title: Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition.
abstract: Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis and chronic bronchitis (CB). Rehydration by hypertonic saline is efficacious but suffers from a short duration of action. We tested whether epithelial sodium channel (ENaC) inhibition would rehydrate normal and dehydrated airways to increase mucociliary clearance (MCC) over a significant time frame. For this, we used a tool compound (Compound A), which displays nanomolar ENaC affinity and retention in the airway surface liquid (ASL). Using normal human bronchial epithelial cultures (HBECs) grown at an air-liquid interface, we evaluated in vitro potency and efficacy using short-circuit current (I(sc)) and ASL height measurements where it inhibited I(sc) and increased ASL height by ∼ 50% (0.052 μM at 6 h), respectively. The in vivo efficacy was investigated in a modified guinea pig tracheal potential difference model, where we observed an effective dose (ED50) of 5 μg/kg (i.t.), and by MCC measures in rats and sheep, where we demonstrated max clearance rates at 100 μg/kg (i.t.) and 75 μg/kg (i.t.), respectively. Acute cigarette smoke-induced ASL height depletion in HBECs was used to mimic the situation in patients with CB, and pretreatment prevented both cigarette smoke-induced ASL dehydration and lessened the decrease in ciliary beat frequency. Furthermore, when added after cigarette smoke exposure, Compound A increased the rate of ASL rehydration. In conclusion, Compound A demonstrated significant effects and a link between increased airway hydration, ciliary function, and MCC. These data support the hypothesis that ENaC inhibition may be efficacious in the restoration of mucus hydration and transport in patients with CB.
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden; annika.astrand@astrazeneca.com.
authors.forename: Annika B M
authors.initials: AB
authors.lastname: Åstrand
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden;
authors.forename: Martin
authors.initials: M
authors.lastname: Hemmerling
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden;
authors.forename: James
authors.initials: J
authors.lastname: Root
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden;
authors.forename: Cecilia
authors.initials: C
authors.lastname: Wingren
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden;
authors.forename: Jelena
authors.initials: J
authors.lastname: Pesic
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden;
authors.forename: Edvin
authors.initials: E
authors.lastname: Johansson
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Alaina L
authors.initials: AL
authors.lastname: Garland
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Arunava
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Robert
authors.initials: R
authors.lastname: Tarran
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism / Q000473:pathology; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D009093:Mucus / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D012756:Sheep; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D053503:Epithelial Sodium Channels
keywords: airway surface liquid; chronic bronchitis; chronic obstructive pulmonary disease; ciliary beat frequency; cystic fibrosis; cystic fibrosis transmembrane conductance regulator; mucociliary clearance; tracheal potential difference