期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：3
页码：E374-E383
DOI：10.1073/pnas.1306798111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 {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, and NADPH oxidase 4 (NOX4) to produce reactive oxygen species, driving internalization of {beta}ENaC, the subunit responsible for cell-surface stability of the {beta}{gamma}ENaC complex. ENaC internalization was dependent on oxidation of {beta}ENaC Cys43. 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.
