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| rdf:type
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| Description
| - 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.
- 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. (en)
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| Title
| - 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 (en)
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| skos:prefLabel
| - 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 (en)
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| skos:notation
| - RIV/60076658:12310/14:43887246!RIV15-MSM-12310___
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| http://linked.open...avai/riv/aktivita
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| http://linked.open...avai/riv/aktivity
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| http://linked.open...iv/cisloPeriodika
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| http://linked.open...vai/riv/dodaniDat
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| http://linked.open...aciTvurceVysledku
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| http://linked.open.../riv/druhVysledku
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| http://linked.open...iv/duvernostUdaju
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| http://linked.open...titaPredkladatele
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| http://linked.open...dnocenehoVysledku
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| http://linked.open...ai/riv/idVysledku
| - RIV/60076658:12310/14:43887246
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| http://linked.open...riv/jazykVysledku
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| http://linked.open.../riv/klicovaSlova
| - tumor necrosis factor; pulmonary edema; protein kinase C-alpha; pneumonia; epithelial sodium channel (en)
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| http://linked.open.../riv/klicoveSlovo
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| http://linked.open...odStatuVydavatele
| - US - Spojené státy americké
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| http://linked.open...ontrolniKodProRIV
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| http://linked.open...i/riv/nazevZdroje
| - AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
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| http://linked.open...in/vavai/riv/obor
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| http://linked.open...ichTvurcuVysledku
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| http://linked.open...cetTvurcuVysledku
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| http://linked.open...UplatneniVysledku
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| http://linked.open...v/svazekPeriodika
| |
| http://linked.open...iv/tvurceVysledku
| - Kaftan, David
- Alli, Abdel
- Apell, Hans-Juergen
- Bagi, Zsolt
- Bao, Hui-Fang
- Chakraborty, Trinad
- Czikora, Istvan
- Eaton, Douglas C.
- Fischer, Bernhard
- Garcia-Gabay, Irene
- Gorshkov, Boris
- Hamacher, Juerg
- Lazrak, Ahmed
- Lemmens-Gruber, Rosa
- Lucas, Rudolf
- Matthay, Michael A.
- Pauly-Evers, Meike
- Pittet, Jean Francois
- Shabbir, Waheed
- Sridhar, Supriya
- Verin, Alexander
- Wendel, Albrecht
- White, Richard
- Zimmermann, Astrid
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| http://linked.open...ain/vavai/riv/wos
| |
| issn
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| number of pages
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| http://bibframe.org/vocab/doi
| - 10.1164/rccm.201405-0833OC
|
| http://localhost/t...ganizacniJednotka
| |
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