The long-term goal of this project is to better define the role of normal airway epithelial ion (and water) transport in lung defense, and identify the primary (and other early) pathogenic events in CF lung disease. The overall hypothesis of this proposal is that the surface epithelia in normal airways exhibit """"""""isotonic volume absorption"""""""", and the primary pathophysiologic event in CF lung disease involves accelerated absorption of isotonic liquid, which limits the normal hydration of mucus in conduct airways. Mucus stasis ensures, with impaction in small airways and predisposition to chronic bacterial infection. We will specifically address an alternative hypothesis, which suggests that normal airways absorb ions, but not volume, and generate a hypotonic airway surface liquid (ASL). Under the """"""""hypotonic ASL"""""""" paradigm, the pathogenesis in CF airways is similar to that of the sweat duct, i.e., an inability to absorb NaCl, which results in higher concentrations of salt relative to normal, and inhibition of salt-sensitive small-peptide anti-microbial activities. We will use specific techniques in vivo, including ion-selective electrodes, to study and lower airway epithelial function and ASL composition. We will study normal subjects, CF patients (including infants and neonates), and pertinent disease-control groups, including patients with pseudohypoaldosteronism (PHA) and Sjogren's syndrome. These studies are designed to define the relative contribution of surface epithelia and SMGs to ASL metabolism, in part to test theories related to SMG dysfunction in the pathogenesis of CF airway disease. We will measure the water content (percent solids) of airway secretions in CF and normals to test the hypothesis that accelerated isotonic volume absorption leads to reduced hydration of mucus in CF. Pertinent data will also be generated that address the role of specific inflammatory or neutrophil functions in early pathogenesis. Finally, studies of BAL in CF infants and neonates will directly test whether mucus obstruction precedes infection, or whether infection occurs first.
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