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

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 and 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). pp. 764-774. ISSN 0022-3565

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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. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry
Depositing User: Tom Gittoes
Date Deposited: 26 Jan 2015 14:48
Last Modified: 26 Jan 2015 14:48
URI: http://sro.sussex.ac.uk/id/eprint/52460
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