Hyperabsorption of Na+ and raised Ca2+-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 (Δ13.8 ± 1.0 mV, n = 10) were raised in CF mice compared with controls [-7.8 ± 0.8 mV, n = 14 (basal); Δ4.5 ± 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 (I(eq);63.5 ± 12 μA/cm2, n = 15) vs. control (30.2 ± 7.2 μA/cm2, n = 16) and amiloride-sensitive I(eq) (Δ46.2 ± 12.5 μA/cm2) vs. control (Δ11.3 ± 4.5 μA/cm2). Tissue from normal mice failed to secrete Cl- in response to ionomycin (ΔI(eq): -1.2 ± 1.9 μA/cm2, n = 18), whereas CF murine tissue responded with a large rise in I(eq) (Δ55.1 ± 19.1 μA/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 Ca2+-mediated Cl- secretory pathway buffers the severity of airway disease in the CF mouse.