ArticleProceedings of the National Academy of Sciences of the United States of America2013
Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers, 1 of them a synthesis that pooled it.
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Who cites it
44 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Rhinorrhea and increased chloride secretion through the CFTR chloride channel-a systematic review.European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2023Pooled it
- Bolus intravenous 0.9% saline leads to interstitial permeability pulmonary edema in healthy volunteers.European journal of applied physiology · 2021Trial
- Epithelial plasma membrane transporters as drug targets.Physiological reviews · 2026Review
- Pleural Effusion Formation Linked to Altered Transporter Expression Involved in Alveolar Fluid Clearance: Insights From the Monocrotaline Model of Pulmonary Hypertension.Basic & clinical pharmacology & toxicology · 2025Article
- Clinical predictors of extubation failure in postoperative critically ill patients: a post-hoc analysis of a multicenter prospective observational study.BMC anesthesiology · 2025Observational
- CFTR as a therapeutic target for severe lung infection.American journal of physiology. Lung cellular and molecular physiology · 2025Review
- Advancements in understanding the mechanisms of lung-kidney crosstalk.Intensive care medicine experimental · 2024Review
- Chloride ions in health and disease.Bioscience reports · 2024Review
- Rescue of alveolar wall liquid secretion blocks fatal lung injury due to influenza-staphylococcal coinfection.The Journal of clinical investigation · 2023Article
- Intraluminal chloride regulates lung branching morphogenesis: involvement of PIEZO1/PIEZO2.Respiratory research · 2023Article
- Molecular mechanisms, physiological roles, and therapeutic implications of ion fluxes in bone cells: Emphasis on the cation-ClJournal of cellular physiology · 2022Review
- Chloride in Heart Failure Syndrome: Its Pathophysiologic Role and Therapeutic Implication.Cardiology and therapy · 2021Review
- Predictors of post-extubation stridor in patients on mechanical ventilation: a prospective observational study.Scientific reports · 2021Observational
- Reply to Eisenhut.American journal of physiology. Lung cellular and molecular physiology · 2021Article
- SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport.American journal of physiology. Lung cellular and molecular physiology · 2021Article
- Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential.Frontiers in pharmacology · 2021Review
- Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity.The Journal of biological chemistry · 2020Article
- Osmotic Adaptation by NaBiomedicines · 2020Review
- Drug development in targeting ion channels for brain edema.Acta pharmacologica Sinica · 2020Article
- Effusion-Serum Chloride Gradient in Heart Failure-Associated Pleural Effusion - Pathophysiologic Implications.Circulation reports · 2020Article
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13 authors at 7 institutions in 2 countries.
Funding
Abstract
Alveolar fluid clearance driven by active epithelial Na(+) and secondary Cl(-) absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na(+) channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl(-) secretion and alveolar Cl(-) influx were quantified by radionuclide tracing and alveolar Cl(-) imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl(-) secretion and alveolar Cl(-) influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na(+)-K(+)-Cl(-) cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR(-/-) mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl(-) secretion that were again CFTR-, NKCC-, and Na(+)-K(+)-ATPase-dependent. Our findings show a reversal of transepithelial Cl(-) and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl(-) and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema.
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