Journal article

Publication year: 2014

Pages: 522-532

Journal: American Journal of Respiratory and Critical Care Medicine

Volume number: 190

Issue number: 5

ISSN: 1073-449X

eISSN: 1535-4970

Open access status: Green

DOI Link: https://doi.org/10.1164/rccm.201405-0833OC

Publisher: American Thoracic Society

Abstract: 

Rationale: Alveolar liquid clearance is regulated by Na+ uptake through the apically expressed epithelial sodium channel (ENaC) and basolaterally localized Na+-K+-ATPase in type II alveolar epithelial cells. Dysfunction of these Na+ transporters during pulmonary inflammation can contribute to pulmonary edema.

Objectives: In this study, we sought to determine the precise mechanism by which the TIP peptide, mimicking the lectin-like domain of tumor necrosis factor (TNF), stimulates Na+ uptake in a homologous cell system in the presence or absence of the bacterial toxin pneumolysin (PLY).

Methods: We used a combined biochemical, electrophysiological, and molecular biological in vitro approach and assessed the physiological relevance of the lectin-like domain of TNF in alveolar liquid clearance in vivo by generating triple-mutant TNF knock-in mice that express a mutant TNF with deficient Na+ uptake stimulatory activity.

Measurements and Main Results: TIP peptide directly activates ENaC, but not the Na+-K+-ATPase, upon binding to the carboxyterminal domain of the a subunit of the channel. In the presence of PLY, a mediator of pneumococcal-induced pulmonary edema, this binding stabilizes the ENaC-PIP2-MARCKS complex, which is necessary for the open probability conformation of the channel and preserves ENaC-alpha protein expression, by means of blunting the protein kinase C-alpha pathway. Triple-mutant TNF knock-in-mice are more prone than wild-type mice to develop edema with low-dose intratracheal PLY, correlating with reduced pulmonary ENaC-alpha subunit expression.

Conclusions: These results demonstrate a novel TNF-mediated mechanism of direct ENaC activation and indicate a physiological role for the lectin-like domain of TNF in the resolution of alveolar edema during inflammation.

Harvard Citation style: Czikora, I., Alli, A., Bao, H., Kaftan, D., Sridhar, S., Apell, H., et al. (2014) A Novel Tumor Necrosis Factor-mediated Mechanism of Direct Epithelial Sodium Channel Activation, American Journal of Respiratory and Critical Care Medicine, 190(5), pp. 522-532. https://doi.org/10.1164/rccm.201405-0833OC

APA Citation style: Czikora, I., Alli, A., Bao, H., Kaftan, D., Sridhar, S., Apell, H., Gorshkov, B., White, R., Zimmermann, A., Wendel, A., Pauly-Evers, M., Hamacher, J., Garcia-Gabay, I., Fischer, B., Verin, A., Bagi, Z., Pittet, J., Shabbir, W., Lemmens-Gruber, R., ...Lucas, R. (2014). A Novel Tumor Necrosis Factor-mediated Mechanism of Direct Epithelial Sodium Channel Activation. American Journal of Respiratory and Critical Care Medicine. 190(5), 522-532. https://doi.org/10.1164/rccm.201405-0833OC