Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease
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 k...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2020-08-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.140076 |
| _version_ | 1818362191196192768 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Génesis Vega |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T21:28:39Z |
| format | Article |
| id | doaj.art-2f2d753697e0401fbc6275362b8638fb |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-13T21:28:39Z |
| publishDate | 2020-08-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-2f2d753697e0401fbc6275362b8638fb2022-12-21T23:30:53ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-08-01516Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung diseaseGénesis VegaAnita GuequénAmber R. PhilpAmbra GianottiLlilian ArzolaManuel VillalónOlga Zegarra-MoranLuis J.V. GaliettaMarcus A. MallCarlos A. FloresAirway 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.https://doi.org/10.1172/jci.insight.140076InflammationPulmonology |
| spellingShingle | 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 Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease JCI Insight Inflammation Pulmonology |
| title | Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease |
| title_full | Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease |
| title_fullStr | Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease |
| title_full_unstemmed | Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease |
| title_short | Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease |
| title_sort | lack of kcnn4 improves mucociliary clearance in muco obstructive lung disease |
| topic | Inflammation Pulmonology |
| url | https://doi.org/10.1172/jci.insight.140076 |
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