Hedgehog pathway activation is altered in COPD patients

Background: An alteration of primary cilia is observed in remodelled airways in the context of COPD. Since this organelle is required to activate Hedgehog (HH) signalling pathway orchestrating cell fate during lung development, we explored HH activation during human airway epithelial cell differentiation and in adult lungs from COPD and non-COPD patients. Methods: Human airway epithelial cells were cultured from nasal polyps and bronchial brushing in air-liquid interface conditions to reconstitute an epithelium representative of the adult airways. ELISA and immunostaining analysis of the principal ligand Sonic Hedgehog (SHH) were performed at different steps of differentiation on airway epithelial cell cultures, bronchial aspirations and formalin-fixed paraffin embedded lung tissues of non-COPD and COPD patients. Results: Non-differentiated airway epithelial cells produced SHH in vitro during the course of differentiation (from 6pg/ml at ALI-0 to 238pg/ml at ALI-35). Depriving culture medium of SHH with a specific antibody induced epithelial remodelling particularly impacting ciliogenesis (2 fold decrease of ciliated cells). SHH was observed on bronchial tissue sections and detected by ELISA with a 2 fold decrease expression for COPD patients. Conclusion: These findings suggest a crucial involvement of HH pathway in airway basal cells to guide differentiation and indicate an alteration of its activation in COPD patients. Measuring HH elements in biological samples may help categorize COPD patients and propose novel diagnostic and therapeutic strategies.