James M. Wilson, Editor ductance, and by analogy with the sweat duct (11, 12) this allows salt levels in the ASL to remain at levels similar to those in plasma. The high salt in the ASL interferes with natural antibiotics such as defensins (13) and lysozyme. In marked contrast, the low volume hypothesis (14) is based on CFTR’s function as a regulator of other channels—in this case ENaC. According to this hypothesis, both normal and CF ASL have plasma-like levels of salt. CFTR mutations eliminate CFTR’s inhibition of ENaC, and because there are significant shunt pathways for Cl–in the airways, increased Na+ transport drives increased absorption of Cl–and water. Thus CF airways display accelerated isotonic fluid absorption that depletes ASL volume and dehydrates mucus, leading to obstruction and infection (15).

How have these two disparate views arisen? The high salt hypothesis. In a clever series of experiments, Smith et al.(9) obtained airway epithelial cells from normal and CF individuals and grew them on filters until they formed monolayers of cells joined by tight junctions. Bacteria were then placed into the fluid covering the apical surfaces of the cultured cells. The dramatic finding was that bacteria flourished in their cultures of CF airway cells, but were killed by their cultures of normal cells! Bacteria placed in the media bathing the basolateral surface of the cells flourished for both kinds of cells, suggesting that normal cultured airway cells produce apical factors that kill bacteria. A further surprise occurred when the salt content of the apical fluid was manipulated. Merely adding pure water to the fluid from CF cells rendered it bactericidal; merely adding salt (NaCl) to fluid from normal cells allowed bacteria to flourish! Smith et al. concluded that both normal and CF airway epithelial cells liberate antibiotics into the ASL, but in the ASL of CF cultures the antibiotics are rendered ineffective by a higher salt concentration (9). These findings galvanized the CF community. They catapulted the field of mucosal defenses to the forefront of CF research and provided an exciting new look at the question of CF lung disease. They also posed a direct challenge to the competing hypothesis of hyperabsorption by CF airways, and helped provoke intense examination of how airways produce and condition ASL.