| Epithelial sodium channels (ENaC) are located throughout the lining of the respiratory tract and play a crucial role in ion and fluid homeostasis. Increasing ENaC activity through stimulation of β2-adrenergic receptors increases sodium and fluid reabsorption from the airspace. In cystic fibrosis lung disease there is a hyperabsorption of sodium through ENaC which results in dehydration of the airway surface liquid. Previous work has identified a common functional genetic variant of SCNN1A, the gene encoding the ENaC alpha-subunit. This variant manifests as an alanine to threonine substitution at amino acid 663 (T663), with the T663 variant resulting in a more active channel. We studied the influence of the T663 variant on exhaled ions, pulmonary function, and the diffusing capacity of the lungs in healthy subjects and in patients with cystic fibrosis. We used exercise, an endogenous β 2-adrenergic agonist, and albuterol, an exogenous β2-adrenergic agonist, to stimulate ENaC activity. Healthy subjects with the alanine variant (A663) had higher baseline exhaled sodium and a significant decrease in exhaled sodium by 90 minutes after albuterol administration, suggesting a removal of sodium from the airways. No changes in exhaled sodium were seen in the T663 variant. In response to exercise the A663 variant had a greater increase in the diffusing capacity of the lung than the T663 variant. Taken together these results suggest that individuals with the T663 variant have a diminished capacity for increasing ENaC activity in response to β2-adrenergic stimulation. In CF patients, the T663 variant had significantly lower baseline pulmonary function, weight, and body mass index. In response to exercise, patients with the T663 variant had a greater increase in the diffusing capacity of the lungs. Finally, we recruited additional CF patients to confirm our findings. Individuals with the T663 variant had significantly lower body mass index, and tended to have lower exhaled chloride and pulmonary function. Overall, these results may suggest that the T663 variant modifies disease severity and may potentiate the pathological drying of the airways in CF. |
