Downregulation of ENaC activity and expression by TNF-alpha in alveolar epithelial cells.
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.
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D053503:Epithelial Sodium Channels; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000166:cytology / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004232:Diuretics; D053503:Epithelial Sodium Channels; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D015222:Sodium Channels; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D000584:Amiloride; D012964:Sodium