Downregulation of ENaC activity and expression by TNF-alpha in alveolar epithelial cells

Am J Physiol Lung Cell Mol Physiol. 2004 Feb;286(2):L301-11. doi: 10.1152/ajplung.00326.2002. Epub 2003 Sep 26.


Sodium absorption by an amiloride-sensitive channel is the main driving force of lung liquid clearance at birth and lung edema clearance in adulthood. In this study, we tested whether tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine involved in several lung pathologies, could modulate sodium absorption in cultured alveolar epithelial cells. We found that TNF-alpha decreased the expression of the alpha-, beta-, and gamma-subunits of epithelial sodium channel (ENaC) mRNA to 36, 43, and 16% of the controls after 24-h treatment and reduced to 50% the amount of alpha-ENaC protein in these cells. There was no impact, however, on alpha(1) and beta(1) Na(+)-K(+)-ATPase mRNA expression. Amiloride-sensitive current and ouabain-sensitive Rb(+) uptake were reduced, respectively, to 28 and 39% of the controls. A strong correlation was found at different TNF-alpha concentrations between the decrease of amiloride-sensitive current and alpha-ENaC mRNA expression. All these data show that TNF-alpha, a proinflammatory cytokine present during lung infection, has a profound influence on the capacity of alveolar epithelial cells to transport sodium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amiloride / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Dactinomycin / pharmacology
  • Diuretics / pharmacology
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Epithelial Sodium Channels
  • Gene Expression / drug effects
  • Male
  • Membrane Potentials / drug effects
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / physiology*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / physiology*
  • Sodium / metabolism
  • Sodium Channels / genetics*
  • Sodium Channels / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Antineoplastic Agents
  • Diuretics
  • Epithelial Sodium Channels
  • Nucleic Acid Synthesis Inhibitors
  • RNA, Messenger
  • Sodium Channels
  • Tumor Necrosis Factor-alpha
  • Dactinomycin
  • Amiloride
  • Sodium