Pharmacologic modulation of salt and water in the airway epithelium in cystic fibrosis

Abstract

Cystic fibrosis (CF) is a recessive genetic disease with thickened airway secretions that result from abnormal airway epithelial ion transport, including defective cyclic AMP-mediated Cl- (liquid) secretion and excessive Na+ (liquid) absorption. These abnormalities reflect mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which normally functions as a cyclic AMP-regulated Cl- channel. Aerosolized pharmacologic agents are being tested as novel treatment for these genetic ion transport defects. Amiloride aerosol inhibits excessive Na+ absorption, and pilot studies in adult patients with CF show improved biorheology and mucociliary clearance of airway secretions, as well as slowing of the decline in lung function. Phase III studies of amiloride in adults and adolescents are underway, and short-term safety studies in children are under way. Aerosolized uridine triphosphate (UTP) induces Cl- secretion in CF airway epithelia via non-CFTR Cl- channels. Initial safety studies suggest that acute aerosolized UTP is well tolerated, and acute studies of the effect on mucociliary clearance are underway. Pharmacotherapy that targets abnormal ion transport holds promise for the treatment of CF airway disease.