Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport

Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L813-9. doi: 10.1152/ajplung.00435.2004. Epub 2005 Jan 7.


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 epithelium-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-/beta gamma) increased Na(+) transport about twofold. 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 approximately 108-fold in patches from NIH-3T3 cells expressing rat alpha-, beta-, and gamma-ENaC subunits. However, no enzyme effects were observed on basally active ENaCs. Trypsin exposure following hNE revealed no additional increase in amiloride-sensitive 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bronchi / cytology
  • Epithelial Sodium Channels
  • Humans
  • Ion Channel Gating / drug effects*
  • Ion Channel Gating / physiology
  • Leukocyte Elastase / pharmacology*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • NIH 3T3 Cells
  • Patch-Clamp Techniques
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / physiology*
  • Sodium / metabolism*
  • Sodium Channels / physiology*
  • Trypsin / pharmacology


  • Epithelial Sodium Channels
  • Sodium Channels
  • Sodium
  • Leukocyte Elastase
  • Trypsin