ArticleAmerican journal of respiratory and critical care medicine2014
A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation.
Article in American journal of respiratory and critical care medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 58 citations in OpenAlex.
- Trial
- Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial.Critical care (London, England) · 2017Trial
- Effects of proximal tubule-specific ATRAP enhancement on hypertension in a remnant kidney chronic kidney disease model of mice.Scientific reports · 2025Article
- The lectin-like domain of TNF reduces pneumonia-induced injury in the perfused human lung.JCI insight · 2025Article
- Endothelial ENaC-α Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia-associated Acute Lung Injury.American journal of respiratory cell and molecular biology · 2025Article
- Endothelial ENaC as a repressor of oxidative stress and a guardian of lung capillary barrier function in bacterial and viral pneumonia.Frontiers in physiology · 2025Review
- The small molecule activator S3969 stimulates the epithelial sodium channel by interacting with a specific binding pocket in the channel's β-subunit.The Journal of biological chemistry · 2024Article
- Select amino acids recover cytokine-altered ENaC function in human bronchial epithelial cells.PloS one · 2024Article
- Editorial: Endocytic and trafficking events in acute lung injury and pulmonary inflammation.Frontiers in immunology · 2024Article
- Proteolytic Activation of the Epithelial Sodium Channel (ENaC): Its Mechanisms and Implications.International journal of molecular sciences · 2023Review
- The Epithelial Sodium Channel-An Underestimated Drug Target.International journal of molecular sciences · 2023Review
- Direct endothelial ENaC activation mitigates vasculopathy induced by SARS-CoV2 spike protein.Frontiers in immunology · 2023Article
- Emerging roles of mechanosensitive ion channels in acute lung injury/acute respiratory distress syndrome.Respiratory research · 2022Review
- Phenotypic and Transcriptional Changes of Pulmonary Immune Responses in Dogs Following Canine Distemper Virus Infection.International journal of molecular sciences · 2022Article
- Potent anti-inflammatory activity of the lectin-like domain of TNF in joints.Frontiers in immunology · 2022Article
- Editorial: Molecular mechanisms of lung endothelial permeability.Frontiers in physiology · 2022Article
- Conformational ensemble of the TNF-derived peptide solnatide in solution.Computational and structural biotechnology journal · 2022Article
- Coronary Microvascular Dysfunction and Heart Failure with Preserved Ejection Fraction - implications for Chronic Inflammatory Mechanisms.Current cardiology reviews · 2022Review
- Dual Role of Hydrogen Peroxide as an Oxidant in Pneumococcal Pneumonia.Antioxidants & redox signaling · 2021Review
- CRISPR/Cas9 Mediated Knock Down of δ-ENaC Blunted the TNF-Induced Activation of ENaC in A549 Cells.International journal of molecular sciences · 2021Article
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Authors and funding
24 authors at 12 institutions in 5 countries.
Funding
Abstract
rationaleAlveolar 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.
objectivesIn 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).
methodsWe 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
resultsTIP 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.
conclusionsThese 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.