Abstract
Efficient clearance of mucus and inhaled pathogens from the lung is dependent on an optimal airway surface liquid (ASL) volume, which is maintained by the regulated transport of sodium and chloride across the airway epithelium. Accumulating evidence suggests that impaired mucus clearance in cystic fibrosis (CF) airways is a result of ASL depletion caused by excessive Na(+) absorption through the epithelial sodium channel (ENaC). However, the cellular mechanisms that result in increased ENaC activity in CF airways are not completely understood. Recently, proteases were shown to modulate the activity of ENaC, but the relevance of this mechanism to the physiologic regulation of ASL volume is unknown. Using primary human airway epithelial cells, we demonstrate that: (i) protease inhibitors are present in the ASL and prevent the activation of near-silent ENaC, (ii) when the ASL volume is increased, endogenous protease inhibitors become diluted, allowing for proteolytic activation of near-silent channels, and (iii) in CF, the normally present near-silent pool of ENaC is constitutively active and the alpha subunit undergoes increased proteolytic processing. These findings indicate that the ASL volume modulates the activity of ENaC by modification of the serine protease-protease inhibitor balance and that alterations in this balance contribute to excessive Na(+) absorption in cystic fibrosis.
Highlights
Mucociliary clearance is the primary innate defense mechanism of the conducting airways, enabling inhaled particulate matter and pathogens to be expelled (1)
Accumulating evidence indicates that mucus clearance is dependent on the presence of a thin layer of fluid, known as the airway surface liquid (ASL),2 which acts as a low viscosity medium that allows the
When the ASL volume is high, protease inhibitors would be diluted, allowing for channel-activating proteases (CAPs)-mediated activation of a pool of inactive ENaC, and a resultant increase in Naϩ and water absorption. We demonstrate that these mechanisms contribute to the regulation of ENaC activity in primary human airway epithelial cells (HAEC) and that an altered protease-protease inhibitor balance contributes to Naϩ hyperabsorption in cystic fibrosis (CF) epithelium
Summary
Using primary human airway epithelial cells, we demonstrate that: (i) protease inhibitors are present in the ASL and prevent the activation of nearsilent ENaC, (ii) when the ASL volume is increased, endogenous protease inhibitors become diluted, allowing for proteolytic activation of near-silent channels, and (iii) in CF, the normally present near-silent pool of ENaC is constitutively active and the ␣ subunit undergoes increased proteolytic processing These findings indicate that the ASL volume modulates the activity of ENaC by modification of the serine protease-protease inhibitor balance and that alterations in this balance contribute to excessive Na؉ absorption in cystic fibrosis. When the ASL volume is high, protease inhibitors would be diluted, allowing for CAP-mediated activation of a pool of inactive ENaC, and a resultant increase in Naϩ and water absorption. We demonstrate that these mechanisms contribute to the regulation of ENaC activity in primary human airway epithelial cells (HAEC) and that an altered protease-protease inhibitor balance contributes to Naϩ hyperabsorption in CF epithelium
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