Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease.
Animals
Calcium
/ metabolism
Cells, Cultured
Cilia
/ drug effects
Disease Models, Animal
Epithelium
/ metabolism
Female
Humans
Intermediate-Conductance Calcium-Activated Potassium Channels
/ antagonists & inhibitors
Lung
/ physiopathology
Lung Diseases, Obstructive
/ etiology
Male
Mice, Inbred C57BL
Mice, Mutant Strains
Mice, Transgenic
Mucociliary Clearance
/ drug effects
Sodium
/ metabolism
Epithelial transport of ions and water
Inflammation
Potassium channels
Pulmonology
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
20 08 2020
20 08 2020
Historique:
received:
08
05
2020
accepted:
08
07
2020
entrez:
21
8
2020
pubmed:
21
8
2020
medline:
12
6
2021
Statut:
epublish
Résumé
Airway mucociliary clearance (MCC) is the main mechanism of lung defense keeping airways free of infection and mucus obstruction. Airway surface liquid volume, ciliary beating, and mucus are central for proper MCC and critically regulated by sodium absorption and anion secretion. Impaired MCC is a key feature of muco-obstructive diseases. The calcium-activated potassium channel KCa.3.1, encoded by Kcnn4, participates in ion secretion, and studies showed that its activation increases Na+ absorption in airway epithelia, suggesting that KCa3.1-induced hyperpolarization was sufficient to drive Na+ absorption. However, its role in airway epithelium is not fully understood. We aimed to elucidate the role of KCa3.1 in MCC using a genetically engineered mouse. KCa3.1 inhibition reduced Na+ absorption in mouse and human airway epithelium. Furthermore, the genetic deletion of Kcnn4 enhanced cilia beating frequency and MCC ex vivo and in vivo. Kcnn4 silencing in the Scnn1b-transgenic mouse (Scnn1btg/+), a model of muco-obstructive lung disease triggered by increased epithelial Na+ absorption, improved MCC, reduced Na+ absorption, and did not change the amount of mucus but did reduce mucus adhesion, neutrophil infiltration, and emphysema. Our data support that KCa3.1 inhibition attenuated muco-obstructive disease in the Scnn1btg/+ mice. K+ channel modulation may be a therapeutic strategy to treat muco-obstructive lung diseases.
Identifiants
pubmed: 32814712
pii: 140076
doi: 10.1172/jci.insight.140076
pmc: PMC7455130
doi:
pii:
Substances chimiques
Intermediate-Conductance Calcium-Activated Potassium Channels
0
Kcnn4 protein, mouse
0
Sodium
9NEZ333N27
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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