HYPERABSORPTION OF NA-MEDIATED CL- SECRETION IN NASAL EPITHELIA OF CFMICE( AND RAISED CA2+)

We investigated the effect of homozygous genetic disruption of the mur ine 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 differen ce (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 (amilori de)], consistent with raised Na+ transport. In vitro studies of freshl y excised nasal epithelia confirmed that CF epithelia exhibited a grea ter basal equivalent short-circuit current (I-eq; 63.5 +/- 12 mu A/cm2 , n = 15) vs. control (30.2 +/- 7.2 mu A/cm(2), n = 16) and amiloride- sensitive I-eq (Delta 46.2 +/- 12.5 mu A/cm(2)) vs. control (Delta 11. 3 +/- 4.5 mu A/cm(2)). Tissue from normal mice failed to secrete Cl- i n response to ionomycin (Delta I-eq: -1.2 +/- 1.9 mu A/cm(2), n = 18), whereas CF murine tissue responded with a large rise in I-eq (Delta 5 5.1 +/- 19.1 mu A/cm(2), n = 13). We conclude that CF murine nasal epi thelia exhibit Na+ hyperabsorption, providing strong evidence for a re gulatory link between CFTR and Na+ channel activity in airway epitheli a. We speculate that upregulation of the Ca2+-mediated Cl- secretory p athway buffers the severity of airway disease in the CF mouse.