Chest
Volume 107, Issue 2, Supplement, February 1995, Pages 71S-76S
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Pharmacologic Treatment of Abnormal Ion Transport in the Airway Epithelium in Cystic Fibrosis

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Cystic fibrosis (CF) is a recessive genetic disease reflecting mutations in the gene coding for the CF transmembrane regulator (CFTR) protein, which normally functions as a cyclic adenosine monophosphate (cAMP)-regulated chloride (Cl) channel. Functional abnormalities include thick airway secretions resulting from defective cAMP-mediated Cl (liquid) secretion and a related defect, excessive sodium (Na+) (liquid) absorption. Novel pharmacologic agents are being tested as therapy for these ion transport defects. Aerosolized amiloride inhibits excessive Na+ absorption, and pilot studies in adult patients with CF show slowing of the disease-associated decline in lung function. Clinical trials of amiloride are currently underway in adults and adolescents, and short-term safety studies have been initiated in children. Aerosolized uridine triphosphate (UTP) induces Cl (and liquid) secretion in CF airway epithelia via non-CFTR Cl channels. Short-term aerosolized UTP is well tolerated by normal subjects and patients with CF, and pilot studies in normal subjects show that aerosolized UTP is an effective stimulator of mucociliary clearance. Pharmacotherapy that modifies airway epithelial ion transport may provide new opportunities for treatment of CF lung disease.

Section snippets

NORMAL AIRWAY EPITHELIAL ION TRANSPORT PHYSIOLOGY

Studies of freshly excised and cultured airway epithelia indicate that active sodium (Na+) absorption is the dominant ion flow across mammalian airway epithelia under basal conditions6, 7 (Fig 1). This active absorption of Na+ provides the driving force for absorption of airway surface liquid. Liquid secretion does not occur in airway epithelia under basal conditions, although liquid (chloride [Cl]) secretion can occur under certain circumstances (see below). The transepithelial absorption of

ABNORMAL AIRWAY EPITHELIAL ION TRANSPORT IN CF

Airway epithelia of patients with CF have defective ion transport that contributes to abnormally thickened airway secretions and predisposes to chronic bacterial infection. Cystic fibrosis airway epithelia exhibit excessive absorption of Na+ (and liquid) that is twofold to threefold greater than normal airway epithelia4, 14, 15, 16 (Fig 2). There is also limited ability to secrete Cl via the CFTR protein (Cl channel) in response to cAMP-mediated stimulation,2, 16, 17, 18 although it should be

PHARMACOTHERAPY OF INCREASED NA+ ABSORPTION ACROSS CF AIRWAY EPITHELIA

Amiloride inhibits Na+ transport across airway epithelia in normal subjects and patients with CF6, 14, 15 (Fig 1 and 2). This effect of amiloride led to the hypothesis that aerosolized amiloride might inhibit excessive Na+ absorption in patients with CF and thereby improve the biorheology and clearance of airway secretions.14 Mucociliary clearance was improved after short-term and repetitive dosing of aerosolized amiloride, as compared with the effects of vehicle.19, 21 Early studies

PHARMACOTHERAPY OF DEFECTIVE CL SECRETION ACROSS CF AIRWAY EPITHELIA

Treatment of abnormal Na+ transport with aerosolized amiloride is not fully protective against the decline in lung function in adult patients with CF, and recent studies have focussed on therapy that targets the defective Cl (liquid) secretion. Triphosphate nucleotides (adenosine triphosphate [ATP] and uridine triphosphate [UTP]) activate Cl secretion in human airway epithelia in vitro and in vivo via extracellular 5’-nucleotide receptors.29, 30, 31 After pretreatment with amiloride, addition

CONCLUSIONS

Abnormal ion transport across airway epithelia of patients with CF provides the rationale for drug therapy with agents that modulate ion transport. In adult patients with CF, aerosolized amiloride inhibits excessive Na+ absorption, improves biorheology and mucociliary clearance of airway secretions, and may retard the decline of lung function. Pilot studies in children with CF suggest that effective doses of amiloride may be delivered to the lower airways by aerosol without excessive systemic

ACKNOWLEDGMENTS

We thank L. Brown for assistance in preparation of this manuscript.

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