Neutrophil Elastase Regulates CFTR Function in Airway Disease

The airways of chronic neutrophilic lung disorders, such as chronic obstructive lung disease (COPD), cystic fibrosis (CF), and non-CF bronchiectasis (NCFBE) are characterized by unrelenting inflammation and alterations in mucociliary transport, leading to chronic bronchitis, recurrent infections, and bronchiectasis. Neutrophil elastase (NE) has classically been associated with lung parenchymal remodeling in airways disease such as COPD, CF and NCFBE, but its contribution to the airway phenotype is less understood. Here, we identify NE as a modulator of decreased cystic fibrosis transmembrane conductance regulator (CFTR) function in airway epithelia through protease activated receptor-2 (PAR-2) activation. Decreased CFTR activity is recapitulated in vivo, with reduced nasal potential difference (NPD) in mice exposed to NE. Primary human bronchial epithelial (HBE) cells demonstrate a decrease in CFTR function and reduction in airway surface liquid (ASL) depth after NE administration, which affects mucociliary transport. Samples from patients with COPD decrease CFTR function on HBE cells and this effect is partially ameliorated by direct NE inhibition. This important signaling pathway modulates an acquired loss of CFTR function, highlighting new therapeutic targets for addressing the underlying mucociliary defects in chronic airway diseases.