The CF salt controversy: In vivo observations and therapeutic approaches

There is controversy over whether abnormalities in the salt concentration o r volume of airway surface liquid (ASL) initiate cystic fibrosis (CF) airwa y disease. In vivo studies of CF mouse nasal epithelia revealed an increase in goblet cell number that was associated with decreased ASL volume rather than abnormal [Cl-]. Aerosolization of osmolytes in vivo failed to raise A SL volume. In vitro studies revealed that osmolytes and pharmacological age nts were effective in producing isotonic volume responses in human airway e pithelia but were typically short acting and less effective in CF cultures with prolonged volume hyperabsorption and mucus accumulation. These data sh ow that (1) therapies can be designed to normalize ASL volume, without prod ucing deleterious compositional changes in ASL, and (2) therapeutic efficac y will likely depend on development of long-acting pharmacologic agents and /or an increased efficiency of osmolyte delivery.