Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease

K. Coote, H. C. Atherton-Watson, R. Sugar, A. Young, A. MacKenzie-Beevor, M. Gosling, G. Bhalay, G. Bloomfield, A. Dunstan, R. J. Bridges, J. R. Sabater, W. M. Abraham, D. Tully, R. Pacoma, A. Schumacher, J. Harris, H. Danahay

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Abstract

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 (IC 50 ∼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-guanidino-benzoic acid 4-carboxymethyl-phenyl ester < aprotinin << soybean trypsin inhibitor = α1-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 (ED 50 = 3 μg/kg). When administered by aerosol inhalation in conscious sheep, camo-stat 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.

Original languageEnglish (US)
Pages (from-to)764-774
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume329
Issue number2
DOIs
StatePublished - May 1 2009

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Coote, K., Atherton-Watson, H. C., Sugar, R., Young, A., MacKenzie-Beevor, A., Gosling, M., Bhalay, G., Bloomfield, G., Dunstan, A., Bridges, R. J., Sabater, J. R., Abraham, W. M., Tully, D., Pacoma, R., Schumacher, A., Harris, J., & Danahay, H. (2009). Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease. Journal of Pharmacology and Experimental Therapeutics, 329(2), 764-774. https://doi.org/10.1124/jpet.108.148155