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

journal contribution
posted on 2023-06-08, 19:46 authored by K Coote, H C Atherton-Watson, R Sugar, A Young, A MacKenzie-Beevor, Martin 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
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 = a1-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.

History

Publication status

  • Published

Journal

Journal of Pharmacology and Experimental Therapeutics

ISSN

0022-3565

Publisher

American Society for Pharmacology and Experimental Therapeutics

Issue

2

Volume

329

Page range

764-774

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-01-26

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