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    Epithelial Sodium Channel Polymorphism Influences Lung Function

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    Author
    Baker, Sarah Elizabeth
    Issue Date
    2013
    Keywords
    ENaC
    Lung Fluid Balance
    Modifying Genes
    SNP
    Physiological Sciences
    Cystic Fibrosis
    Advisor
    Snyder, Eric M.
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Epithelial sodium channels (ENaC) are located throughout the epithelial lining of the respiratory tract and play a crucial role in ion and fluid homeostasis of the lungs. Increasing ENaC activity through stimulation of β₂-adrenergic receptors has been shown to increase sodium and fluid reabsorption from the airspace to the interstitial space. 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 due to a greater number of channels in the membrane. We sought to determine the influence of the T663 variant on exhaled ions, pulmonary function, and the diffusing capacity of the lungs in healthy subjects as well as in patients with cystic fibrosis. We used exercise, which can increase endogenous epinephrine by up to 1000 fold at peak exercise, and albuterol, an exogenous β₂-adrenergic agonist, to stimulate ENaC activity. In healthy individuals we hypothesized that the T663 variant would be beneficial for lung function due to a greater fluid removal, which could improve gas transfer in a healthy lung. In the CF patients we predicted that the T663 variant would be detrimental to lung function due to an exaggerated absorption of sodium and drying/thickening of the mucus layer in the airways. Measurements of exhaled sodium were made in the healthy subjects at baseline, 30, 60, and 90 minutes post-albuterol administration. Subjects with the A663 variant had higher baseline exhaled sodium and a significant decrease in exhaled sodium by 90 minutes after β₂-adrenergic stimulation with albuterol, suggesting a removal of sodium from the airways. No changes in exhaled sodium were seen in the T663 variant in response to albuterol. In response to exercise the A663 variant had a greater increase in the diffusing capacity of the lung than the T663 variant, possibly due to differences in alveolar sodium and therefore fluid handling. Taken together, these results suggest that healthy humans with the A663 variant can increase ENaC activity in response to β₂-adrenergic stimulation, whereas 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, possibly due to purinergic inhibition of ENaC. Finally, we recruited additional CF patients to confirm our pulmonary function findings. Individuals with at least one allele resulting in the T663 variant had significantly lower body mass index, and tended to have lower exhaled chloride and pulmonary function. These results suggest greater dehydration of the lung in CF patients with the T663 variant. Overall, these results may suggest that the T663 variant modifies disease severity in CF, although more work is certainly warranted to confirm this result.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Physiological Sciences
    Degree Grantor
    University of Arizona
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