Lack ofKcnn4improves mucociliary clearance in muco-obstructive lung disease

Abstract

Airway mucociliary clearance (MCC) is the main mechanism of lung defense keeping the airways free of infection and mucus obstruction. Airways surface liquid (ASL) volume, ciliary beating and mucus are central for proper MCC, and are critically regulated by sodium (Na + ) absorption and anion secretion. Impaired MCC is a key feature of muco-obstructive disease. The calcium-activated potassium (K + )channel KCa.3.1, encoded by the Kcnn4 gene, participates in intestinal ion secretion and previous studies showed that its activation increase Na + absorption in airway epithelia, suggesting that hyperpolarization induced by KCa3.1 was sufficient to drive Na + absorption.However, its role in airway epithelial function is not fully understood. We therefore aimed to elucidate the role of KCa3.1 in MCC in a genetically engineered mouse model. We show that KCa3.1 inhibition reduced Na + absorption in mouse and human airway epithelium. Furthermore, the genetic deletion of Kcnn4 enhanced cilia beating frequency (CBF) and MCC ex vivo and in vivo.Kcnn4 was silenced in the Scnn1b-transgenic mouse (Scnn1b tg/+ ), a model of muco-obstructive lung disease triggered by increased epithelial Na + -absorption, leading to improvements in MCC and reduction of Na + -absorption. KCa3.1 deletion 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 Scnn1b tg/+ mice. K + -channel modulation may be a novel therapeutic strategy to treat muco-obstuctive lung diseases.

CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A

“…Activation of KCNN4 is essential to maintain the electrical driving force for Cl − secretion during Ca 2+ —dependent stimulation. Thus, we would disagree with a recent report that claims inhibition of KCNN4 to reduce Na + absorption and to improve mucociliary clearance in patients with cystic fibrosis [ 42 ]. In fact, ASL in human airways relies essentially on submucosal gland secretion, which essentially need KCNN4.…”