Astragaloside IV modulates TGF-ß1-dependent epithelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis.

ABSTRACT

Epithelial-mesenchymal transition (EMT) plays an important role in idiopathic pulmonary fibrosis (IPF). Astragaloside IV (ASV), a natural saponin from astragalus membranaceus, has shown anti-fibrotic property in bleomycin (BLM)-induced pulmonary fibrosis. The current study was undertaken to determine whether EMT was involved in the beneficial of ASV against BLM-induced pulmonary fibrosis and to elucidate its potential mechanism. As expected, in BLM-induced IPF, ASV exerted protective effects on pulmonary fibrosis and ASV significantly reversed BLM-induced EMT. Intriguing, transforming growth factor-ß1 (TGF-ß1) was found to be up-regulated, whereas Forkhead box O3a (FOXO3a) was hyperphosphorylated and less expressed. However, ASV treatment inhibited increased TGF-ß1 and activated FOXO3a in lung tissues. TGF-ß1 was administered to alveolar epithelial cells A549 to induce EMT in vitro. Meanwhile, stimulation with TGF-ß1-activated phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway and induced FOXO3a hyperphosphorylated and down-regulated. It was found that overexpression of FOXO3a leading to the suppression of TGF-ß1-induced EMT. Moreover, ASV treatment, similar with the TGF-ß1 or PI3K/Akt inhibitor, reverted these cellular changes and inhibited EMT in A549 cells. Collectively, the results suggested that ASV significantly inhibited TGF-ß1/PI3K/Akt-induced FOXO3a hyperphosphorylation and down-regulation to reverse EMT during the progression of fibrosis.