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A novel tumor necrosis factor–mediated mechanism of direct epithelial sodium channel activation

A novel tumor necrosis factor–mediated mechanism of direct epithelial sodium channel activation


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Prüfsumme: MD5:d40778f2318108a890c7fa783783dbf9
Prüfsumme: MD5:cee884dfd814685f1db8a2be16927d69

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

@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} }

Apell, Hans-Jürgen Kaftan, David Alli, Abdel White, Richard Apell, Hans-Jürgen Verin, Alexander Czikora, István Pittet, Jean Francois Eaton, Douglas C. Garcia-Gabay, Irène Wendel, Albrecht Chakraborty, Trinad Shabbir, Waheed A novel tumor necrosis factor–mediated mechanism of direct epithelial sodium channel activation Alli, Abdel Matthay, Michael A. Bagi, Zsolt Sridhar, Supriya eng Chakraborty, Trinad White, Richard Zimmermann, Astrid Pauly-Evers, Meike 2014-09-29T07:27:32Z Pittet, Jean Francois Kaftan, David Pauly-Evers, Meike Bao, Hui-Fang Hamacher, Jürg Gorshkov, Boris American Journal of Respiratory and Critical Care Medicine ; 190 (2014), 5. - S. 522-532 Lemmens-Gruber, Rosa Czikora, István Lazrak, Ahmed Hamacher, Jürg Shabbir, Waheed Gorshkov, Boris 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.<br />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).<br />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.<br />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.<br />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. 2014-09-01 deposit-license Lucas, Rudolf Fischer, Bernhard Sridhar, Supriya Fischer, Bernhard 2014-09-29T07:27:32Z Bao, Hui-Fang Wendel, Albrecht Verin, Alexander Lemmens-Gruber, Rosa Garcia-Gabay, Irène Bagi, Zsolt Lucas, Rudolf Zimmermann, Astrid Matthay, Michael A. Eaton, Douglas C. Lazrak, Ahmed

Dateiabrufe seit 01.10.2014 (Informationen über die Zugriffsstatistik)

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