Resolution of Cystic Fibrosis Lung Disease and Inflammation Driven by Mucus Obstruction with Resolvin D1
Progressive lung disease remains the major cause of morbidity and mortality of people with cystic fibrosis (CF). CF lung disease evolves from mucus obstruction into non-resolving airway inflammation, bronchiectasis, and damage that impairs respiratory and fitness activity. Therefore, therapeutic strategies that promote resolution of airway inflammation in CF to alleviate the burden of airflow obstruction and improve physical capacity are of wide interest. Here, we report that the proresolving lipid mediator resolvin (Rv) D1 halts mucus-driven inflammation in CF human cells and in vivo. RvD1 dampened migration and pathogenic phenotypes of neutrophils from volunteers with CF as well as inflammatory signaling pathways of CF bronchial epithelial cells triggered by CF mucus. In mice overexpressing the ß-subunit of the epithelial Na+ channel (ßENaC) RvD1 administration prevented and reverted lung inflammation caused by mucus accumulation and promoted the resolution of pulmonary exacerbation caused by P. aeruginosa. RvD1 also significantly improved physical activity and energy expenditure that are impaired in ßENaC mice compared to wild type littermates. These findings demonstrate efficacy of RvD1 in enhancing resolution of lung disease and chronic inflammation associated with mucus obstruction and provide proof of concept for its potential therapeutic approach in FC. Overall design: To investigate the impact of RvD1 in mucus-derived inflammation in cystic fibrosis models, we carried out RNASeq analyses to evaluate global changes in transcriptome of cystic fibrosis primary epithelial cells CFBEC exposed to airway supernatant (ASN) and vehicle or RvD1. We performed gene expression profiling of CFBEC from three biological replicates, treated with vehicle or RvD1. Comparative gene expression analyses among vehicle- and RvD1-exposed CFBEC