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Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease
Génesis Vega, … , Marcus A. Mall, Carlos A. Flores
Génesis Vega, … , Marcus A. Mall, Carlos A. Flores
Published August 20, 2020
Citation Information: JCI Insight. 2020;5(16):e140076. https://doi.org/10.1172/jci.insight.140076.
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Research Article Inflammation Pulmonology

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

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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 1

KCa3.1 participates in sodium absorption and anion secretion of mouse and human epithelium.

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KCa3.1 participates in sodium absorption and anion secretion of mouse an...
Representative short-circuit current traces of (A) WT and (B) Kcnn4–/– mouse tracheae used to calculate the following: (C) Vte, (D) Rte, (E) ISC, (F) Amiloride-sensitive current, (G) amiloride-insensitive current, (H) cAMP-induced anion current and Ca+2-activated anion current at (I) peak or (J) plateau phases; n = 9 for each group. (K) Representative Ussing chamber recordings of HBECs incubated with TRAM-34 and controls showing amiloride addition. (L) Summary of TRAM-34 effect on amiloride-sensitive Na+ absorption; n = 6 different cell cultures for each condition. Statistical differences were calculated using rank-sum test. Detailed values including data for Kcne3–/– are included in Table 1.

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