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Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease
Authors
A Dunstan (13471987)
A MacKenzie-Beevor (16207943)
+15 more
A Schumacher (6983261)
A Young (7674896)
D Tully (16207958)
G Bhalay (16207946)
G Bloomfield (16205906)
H C Atherton-Watson (16207937)
H Danahay (16205894)
J Harris (5841908)
J R Sabater (16207952)
K Coote (16205897)
Martin Gosling (4465864)
R J Bridges (16207949)
R Pacoma (16207961)
R Sugar (16207940)
W M Abraham (16207955)
Publication date
1 May 2009
Publisher
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 = 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
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Last time updated on 05/12/2023