title: TGF-β directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury.
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.
authors: Department of Internal Medicine, Department of Biochemistry, Justus Liebig University, Universities of Giessen and Marburg Lung Center, German Center for Lung Research, 35392 Giessen, Germany.
authors: Dorothea M
authors: DM
authors: Peters
authors: István
authors: I
authors: Vadász
authors: Lukasz
authors: L
authors: Wujak
authors: Malgorzata
authors: M
authors: Wygrecka
authors: Andrea
authors: A
authors: Olschewski
authors: Christin
authors: C
authors: Becker
authors: Susanne
authors: S
authors: Herold
authors: Rita
authors: R
authors: Papp
authors: Konstantin
authors: K
authors: Mayer
authors: Sebastian
authors: S
authors: Rummel
authors: Ralph P
authors: RP
authors: Brandes
authors: Andreas
authors: A
authors: Günther
authors: Siegfried
authors: S
authors: Waldegger
authors: Oliver
authors: O
authors: Eickelberg
authors: Werner
authors: W
authors: Seeger
authors: Rory E
authors: RE
authors: Morty
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007477:Ions; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010477:Perfusion; D010739:Phospholipase D / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D011817:Rabbits; D017382:Reactive Oxygen Species; D012128:Respiratory Distress Syndrome / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D053503:Epithelial Sodium Channels; D007477:Ions; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D010739:Phospholipase D; C106801:phospholipase D1; D000251:Adenosine Triphosphatases
keywords: alveolar epithelium; fluid homeostasis