Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 3, Pages E374-E383Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1306798111
Keywords
alveolar epithelium; fluid homeostasis
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Funding
- von Behring-Rontgen Foundation [51-0031]
- University Medical Center Giessen and Marburg [62580935, 62589064]
- Federal Ministry of Higher Education, Research and the Arts of the State of Hessen Landes-Offensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz Programme
- German Center for Lung Research
- German Research Foundation [Mo 1789/1]
- ECCPS
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TGF-beta is a pathogenic factor in patients with acute respiratory distress syndrome (ARDS), a condition characterized by alveolar edema. A unique TGF-beta pathway is described, which rapidly promoted internalization of the alpha beta gamma epithelial sodium channel (ENaC) complex from the alveolar epithelial cell surface, leading to persistence of pulmonary edema. TGF-beta 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-beta. TGF-beta rapidly and sequentially activated phospholipase D1, phosphatidylinositol-4- phosphate 5-kinase 1 alpha, and NADPH oxidase 4 (NOX4) to produce reactive oxygen species, driving internalization of beta ENaC, the subunit responsible for cell-surface stability of the alpha beta gamma ENaC complex. ENaC internalization was dependent on oxidation of beta ENaC Cys(43). Treatment of alveolar epithelial cells with bronchoalveolar lavage fluids from ARDS patients drove beta ENaC internalization, which was inhibited by a TGF-beta neutralizing antibody and a Tgfbr1 inhibitor. Pharmacological inhibition of TGF-beta 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-beta-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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