Fig. 3

Ion transport generates the airway surface liquid height. Sodium ion absorption and chloride ion secretion generate an osmotic gradient for water flux across the airway epithelium. In healthy airways, the transepithelial transport of Na⁺ and Cl⁻ is balanced so as to generate an optimal ASLh between 7 and 10 µm corresponding to the length of outstretched cilia. Sodium absorption occurs as a two-step process with sodium entry via ENaC Na⁺ channels in the apical membranes and then Na⁺ is pumped out of the cells into the blood side via Na/K-ATPase in the basolateral membranes. The electrical charge balance for Na⁺ absorption is generated by the activity of KATP (Kir6.1) potassium ion channels in the basolateral membranes. Inhibition of any one of these transporters (ENaC, Na/K-ATPase, KATP) will tend to decrease sodium and water absorption, and as a consequence increase ASLh, whereas stimulation of the Na⁺ transport pathways will decrease ASLh. Chloride ion secretion also occurs as a two-step process, with Cl⁻ entering the airway epithelial cell across the basolateral membranes via the Na:K:2Cl cotransporter and then transported down an electrochemical gradient into the ASL via CFTR Cl⁻ channels which support basal and cAMP-stimulated Cl⁻ secretion. Calcium-activated CaCC Cl⁻ channels are the pathway for calcium-activated Cl⁻ secretion. The charge balance for CFTR-mediated Cl⁻ secretion is provided by the cAMP activated KCNQ1:KCNE3 K⁺ channel, and for CaCC channels via calcium-activated KCNN4 K⁺ channels. Inhibition of any one the chloride ion secretion pathways will decrease water flux into the ASL and reduce ASLh, whereas stimulation of chloride ion secretion transporters will increase ASLh