TGF-beta is a pathogenic factor in patients with acute respiratory distress syndrome (ARDS), a devastating condition characterized by alveolar edema. In the present study, a novel TGF-beta signaling pathway is described, which rapidly and dramatically promotes endocytosis of the epithelial sodium channel (ENaC) from the surface of alveolar epithelial cells. Elevated TGF-beta levels were demonstrated in bronchoalveolar lavage fluids from ARDS patients, where TGF-beta was identified as the principle in lung fluid of ARDS patients that promoted ENaC endocytosis. Administration of TGF-beta to the alveolar airspaces of isolated rabbit lungs caused pronounced fluid retention and impaired sodium transport. The same effect could be observed in the presence of amiloride, an inhibitor of the epithelial sodium channel, and was abrogated after treatment with SB431542, an inhibitor of TGF-beta signaling via the type I TGF-beta receptor, suggesting ENaC as the target of TGF-beta. Moreover, preapplication of PO abrogated the effects of TGF-beta on net lung mass, indicating a role for F to G actin conversion in mediating the effect of TGF-beta on lung fluid dynamics.TGF-beta rapidly activated phospholipase D1, which activated phosphatidylinositol-4-phosphate 5-kinase 1 alpha, which drove NADPH oxidase 4 activation, generating reactive oxygen species which promoted beta-ENaC endocytosis in a manner dependent on Cys43 of beta-ENaC. This led to loss of sodium absorbing capacity of the epithelial cells, and alveolar flooding, promoting the formation or persistence of alveolar edema. These data describe a novel TGF-beta-dependent mechanism that regulates ion and fluid transport in the lung that is relevant to pathological mechanisms at play in ARDS patients.
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