In the setting of CF lung disease, the absence of CFTR-mediated chloride secretion and, hence, the ability to add volume to the ASL layer in response to stimuli that signal through intracellular cAMP levels, is lost. Fortunately, CACCs partially buffer against the loss of CFTR chloride channel activity. Equally important, the inhibitory effect that CFTR exerts on ENaC is lost, and sodium/water absorption proceeds at an unregulated rate, predisposing the airway to further dehydration. The reserve capacity to secrete chloride/water afforded by ATP signaling is vulnerable to insults (eg, viral infection) that reduce the capacity to balance sodium absorption and CACC-mediated chloride secretion.23 During these insults, ion transport abnormalities manifest as PCL volume depletion and mucus layer dehydration.1 Both of these phenomena contribute to reductions in mucociliary and cough clearance, as cilial movement is restricted in PCL that is more shallow than the height of the cilia themselves, and because the mucus layer is less transportable when dehydrated and ultimately adheres to the airway surface (Fig 2, bottom left, C, and bottom right, D). Mucus stasis results, and adherent mucus is the nidus for the onset of first intermittent, and then chronic bacterial airway infection. In some models of CF pathogenesis, inherent glandular defects or inflammatory responses are believed to be key determinants of lung pathology. In any event, secondary steps of CF lung disease pathogenesis then result from the ensuing robust inflammatory response that, while failing to clear the underlying infection, destroys airway walls and lung parenchyma, ultimately leading to bronchiectasis and respiratory failure in the majority of patients.