1. V-Type ATPase Mediates Airway Surface Liquid Acidification in Pig Small Airway Epithelial Cells.
- Author
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Li X, Villacreses R, Thornell IM, Noriega J, Mather S, Brommel CM, Lu L, Zabner A, Ehler A, Meyerholz DK, Stoltz DA, and Zabner J
- Subjects
- Animals, Animals, Genetically Modified, Cystic Fibrosis genetics, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Female, Hydrogen-Ion Concentration, Male, Swine, Vacuolar Proton-Translocating ATPases antagonists & inhibitors, Vacuolar Proton-Translocating ATPases genetics, Bicarbonates metabolism, Cystic Fibrosis metabolism, Epithelial Cells metabolism, Respiratory Mucosa metabolism, Vacuolar Proton-Translocating ATPases metabolism
- Abstract
In a newborn pig cystic fibrosis (CF) model, the ability of gland-containing airways to fight infection was affected by at least two major host-defense defects: impaired mucociliary transport and a lower airway surface liquid (ASL) pH. In the gland-containing airways, the ASL pH is balanced by CFTR (CF transmembrane conductance regulator) and ATP12A, which, respectively, control HCO
3 - transport and proton secretion. We found that, although porcine small airway tissue expressed lower amounts of ATP12A, the ASL of epithelial cultures from CF distal small airways (diameter < 200 μm) were nevertheless more acidic (compared with non-CF airways). Therefore, we hypothesized that gland-containing airways and small airways control acidification using distinct mechanisms. Our microarray data suggested that small airway epithelia mediate proton secretion via ATP6V0D2, an isoform of the V0 d subunit of the H+ -translocating plasma membrane V-type ATPase. Immunofluorescence of small airways verified the expression of the V0 d2 subunit isoform at the apical surface of Muc5B+ secretory cells, but not ciliated cells. Inhibiting the V-type ATPase with bafilomycin A1 elevated the ASL pH of small airway cultures, in the presence or absence of HCO3 - , and decreased ASL viscosity. These data suggest that, unlike large airways, which are acidified by ATP12A activity, small airways are acidified by V-type ATPase, thus identifying V-type ATPase as a novel therapeutic target for small airway diseases.- Published
- 2021
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