Potentiating TMEM16A does not stimulate airway mucus secretion or bronchial and pulmonary arterial smooth muscle contraction.
Anoctamin‐1
ETX001
bronchoconstriction
mucin
vasoconstriction
Journal
FASEB bioAdvances
ISSN: 2573-9832
Titre abrégé: FASEB Bioadv
Pays: United States
ID NLM: 101733210
Informations de publication
Date de publication:
Aug 2020
Aug 2020
Historique:
received:
11
05
2020
revised:
11
05
2020
accepted:
10
06
2020
entrez:
22
8
2020
pubmed:
22
8
2020
medline:
22
8
2020
Statut:
epublish
Résumé
The calcium-activated chloride channel (CaCC) TMEM16A enables chloride secretion across several transporting epithelia, including in the airways. Additional roles for TMEM16A have been proposed, which include regulating mucus production and secretion and stimulating smooth muscle contraction. The aim of the present study was to test whether the pharmacological regulation of TMEM16A channel function, could affect any of these proposed biological roles in the airways. In vitro, neither a potent and selective TMEM16A potentiator (ETX001) nor the potent TMEM16A inhibitor (Ani9) influenced either baseline mucin release or goblet cell numbers in well-differentiated primary human bronchial epithelial (HBE) cells. In vivo, a TMEM16A potentiator was without effect on goblet cell emptying in an IL-13 stimulated goblet cell metaplasia model. Using freshly isolated human bronchi and pulmonary arteries, neither ETX001 or Ani9 had any effect on the contractile or relaxant responses of the tissues. In vivo, ETX001 also failed to influence either lung or cardiovascular function when delivered directly into the airways of telemetered rats. Together, these studies do not support a role for TMEM16A in the regulation of goblet cell numbers or baseline mucin release, or on the regulation of airway or pulmonary artery smooth muscle contraction.
Identifiants
pubmed: 32821878
doi: 10.1096/fba.2020-00035
pii: FBA21148
pmc: PMC7429354
doi:
Types de publication
Journal Article
Langues
eng
Pagination
464-477Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL129795
Pays : United States
Informations de copyright
© 2020 Enterprise Therapeutics Ltd.
Déclaration de conflit d'intérêts
All work has been funded by Enterprise Therapeutics Ltd. HD, SPC, and MG are full‐time employees of Enterprise Therapeutics Ltd.
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