Hyperabsorption of Na+ and raised Ca(2+)-mediated Cl- secretion in nasal epithelia of CF mice.
We investigated the effect of homozygous genetic disruption of the murine cystic fibrosis transmembrane regulator (CFTR) gene on regulation of the rates of Na+ absorption and Cl- secretion by nasal epithelia in cystic fibrosis (CF) mice. The basal in vivo nasal potential difference (PD; -28.8 +/- 1.8 mV, n = 10) and amiloride-sensitive PD (delta 13.8 +/- 1.0 mV, n = 10) were raised in CF mice compared with controls [-7.8 +/- 0.8 mV, n = 14 (basal); delta 4.5 +/- 0.7 mV, n = 14 (amiloride)], consistent with raised Na+ transport. In vitro studies of freshly excised nasal epithelia confirmed that CF epithelia exhibited a greater basal equivalent short-circuit current (Ieq; 63.5 +/- 12 microA/cm2, n = 15) vs. control (30.2 +/- 7.2 microA/cm2, n = 16) and amiloride-sensitive Ieq (delta 46.2 +/- 12.5 microA/cm2) vs. control (delta 11.3 +/- 4.5 microA/cm2). Tissue from normal mice failed to secrete Cl- in response to ionomycin (delta Ieq: -1.2 +/- 1.9 microA/cm2, n = 18), whereas CF murine tissue responded with a large rise in Ieq (delta 55.1 +/- 19.1 microA/cm2, n = 13). We conclude that CF murine nasal epithelia exhibit Na+ hyperabsorption, providing strong evidence for a regulatory link between CFTR and Na+ channel activity in airway epithelia. We speculate that upregulation of the Ca(2+)-mediated Cl- secretory pathway buffers the severity of airway disease in the CF mouse.
Grubb
B R
BR
Division of Pulmonary Diseases, University of North Carolina at Chapel Hill 27599.
Vick
R N
RN
Boucher
R C
RC
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002034:Bumetanide / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D018118:Chloride Channels / Q000235:genetics* / Q000502:physiology; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005260:Female; D006720:Homozygote; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D009297:Nasal Mucosa / Q000378:metabolism / Q000502:physiology*; D012964:Sodium / Q000378:metabolism*; D013997:Time Factors
D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D002034:Bumetanide; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D015759:Ionomycin; D000584:Amiloride; D012964:Sodium; D002118:Calcium