Type of Publication: | Journal article |
URI (citable link): | http://nbn-resolving.de/urn:nbn:de:bsz:352-290230 |
Author: | Czikora, István; Alli, Abdel; Bao, Hui-Fang; Kaftan, David; Sridhar, Supriya; Apell, Hans-Jürgen; Gorshkov, Boris; White, Richard; Zimmermann, Astrid; Wendel, Albrecht; Pauly-Evers, Meike; Hamacher, Jürg; Garcia-Gabay, Irène; Fischer, Bernhard; Verin, Alexander; Bagi, Zsolt; Pittet, Jean Francois; Shabbir, Waheed; Lemmens-Gruber, Rosa; Chakraborty, Trinad; Lazrak, Ahmed; Matthay, Michael A.; Eaton, Douglas C.; Lucas, Rudolf |
Year of publication: | 2014 |
Published in: | American Journal of Respiratory and Critical Care Medicine ; 190 (2014), 5. - pp. 522-532. - ISSN 1073-449X. - eISSN 1535-4970 |
Pubmed ID: | 25029038 |
DOI (citable link): | https://dx.doi.org/10.1164/rccm.201405-0833OC |
Summary: |
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 carboxy-terminal domain of the α 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-α protein expression, by means of blunting the protein kinase C-α 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-α 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. |
Subject (DDC): | 610 Medicine |
Link to License: | In Copyright |
Bibliography of Konstanz: | Yes |
CZIKORA, István, Abdel ALLI, Hui-Fang BAO, David KAFTAN, Supriya SRIDHAR, Hans-Jürgen APELL, Boris GORSHKOV, Richard WHITE, Astrid ZIMMERMANN, Albrecht WENDEL, Meike PAULY-EVERS, Jürg HAMACHER, Irène GARCIA-GABAY, Bernhard FISCHER, Alexander VERIN, Zsolt BAGI, Jean Francois PITTET, Waheed SHABBIR, Rosa LEMMENS-GRUBER, Trinad CHAKRABORTY, Ahmed LAZRAK, Michael A. MATTHAY, Douglas C. EATON, Rudolf LUCAS, 2014. A novel tumor necrosis factor–mediated mechanism of direct epithelial sodium channel activation. In: American Journal of Respiratory and Critical Care Medicine. 190(5), pp. 522-532. ISSN 1073-449X. eISSN 1535-4970. Available under: doi: 10.1164/rccm.201405-0833OC
@article{Czikora2014-09-01novel-29023, title={A novel tumor necrosis factor–mediated mechanism of direct epithelial sodium channel activation}, year={2014}, doi={10.1164/rccm.201405-0833OC}, number={5}, volume={190}, issn={1073-449X}, journal={American Journal of Respiratory and Critical Care Medicine}, pages={522--532}, author={Czikora, István and Alli, Abdel and Bao, Hui-Fang and Kaftan, David and Sridhar, Supriya and Apell, Hans-Jürgen and Gorshkov, Boris and White, Richard and Zimmermann, Astrid and Wendel, Albrecht and Pauly-Evers, Meike and Hamacher, Jürg and Garcia-Gabay, Irène and Fischer, Bernhard and Verin, Alexander and Bagi, Zsolt and Pittet, Jean Francois and Shabbir, Waheed and Lemmens-Gruber, Rosa and Chakraborty, Trinad and Lazrak, Ahmed and Matthay, Michael A. and Eaton, Douglas C. and Lucas, Rudolf} }
Czikora_290230.pdf | 512 |
Czikora_290230_Suppl.pdf | 195 |