Mechanisms of TNF-α stimulation of amiloride-sensitive sodium transport across alveolar epithelium

Norimasa Fukuda, Christian Jayr, Ahmed Lazrak, Yibing Wang, Rudolf Lucas, Sadis Matalon, Michael A. Matthay

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


Because tumor necrosis factor (TNF)-α can upregulate alveolar fluid clearance (AFC) in pneumonia or septic peritonitis, the mechanisms responsible for the TNF-α-mediated increase in epithelial fluid transport were studied. In rats, 5 μg of TNF-α in the alveolar instillate increased AFC by 67%. This increase was inhibited by amiloride but not by propranolol. We also tested a triple-mutant TNF-α that is deficient in the lectinlike tip portion of the molecule responsible for its membrane conductance effect; the mutant also has decreased binding affinity to both TNF-α receptors. The triple-mutant TNF-α did not increase AFC. Perfusion of human A549 cells, patched in the whole cell mode, with TNF-α (120 ng/ml) resulted in a sustained increase in Na+ currents from 82 ± 9 to 549 ± 146 pA (P < 0.005; n = 6). The TNF-α-elicited Na+ current was inhibited by amiloride, and there was no change when A549 cells were perfused with the triple-mutant TNF-α or after preincubation with blocking antibodies to the two TNF-α receptors before perfusion with TNF-α. In conclusion, although TNF-α can initiate acute inflammation and edema formation in the lung, TNF-α can also increase AFC by an amiloride-sensitive, cAMP-independent mechanism that enhances the resolution of alveolar edema in pathological conditions by either binding to its receptors or activating Na+ channels by means of its lectinlike domain.

Original languageEnglish (US)
Pages (from-to)L1258-L1265
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number6 24-6
StatePublished - 2001
Externally publishedYes


  • Acute lung injury
  • Alveolar epithelial cell
  • Patch clamp
  • Pneumonia
  • Pulmonary edema
  • Tumor necrosis factor receptor
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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