PHARMACOLOGICAL TREATMENT OF ABNORMAL ION-TRANSPORT IN THE AIRWAY EPITHELIUM IN CYSTIC-FIBROSIS

Cystic fibrosis (CF) is a recessive genetic disease reflecting mutatio ns in the gene coding for the CF transmembrane regulator (CFTR) protei n, which normally functions as a cyclic adenosine monophosphate (cAMP) -regulated chloride (Cl-) channel, Functional abnormalities include th ick airway secretions resulting from defective cAMP-mediated Cl- (liqu id) secretion and a related defect, excessive sodium (Na+) (liquid) ab sorption. Novel pharmacologic agents are being tested as therapy for t hese ion transport defects. Aerosolized amiloride inhibits excessive N af absorption, and pilot studies in adult patients with CF show slowin g of the disease-associated decline in lung function. Clinical trials of amiloride are currently underway in adults and adolescents, and sho rt-term safety studies have been initiated in children. Aerosolized ur idine triphosphate (UTP) induces Cl- (and liquid) secretion in CF airw ay epithelia via non-CFTR Cl- channels. Short-term aerosolized UTP is well tolerated by normal subjects and patients with CF, and pilot stud ies in normal subjects show that aerosolized UTP is an effective stimu lator of mucociliary clearance. Pharmacotherapy that modifies airway e pithelial ion transport may provide new opportunities for treatment of CF lung disease.