Slippery When Wet: Airway Surface Liquid Homeostasis and Mucus Hydration

The ability to regulate cell volume is crucial for normal physiology; equally the regulation of extracellular fluid homeostasis is of great importance. Alteration of normal extracellular fluid homeostasis contributes to the development of several diseases including cystic fibrosis. With regard to the airway surface liquid (ASL), which lies apically on top of airway epithelia, ion content, pH, mucin and protein abundance must be tightly regulated. Furthermore, airway epithelia must be able to switch from an absorptive to a secretory state as required. A heterogeneous population of airway epithelial cells regulate ASL solute and solvent composition, and directly secrete large mucin molecules, antimicrobials, proteases and soluble mediators into the airway lumen. This review focuses on how epithelial ion transport influences ASL hydration and ASL pH, with a specific focus on the roles of anion and cation channels and exchangers. The role of ions and pH in mucin expansion is also addressed. With regard to fluid volume regulation, we discuss the roles of nucleotides, adenosine and the short palate lung and nasal epithelial clone 1 (SPLUNC1) as soluble ASL mediators. Together, these mechanisms directly influence ciliary beating and in turn mucociliary clearance to maintain sterility and to detoxify the airways. Whilst all of these components are regulated in normal airways, defective ion transport and/or mucin secretion proves detrimental to lung homeostasis as such we address how defective ion and fluid transport, and a loss of homeostatic mechanisms, contributes to the development of pathophysiologies associated with cystic fibrosis.