Rational Drug Development for Mucous Dehydration and Mucous Metaplasia

Airway diseases that are clinically characterized by mucous hypersecretion are associated with dehydrated secretions and impaired mucociliary clearance. The failure to clear pro-inflammatory proteases can further exacerbate the mucous dehydration, giving rise to a positive feedback loop that produces a mucous metaplasia and lung remodeling. Increased understanding of the complex mechanisms that regulate airway hydration in health and disease is a prerequisite for rational design of novel therapies. Clinical trials of aerosolized osmolytes and of modulators of epithelial ion channels have provided support for the hypothesis that correcting mucus hydration improves clinical benefit, with the caveat that many of these agents have direct mucolytic properties that are likely to be synergistic with enhanced hydration.