LAUSR

RATIONALE Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large conductance, Ca2+-activated and voltage-dependent K+ channels (BK), critical for mucociliary function in the absence of CFTR. OBJECTIVES AND METHODS Losartan's anti-inflammatory effectiveness to rescue BK activity and thereby mucociliary function was tested in vitro using primary, fully re-differentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacological sheep model of CF- and inflammation-associated mucociliary dysfunction. MEASUREMENTS AND MAIN RESULTS Nasal scrapings from CF patients showed that neutrophilic inflammation correlated with reduced expression of LRRC26, the γ subunit mandatory for BK function in the airways. TGF-β1, downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression); ciliary beat frequency and airway surface liquid (ASL) volume improved; and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic sheep model of CF, ewes inhaled CFTRinh172 and neutrophil elastase for three days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration and increased TGF-β1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-β1. CONCLUSIONS Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade.