@article{Czikora2014-09-01novel-29023,
  year={2014},
  doi={10.1164/rccm.201405-0833OC},
  title={A novel tumor necrosis factor–mediated mechanism of direct epithelial sodium channel activation},
  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}
}

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    <dc:creator>Eaton, Douglas C.</dc:creator>
    <dc:creator>Lemmens-Gruber, Rosa</dc:creator>
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    <dc:contributor>Pittet, Jean Francois</dc:contributor>
    <dc:creator>Fischer, Bernhard</dc:creator>
    <dc:creator>Alli, Abdel</dc:creator>
    <dc:contributor>Verin, Alexander</dc:contributor>
    <dc:creator>Wendel, Albrecht</dc:creator>
    <dc:creator>Gorshkov, Boris</dc:creator>
    <dc:creator>Chakraborty, Trinad</dc:creator>
    <dc:contributor>Hamacher, Jürg</dc:contributor>
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    <dc:contributor>Wendel, Albrecht</dc:contributor>
    <dc:contributor>Lazrak, Ahmed</dc:contributor>
    <dc:contributor>Gorshkov, Boris</dc:contributor>
    <dc:creator>Zimmermann, Astrid</dc:creator>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2014-09-29T07:27:32Z</dc:date>
    <dc:contributor>Garcia-Gabay, Irène</dc:contributor>
    <dc:contributor>Kaftan, David</dc:contributor>
    <dc:creator>Czikora, István</dc:creator>
    <dc:contributor>Alli, Abdel</dc:contributor>
    <dc:contributor>Bagi, Zsolt</dc:contributor>
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    <dc:contributor>Matthay, Michael A.</dc:contributor>
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    <dc:contributor>Zimmermann, Astrid</dc:contributor>
    <dc:contributor>White, Richard</dc:contributor>
    <dc:contributor>Lemmens-Gruber, Rosa</dc:contributor>
    <dc:contributor>Czikora, István</dc:contributor>
    <dc:creator>Pauly-Evers, Meike</dc:creator>
    <dc:creator>Apell, Hans-Jürgen</dc:creator>
    <dc:creator>Kaftan, David</dc:creator>
    <dc:creator>Bao, Hui-Fang</dc:creator>
    <dc:creator>Sridhar, Supriya</dc:creator>
    <dc:creator>Verin, Alexander</dc:creator>
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    <dc:creator>Matthay, Michael A.</dc:creator>
    <dc:contributor>Apell, Hans-Jürgen</dc:contributor>
    <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/29023"/>
    <dc:creator>White, Richard</dc:creator>
    <dc:creator>Garcia-Gabay, Irène</dc:creator>
    <dc:contributor>Bao, Hui-Fang</dc:contributor>
    <dc:contributor>Eaton, Douglas C.</dc:contributor>
    <dc:creator>Lucas, Rudolf</dc:creator>
    <dc:creator>Shabbir, Waheed</dc:creator>
    <dc:contributor>Sridhar, Supriya</dc:contributor>
    <dc:creator>Pittet, Jean Francois</dc:creator>
    <dc:contributor>Chakraborty, Trinad</dc:contributor>
    <dc:rights>terms-of-use</dc:rights>
    <dc:creator>Hamacher, Jürg</dc:creator>
    <dc:creator>Lazrak, Ahmed</dc:creator>
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    <dc:contributor>Fischer, Bernhard</dc:contributor>
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    <dcterms:abstract xml:lang="eng">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.&lt;br /&gt;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).&lt;br /&gt;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.&lt;br /&gt;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.&lt;br /&gt;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.</dcterms:abstract>
    <dcterms:title>A novel tumor necrosis factor–mediated mechanism of direct epithelial sodium channel activation</dcterms:title>
    <dcterms:issued>2014-09-01</dcterms:issued>
    <dcterms:bibliographicCitation>American Journal of Respiratory and Critical Care Medicine ; 190 (2014), 5. - S. 522-532</dcterms:bibliographicCitation>
    <dc:contributor>Lucas, Rudolf</dc:contributor>
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    <dc:creator>Bagi, Zsolt</dc:creator>
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    <dc:contributor>Pauly-Evers, Meike</dc:contributor>
    <dc:contributor>Shabbir, Waheed</dc:contributor>
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