Identification of the SPLUNC1 ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airway epithelial cultures.

Détails

Ressource 1Télécharger: BIB_4553A8671041.P001.pdf (830.33 [Ko])
Etat: Serval
Version: Author's accepted manuscript
ID Serval
serval:BIB_4553A8671041
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Identification of the SPLUNC1 ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airway epithelial cultures.
Périodique
American Journal of Physiology. Lung Cellular and Molecular Physiology
Auteur(s)
Hobbs C.A., Blanchard M.G., Alijevic O., Tan C.D., Kellenberger S., Bencharit S., Cao R., Kesimer M., Walton W.G., Henderson A.G., Redinbo M.R., Stutts M.J., Tarran R.
ISSN
1522-1504 (Electronic)
ISSN-L
1040-0605
Statut éditorial
Publié
Date de publication
2013
Peer-reviewed
Oui
Volume
305
Numéro
12
Pages
L990-L1001
Langue
anglais
Notes
Publication types: Journal Article Publication Status: ppublish
Résumé
The epithelial sodium channel (ENaC) is responsible for Na(+) and fluid absorption across colon, kidney, and airway epithelia. Short palate lung and nasal epithelial clone 1 (SPLUNC1) is a secreted, innate defense protein and an autocrine inhibitor of ENaC that is highly expressed in airway epithelia. While SPLUNC1 has a bactericidal permeability-increasing protein (BPI)-type structure, its NH2-terminal region lacks structure. Here we found that an 18 amino acid peptide, S18, which corresponded to residues G22-A39 of the SPLUNC1 NH2 terminus inhibited ENaC activity to a similar degree as full-length SPLUNC1 (∼2.5 fold), while SPLUNC1 protein lacking this region was without effect. S18 did not inhibit the structurally related acid-sensing ion channels, indicating specificity for ENaC. However, S18 preferentially bound to the βENaC subunit in a glycosylation-dependent manner. ENaC hyperactivity is contributory to cystic fibrosis (CF) lung disease. Unlike control, CF human bronchial epithelial cultures (HBECs) where airway surface liquid (ASL) height was abnormally low (4.2 ± 0.6 μm), addition of S18 prevented ENaC-led ASL hyperabsorption and maintained CF ASL height at 7.9 ± 0.6 μm, even in the presence of neutrophil elastase, which is comparable to heights seen in normal HBECs. Our data also indicate that the ENaC inhibitory domain of SPLUNC1 may be cleaved away from the main molecule by neutrophil elastase, suggesting that it may still be active during inflammation or neutrophilia. Furthermore, the robust inhibition of ENaC by the S18 peptide suggests that this peptide may be suitable for treating CF lung disease.
Pubmed
Web of science
Création de la notice
24/01/2014 19:46
Dernière modification de la notice
03/03/2018 16:45
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