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

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

doi:10.1172/jci.insight.140076

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.

Highlights

Mucociliary clearance (MCC) is a key process, which sustains airway innate defense, and its proper function relies on coordinate regulation of epithelial ion and fluid transport, mucus homeostasis, and ciliary beating [1, 2]
We observed that the transepithelial potential (Vte) was significantly reduced in the Kcnn4–/– trachea when compared with WT trachea (Figure 1C)
We tested if the silencing of another K+ channel, the KCNQ1/KCNE3, that is important for anion secretion affected Na+ absorption using Kcne3–/– tracheae, but we observed no changes (Table 1)

Summary

Introduction

Mucociliary clearance (MCC) is a key process, which sustains airway innate defense, and its proper function relies on coordinate regulation of epithelial ion and fluid transport, mucus homeostasis, and ciliary beating [1, 2]. Disruption of any of these epithelial functions reduces airway clearance capacity, as observed in asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis or primary ciliary dyskinesia, all lung diseases characterized by mucus accumulation, airway obstruction, infections, and progressive bronchiectasis [3,4,5]. The absence of chloride secretion into the airway lumen dehydrates the airway surface liquid (ASL) and impairs cilia movement, whereas absent HCO3– secretion (that can be secondary to Cl–/HCO3– exchange or directly through CFTR) affects mucins deployment, making it sticky and hard to transport. Reduced HCO3– secretion produces acidic pH, which in turn decreases activity of ASL antimicrobial molecules, favoring infection settlement [7]

Objectives

Methods

Results

Conclusion