Involvement of Hedgehog pathway in airway cell differentiation

Background: Airway remodelling is a hallmark of COPD but its physiopathology remains unclear. Since Hedgehog (HH) pathway has been shown to regulate repair and regeneration in the mouse lung, we investigated its role in human airway epithelial cell differentiation in the context of COPD. Methods: Sections from formalin-fixed paraffin embedded lung tissues of non-COPD and COPD patients were stained to characterize the localization and activation of HH pathway elements. Human airway primary cells obtained from nasal polyps were differentiated in vitro at the air-liquid interface. RT-qPCRs, western-blots and immunofluorescent studies were performed during the kinetic of epithelial cell differentiation with or without HH inhibitors. Results: A comparison of immunostaining analysis on tissue sections pointed towards an alteration of HH pathway in COPD patients including a decrease of Gli2 expression. Hedgehog pathway was activated in the course of airway epithelial cells differentiation in vitro as shown by the increase of the transcription factors Gli1 and Gli2 (protein and RNA expression). Hedgehog inhibitors induced epithelial remodelling characterized by a 2 fold decrease of ciliated cells and a 2 fold increase of secretory cells. Conclusion: These findings indicate that HH pathway contributes to airway epithelial cell plasticity and suggest its involvement in airway remodelling in COPD. Restoring HH signalling may help correct the remodelling observed in COPD patients.