cAMP triggers Na+ absorption by distal airway surface epithelium in cystic fibrosis swine

Abstract

A controversial hypothesis pertaining to cystic fibrosis (CF) lung disease is that the CF transmembrane conductance regulator (CFTR) channel fails to inhibit the epithelial Na⁺ channel (ENaC), yielding increased Na⁺ reabsorption and airway dehydration. We use a non-invasive self-referencing Na⁺-selective microelectrode technique to measure Na⁺ transport across individual folds of distal airway surface epithelium preparations from CFTR^-/- (CF) and wild-type (WT) swine. We show that, under unstimulated control conditions, WT and CF epithelia exhibit similar, low rates of Na⁺ transport that are unaffected by the ENaC blocker amiloride. However, in the presence of the cyclic AMP (cAMP)-elevating agents forskolin+IBMX (isobutylmethylxanthine), folds of WT tissues secrete large amounts of Na⁺, while CFTR^-/- tissues absorb small, but potentially important, amounts of Na⁺. In cAMP-stimulated conditions, amiloride inhibits Na⁺ absorption in CFTR^-/- tissues but does not affect secretion in WT tissues. Our results are consistent with the hypothesis that ENaC-mediated Na⁺ absorption may contribute to dehydration of CF distal airways.

Keywords: CF; CFTR; ENaC; airway dehydration; cystic fibrosis; distal airways.