Allosteric inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) slows airway mucus transport in normal sheep

Rationale: Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are associated with increased concentrations of airway neutrophil elastase. One of the consequences of this elastase increase is slowed mucus clearance. To model the pathophysiological airway effects of increased elastase, we have challenged sheep with aerosolized human neutrophil elastase (HNE) and showed a slowing of mucociliary clearance (MCC)-and its surrogate marker tracheal mucus velocity (TMV). Furthermore, we have used this challenge model to identify agents that can prevent and/or reverse the HNE-induced effects. The mechanism by which HNE slows MCC is not completely known, but recent studies have suggested that HNE can directly cause CFTR degradation. Therefore, we hypothesized that if HNE was affecting CFTR function, then we should be able to replicate the mucociliary dysfunction seen with HNE, by directly interfering with CFTR. Methods: To inhibit CFTR function we used CFTR (inh)-172. We measured TMV before and for 8h after treating sheep with aerosol CFTR (inh)-172 (1 or 10mg) or HNE (1190 mU) for comparison (n=9). Results: 10mg of CFTR (inh)-172 decreased (x ± SD) TMV at 2h (67 ± 2 % of baseline) and TMV remained depressed for 8h (66 ± 9% of baseline). The effect of CFTR (inh)-172 was dose related as 1mg had no effect on TMV. The findings for HNE challenge were superimposable to that seen with CFTR (inh)-172. Conclusions: Allosteric inhibition of CFTR slows mucus transport in vivo. This may be a useful in vivo model to study dysfunctional CFTR-induced mucus stasis.