New Concepts of the Pathogenesis of Cystic Fibrosis Lung Disease

Although there has been impressive progress in the elucidation of the genetic and molecular basis of cystic fibrosis (CF), the pathogenesis of CF lung disease remains obscure. The elucidation of the pathogenesis of CF lung disease requires both a full description of normal innate airway defence and how absent function of the cystic fibrosis transmembrane regulator protein (CFTR) adversely perturbs this activity. Recent data have linked the abnormal ion transport properties of CF airway epithelia to depleted airway surface liquid (ASL) volume, reflecting the combined defects of accelerated Na+ transport and the failure to secrete Cl-. Depletion of a specific compartment of the ASL, i.e. the periciliary liquid (PCL), appears to abrogate both cilia-dependent and cough clearance. Subsequent to PCL depletion, mucus adheres to airway surfaces and persistent mucin secretion generates the formation of "thickened" mucus plaques and plugs, which become the nidus for bacterial infection. The paucity of liquid in these plaques/plugs, and the hypoxia in this environment, appear to promote biofilm bacterial infection. Therapeutic agents that restore airway surface liquid volume, i.e. blockers of Na+ transport, initiators of Cl- transport and osmolytes, are reviewed, as are strategies that may be required to use volume-restoring agents safely in patients with cystic fibrosis.