Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease
Génesis Vega, Anita Guequén, Amber R. Philp, Ambra Gianotti, Llilian Arzola, Manuel Villalón, Olga Zegarra-Moran, Luis J.V. Galietta, Marcus A. Mall, Carlos A. Flores
Génesis Vega, Anita Guequén, Amber R. Philp, Ambra Gianotti, Llilian Arzola, Manuel Villalón, Olga Zegarra-Moran, Luis J.V. Galietta, Marcus A. Mall, Carlos A. Flores
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Research Article Inflammation Pulmonology

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease

Abstract

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.

Authors

Génesis Vega, Anita Guequén, Amber R. Philp, Ambra Gianotti, Llilian Arzola, Manuel Villalón, Olga Zegarra-Moran, Luis J.V. Galietta, Marcus A. Mall, Carlos A. Flores

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Figure 5

Genetic silencing of Kcnn4 improved mucus clearance in mouse airways.

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Genetic silencing of Kcnn4 improved mucus clearance in mouse airways. In...
Intraluminal (A) and intracellular (B) mucus volume was determined in the proximal and distal airways. Differences were calculated with ANOVA on ranks; n = 12, 12, 12 and 9 animals for WT, Kcnn4+/+, Scnn1btg/+, and double mutants, respectively. Representative images of mucus attachment to the epithelial surface for Scnn1btg/+ (n = 15) and double mutants (n = 13) (C). Selected areas of main images (scale bar: 50 μm) are noted as 1–3 in red letters, and are shown amplified separately (scale bar: 20 μm). Summary of the percentage of epithelium surface covered my mucus in proximal and distal airways (D). Only paired samples from the same animal were included; n = 13, 16, 15, and 13 for WT, Kcnn4+/+, Scnn1btg/+, and double mutants, respectively. *P < 0.05 vs. WT and Kcnn4–/– ANOVA on ranks. The P values for each proximal vs. distal airways comparison were calculated by rank-sum test.