Home News About Us Contact Contributors Disclaimer Privacy Policy Help FAQ

Quick Search
My eDoc
Session History
Support Wiki
Direct access to
document ID:

          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents

ID: 711876.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
TGF-beta directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury
Authors:Peters, D. M.; Vadasz, I.; Wujak, L.; Wygrecka, M.; Olschewski, A.; Becker, C.; Herold, S.; Papp, R.; Mayer, K.; Rummel, S.; Brandes, R. P.; Gunther, A.; Waldegger, S.; Eickelberg, O.; Seeger, W.; Morty, R. E.
Date of Publication (YYYY-MM-DD):2014-01-21
Title of Journal:Proc Natl Acad Sci u S A
Issue / Number:3
Start Page:E374
End Page:83
Audience:Not Specified
Abstract / Description: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 alphabetagamma 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 1alpha, and NADPH oxidase 4 (NOX4) to produce reactive oxygen species, driving internalization of betaENaC, the subunit responsible for cell-surface stability of the alphabetagammaENaC complex. ENaC internalization was dependent on oxidation of betaENaC Cys(43). Treatment of alveolar epithelial cells with bronchoalveolar lavage fluids from ARDS patients drove betaENaC 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.
Free Keywords:Acute Lung Injury/*metabolism; Adenosine Triphosphatases/metabolism; Adult; Aged; Animals; Epithelial Sodium Channels/*metabolism; Female; *Gene Expression Regulation; Humans; Ions; Lung/metabolism; Male; Mice; Mice, Knockout; Middle Aged; Perfusion; Phospholipase D/metabolism; Phosphotransferases (Alcohol Group Acceptor)/metabolism; Pulmonary Alveoli/metabolism; Rabbits; Reactive Oxygen Species; Respiratory Distress Syndrome, Adult/metabolism; Transforming Growth Factor beta/*metabolism; alveolar epithelium; fluid homeostasis
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:%^ 1435822045
Identifiers:ISSN:1091-6490 (Electronic) 0027-8424 (Linking) %R 10.1073/pnas.1306798111
The scope and number of records on eDoc is subject to the collection policies defined by each institute - see "info" button in the collection browse view.