ArticleProceedings of the National Academy of Sciences of the United States of America2014
TGF-β directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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78 citing papers in PubMed, 131 citations in OpenAlex.
- Antifibrotic Drugs Regulate the Expression of Epithelial Sodium Channels in the Lungs.Advances in respiratory medicine · 2026Article
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- Alveolar Epithelial Cell Dysfunction in Acute Respiratory Distress Syndrome: Mechanistic Insights and Targeted Interventions.Biomedicines · 2025Review
- Mechanisms of impaired alveolar fluid clearance.Anatomical record (Hoboken, N.J. : 2007) · 2025Review
- Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies.Signal transduction and targeted therapy · 2025Review
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- Longitudinal plasma proteomics reveals biomarkers of alveolar-capillary barrier disruption in critically ill COVID-19 patients.Nature communications · 2024Article
- Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS).Respiratory research · 2024Review
- Deficiency and dysfunctional roles of natural killer T cells in patients with ARDS.Frontiers in immunology · 2024Article
- Progression of Acute Lung Injury in Intratracheal LPS Rat Model: Efficacy of Fluticasone, Dexamethasone, and Pirfenidone.Pharmacology · 2024Article
- Select amino acids recover cytokine-altered ENaC function in human bronchial epithelial cells.PloS one · 2024Article
- Alveolar macrophages in tissue homeostasis, inflammation, and infection: evolving concepts of therapeutic targeting.The Journal of clinical investigation · 2023Review
- Mechanisms and Effects of Macrophage Polarization and Its Specifics in Pulmonary Environment.Physiological research · 2023Review
- TGF Beta as a Prognostic Biomarker of COVID-19 Severity in Patients with NAFLD-A Prospective Case-Control Study.Microorganisms · 2023Article
- The potential role of the pseudobranch of molly fish (Poecilia sphenops) in immunity and cell regeneration.Scientific reports · 2023Article
- Submersion and hypoxia inhibit alveolar epithelial NaRespiratory research · 2023Article
- Regulation of Epithelial Sodium Transport by SARS-CoV-2 Is Closely Related with Fibrinolytic System-Associated Proteins.Biomolecules · 2023Review
18 more citing papers are in PubMed but not listed here.
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16 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TGF-β is a pathogenic factor in patients with acute respiratory distress syndrome (ARDS), a condition characterized by alveolar edema. A unique TGF-β pathway is described, which rapidly promoted internalization of the αβγ epithelial sodium channel (ENaC) complex from the alveolar epithelial cell surface, leading to persistence of pulmonary edema. TGF-β applied to the alveolar airspaces of live rabbits or isolated rabbit lungs blocked sodium transport and caused fluid retention, which--together with patch-clamp and flow cytometry studies--identified ENaC as the target of TGF-β. TGF-β rapidly and sequentially activated phospholipase D1, phosphatidylinositol-4-phosphate 5-kinase 1α, and NADPH oxidase 4 (NOX4) to produce reactive oxygen species, driving internalization of βENaC, the subunit responsible for cell-surface stability of the αβγENaC complex. ENaC internalization was dependent on oxidation of βENaC Cys(43). Treatment of alveolar epithelial cells with bronchoalveolar lavage fluids from ARDS patients drove βENaC internalization, which was inhibited by a TGF-β neutralizing antibody and a Tgfbr1 inhibitor. Pharmacological inhibition of TGF-β signaling in vivo in mice, and genetic ablation of the nox4 gene in mice, protected against perturbed lung fluid balance in a bleomycin model of lung injury, highlighting a role for both proximal and distal components of this unique ENaC regulatory pathway in lung fluid balance. These data describe a unique TGF-β-dependent mechanism that regulates ion and fluid transport in the lung, which is not only relevant to the pathological mechanisms of ARDS, but might also represent a physiological means of acutely regulating ENaC activity in the lung and other organs.
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