Chest
Pharmacologic Treatment of Abnormal Ion Transport in the Airway Epithelium in Cystic Fibrosis
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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2002, Journal of PediatricsCitation Excerpt :Short of inserting a healthy gene or chaperoning the CFTR protein to the cell membrane, it may be possible to improve the ion transport properties of epithelial cells. Amiloride decreases the absorption of sodium in CF cells,51 whereas UTP increases chloride transport through non-CFTR channels.51 Clinical trials of UTP analogs are under way.
Supported by grants HL34322, NIH R00046, CFF R026, and CFF A592 from the National Institutes of Health, Bethesda, Md.