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Statements

Subject Item
n2:RIV%2F60076658%3A12310%2F14%3A43887246%21RIV15-MSM-12310___
rdf:type
skos:Concept n18:Vysledek
dcterms: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.
dcterms: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
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
skos:notation
RIV/60076658:12310/14:43887246!RIV15-MSM-12310___
n3:aktivita
n16:I
n3:aktivity
I
n3:cisloPeriodika
5
n3:dodaniDat
n10:2015
n3:domaciTvurceVysledku
n4:4523318
n3:druhVysledku
n15:J
n3:duvernostUdaju
n12:S
n3:entitaPredkladatele
n11:predkladatel
n3:idSjednocenehoVysledku
1011
n3:idVysledku
RIV/60076658:12310/14:43887246
n3:jazykVysledku
n9:eng
n3:klicovaSlova
tumor necrosis factor; pulmonary edema; protein kinase C-alpha; pneumonia; epithelial sodium channel
n3:klicoveSlovo
n6:epithelial%20sodium%20channel n6:tumor%20necrosis%20factor n6:pneumonia n6:protein%20kinase%20C-alpha n6:pulmonary%20edema
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[CC7A5B5FAEA5]
n3:nazevZdroje
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
n3:obor
n13:CE
n3:pocetDomacichTvurcuVysledku
1
n3:pocetTvurcuVysledku
24
n3:rokUplatneniVysledku
n10:2014
n3:svazekPeriodika
190
n3:tvurceVysledku
Lazrak, Ahmed Czikora, Istvan Alli, Abdel Lucas, Rudolf Sridhar, Supriya Verin, Alexander Wendel, Albrecht Pauly-Evers, Meike Bagi, Zsolt Gorshkov, Boris White, Richard Fischer, Bernhard Apell, Hans-Juergen Hamacher, Juerg Pittet, Jean Francois Kaftan, David Lemmens-Gruber, Rosa Matthay, Michael A. Eaton, Douglas C. Zimmermann, Astrid Shabbir, Waheed Garcia-Gabay, Irene Chakraborty, Trinad Bao, Hui-Fang
n3:wos
000341554400007
s:issn
1073-449X
s:numberOfPages
11
n17:doi
10.1164/rccm.201405-0833OC
n14:organizacniJednotka
12310