Abstract
BackgroundThe hedgehog (HH) pathway has been associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies and recent studies suggest that HH signalling could be altered in COPD. We therefore used minimally invasive endobronchial procedures to assess activation of the HH pathway including the main transcription factor, Gli2, and the ligand, Sonic HH (Shh).MethodsThirty non-COPD patients and 28 COPD patients were included. Bronchial brushings, bronchoalveolar lavage fluid (BALF) and bronchial biopsies were obtained from fiberoptic bronchoscopy. Characterization of cell populations and subcellular localization were evaluated by immunostaining. ELISA and RNAseq analysis were performed to identify Shh proteins in BAL and transcripts on lung tissues from non-COPD and COPD patients with validation in an external and independent cohort.ResultsCompared to non-COPD patients, COPD patients exhibited a larger proportion of basal cells in bronchial brushings (26 ± 11% vs 13 ± 6%; p < 0.0001). Airway basal cells of COPD subjects presented less intense nuclear staining for Gli2 in bronchial brushings and biopsies (p < 0.05). Bronchial BALF from COPD patients contained lower Shh concentrations than non-COPD BALF (12.5 vs 40.9 pg/mL; p = 0.002); SHH transcripts were also reduced in COPD lungs in the validation cohort (p = 0.0001).ConclusionThis study demonstrates the feasibility of assessing HH pathway activation in respiratory samples collected by bronchoscopy and identifies impaired bronchial epithelial HH signalling in COPD.
Highlights
The hedgehog (HH) pathway has been associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies and recent studies suggest that HH signalling could be altered in COPD
We recently demonstrated that the HH pathway was inextricably linked to airway epithelial cell (AEC) differentiation in adulthood [15]
To further explore this hypothesis, we focused on the critical molecular players responsible for the biological effects of the HH pathway: the activating ligand, Sonic HH (Shh), its main receptor Patched 1 (Ptch1), its main co-receptor Hhip, and its main transcription factor Glioma-associated oncogene 2 (Gli2), while previous studies have exclusively focused on analysis of the Ptch1 ligand receptor [31]
Summary
The hedgehog (HH) pathway has been associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies and recent studies suggest that HH signalling could be altered in COPD. We used minimally invasive endobronchial procedures to assess activation of the HH pathway including the main transcription factor, Gli, and the ligand, Sonic HH (Shh). Tobacco smoke is known to be the main risk factor, leading to epithelial and subepithelial bronchial remodelling [2], including airway basal cell progenitor alterations [3]. These morphological changes result in non-reversible chronic. Assessment of the HH pathway in clinical practice remains challenging
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