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

Research output: Contribution to journalArticle

47 Citations (Scopus)

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

Fingerprint

Epithelial Sodium Channels
Mucociliary Clearance
Peptide Hydrolases
Protease Inhibitors
Trypsin
Epithelial Cells
Topical Administration
Aprotinin
Benzoic Acid
Trypsin Inhibitors
Trachea
Aerosols
Soybeans
Inhalation
Sheep
Guinea Pigs
Esters
Molecular Weight
camostat

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

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.; Danahay, H.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 329, No. 2, 01.05.2009, p. 764-774.

Research output: Contribution to journalArticle

Coote, K, Atherton-Watson, HC, Sugar, R, Young, A, MacKenzie-Beevor, A, Gosling, M, Bhalay, G, Bloomfield, G, Dunstan, A, Bridges, RJ, Sabater, JR, Abraham, WM, 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, vol. 329, no. 2, pp. 764-774. https://doi.org/10.1124/jpet.108.148155
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. / Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease. In: Journal of Pharmacology and Experimental Therapeutics. 2009 ; Vol. 329, No. 2. pp. 764-774.
@article{6ff0f6d8e78846dfb689bab20972a8c7,
title = "Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease",
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.",
author = "K. Coote and Atherton-Watson, {H. C.} and R. Sugar and A. Young and A. MacKenzie-Beevor and M. Gosling and G. Bhalay and G. Bloomfield and A. Dunstan and Bridges, {R. J.} and Sabater, {J. R.} and Abraham, {W. M.} and D. Tully and R. Pacoma and A. Schumacher and J. Harris and H. Danahay",
year = "2009",
month = "5",
day = "1",
doi = "10.1124/jpet.108.148155",
language = "English",
volume = "329",
pages = "764--774",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease

AU - Coote, K.

AU - Atherton-Watson, H. C.

AU - Sugar, R.

AU - Young, A.

AU - MacKenzie-Beevor, A.

AU - Gosling, M.

AU - Bhalay, G.

AU - Bloomfield, G.

AU - Dunstan, A.

AU - Bridges, R. J.

AU - Sabater, J. R.

AU - Abraham, W. M.

AU - Tully, D.

AU - Pacoma, R.

AU - Schumacher, A.

AU - Harris, J.

AU - Danahay, H.

PY - 2009/5/1

Y1 - 2009/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=65649148597&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65649148597&partnerID=8YFLogxK

U2 - 10.1124/jpet.108.148155

DO - 10.1124/jpet.108.148155

M3 - Article

VL - 329

SP - 764

EP - 774

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -