Airway surface liquid volume regulation determines different airway phenotypes in liddle compared with betaENaC-overexpressing mice

J Biol Chem. 2010 Aug 27;285(35):26945-26955. doi: 10.1074/jbc.M110.151803. Epub 2010 Jun 21.


Studies in cystic fibrosis patients and mice overexpressing the epithelial Na(+) channel beta-subunit (betaENaC-Tg) suggest that raised airway Na(+) transport and airway surface liquid (ASL) depletion are central to the pathogenesis of cystic fibrosis lung disease. However, patients or mice with Liddle gain-of-function betaENaC mutations exhibit hypertension but no lung disease. To investigate this apparent paradox, we compared the airway phenotype (nasal versus tracheal) of Liddle with CFTR-null, betaENaC-Tg, and double mutant mice. In mouse nasal epithelium, the region that functionally mimics human airways, high levels of CFTR expression inhibited Liddle epithelial Nat channel (ENaC) hyperfunction. Conversely, in mouse trachea, low levels of CFTR failed to suppress Liddle ENaC hyperfunction. Indeed, Na(+) transport measured in Ussing chambers ("flooded" conditions) was raised in both Liddle and betaENaC-Tg mice. Because enhanced Na(+) transport did not correlate with lung disease in these mutant mice, measurements in tracheal cultures under physiologic "thin film" conditions and in vivo were performed. Regulation of ASL volume and ENaC-mediated Na(+) absorption were intact in Liddle but defective in betaENaC-Tg mice. We conclude that the capacity to regulate Na(+) transport and ASL volume, not absolute Na(+) transport rates in Ussing chambers, is the key physiologic function protecting airways from dehydration-induced lung disease.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Epithelial Sodium Channels / biosynthesis*
  • Epithelial Sodium Channels / genetics
  • Gene Expression Regulation*
  • Humans
  • Ion Transport / genetics
  • Liddle Syndrome / metabolism*
  • Liddle Syndrome / pathology
  • Mice
  • Mice, Knockout
  • Mutation*
  • Nasal Mucosa / metabolism
  • Nasal Mucosa / pathology
  • Organ Culture Techniques
  • Sodium / metabolism*
  • Trachea / metabolism
  • Trachea / pathology


  • Epithelial Sodium Channels
  • Scnn1b protein, mouse
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Sodium