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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Camostat Attenuates Airway Epithelial Sodium Channel Function in Vivo through the Inhibition of a Channel-Activating Protease

Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (K.C., H.C.A.-W., R.S., A.Y., A.M-B., M.G., G.Bh., G.Bl., A.D., H.D.); Rosalind-Franklin Institute, North Chicago, Illinois (R.J.B.); Department of Research, Mount Sinai Medical Center, Miami Beach, Florida (J.R.S., W.M.A.); and Genomics Institute of the Novartis Foundation, La Jolla, California (D.T., R.P., A.S., J.H.)

Inhibition of airway epithelial sodium channel (ENaC) function enhances mucociliary clearance (MCC). ENaC is positively regulated by channel-activating proteases (CAPs), and CAP inhibitors are therefore predicted to be beneficial in diseases associated with impaired MCC. The aims of the present study were to 1) identify low-molecular-weight inhibitors of airway CAPs and 2) to establish whether such CAP inhibitors would translate into a negative regulation of ENaC function in vivo, with a consequent enhancement of MCC. To this end, camostat, a trypsin-like protease inhibitor, provided a potent (IC₅₀ 50 nM) and prolonged attenuation of ENaC function in human airway epithelial cell models that was reversible upon the addition of excess trypsin. In primary human bronchial epithelial cells, a potency order of placental bikunin > camostat > 4-guanidinobenzoic acid 4-carboxymethyl-phenyl ester > aprotinin >> soybean trypsin inhibitor = 1-antitrypsin, was largely consistent with that observed for inhibition of prostasin, a molecular candidate for the airway CAP. In vivo, topical airway administration of camostat induced a potent and prolonged attenuation of ENaC activity in the guinea pig trachea (ED₅₀ = 3 µg/kg). When administered by aerosol inhalation in conscious sheep, camostat enhanced MCC out to at least 5 h after inhaled dosing. In summary, camostat attenuates ENaC function and enhances MCC, providing an opportunity for this approach toward the negative regulation of ENaC function to be tested therapeutically.

Address correspondence to: Dr. Henry Danahay, Novartis Institutes for Biomedical Research, Horsham, West Sussex, RH12 5AB, UK. E-mail: henry.danahay{at}novartis.com

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