTC, SMO and GLI3 mRNA were strongly inhibited while GLI2 was increased. Cyclopamine inhibited TGF-β induced expression of myofibroblast differentiation markers in control fibroblasts. IPF fibroblasts were less sensitive to cyclopamine treatment. Though, addition of recombinant SHH had no effect. Conclusions: Our results show that the signaling pathway downstream of SMO is activated in IPF. SMO activity is also necessary to TGF-β induced myofibroblastic differentiation. These data support a pro-fibrotic action of the SHH pathway in IPF.