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1 Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: ray_caldwell{at}med.unc.edu.
Neutrophil elastase is a serine protease that is abundant in the airways of individuals with cystic fibrosis (CF), a genetic disease manifested by excessive airway Na+-absorption and consequent depletion of the airway surface liquid layer. Although endogenous epithelial-derived serine proteases regulate
epithelial Na+-transport, the effects of neutrophil elastase on epithelial Na+-transport and epithelial Na+-channel (ENaC) activity are unknown. Low micromolar concentrations of human neutrophil elastase (hNE) applied to the apical surface of a human bronchial cell line (16HBE14o-/
) increased Na+-transport ~2-fold. Similar effects were observed with trypsin, also a serine protease. Proteolytic inhibitors of hNE or trypsin selectively abolished the enzyme-induced increase of epithelial Na+-transport. At the level of the single channel, submicromolar concentrations of hNE increased activity of near-silent ENaC ~108-fold in patches from NIH-3T3 cells expressing rat 
-, -, and -ENaC subunits. However, no enzyme effects were observed on basally active ENaCs. Trypsin exposure following hNE revealed no additional increase in amiloridesensitive short-circuit current or in ENaC activity, suggesting these enzymes share a common mode of action for increasing Na+-transport, likely through proteolytic activation of ENaC. The hNE-induced increase of near-silent ENaC activity in CF airways could contribute to Na+-hyperabsorption, reduced airway surface liquid height, and dehydrated mucus culminating in inefficient mucociliary clearance.
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