Oxidized-low density lipoprotein (Ox-LDL) has been shown to play an important role in impaired surfactant metabolism and transforming growth factor-β1 (TGF-β1) is a critical mediator in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In this study, we investigated whether Ox-LDL can induce TGF-β1 protein production, and if so, how it achieves this induction in human alveolar epithelial cells (A549). We show here that Ox-LDL not only caused a dose- and time-dependent up-regulation of TGF-β1 production, but also increased Smad3 phosphorylation, Ras/extracellular signal-regulated kinase (ERK) activity and phospholipid transfer protein (PLTP) expression in A549 cells. The inhibition of Ras/ERK activity with specific inhibitors significantly suppressed Ox-LDL-induced TGF-β1 production, Smad3 phosphorylation and PLTP expression. Furthermore, treatment of cells with PLTP siRNA suppressed both TGF-β1 release and Smad3 activation induced by Ox-LDL, but not the activation of Ras/ERK cascade. Taken together, we provide evidences that induction of TGF-β1 production and Smad3 phosphorylation by Ox-LDL is mediated by Ras/ERK/PLTP pathway in human alveolar epithelial cells.
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