Apolipoprotein A1 Inhibits TGF-β1-Induced Epithelial-to-Mesenchymal Transition of Alveolar Epithelial Cells

Abstract

Background: Idiopathic pulmonary fibrosis (IPP) is a progressive and lethal lung disease characterized by the accumulation of excessive fibroblasts and myofibroblasts in the extracellular matrix. The transforming growth factor beta 1 (TGF-beta 1)-induced epithelial-to-mesenchymal transition (EMT) is thought to be a possible source of fibroblasts/myofibroblasts in IPF lungs. We have previously reported that apolipoprotein A1 (ApoA1) has anti-fibrotic activity in experimental lung fibrosis. In this study, we deteimine whether ApoA1 modulates TGF-beta 1-induced EMT in experimental lung fibrosis and clarify its mechanism of action. Methods: The A549 alveolar epithelial cell line was treated with TGE-beta 1 with or without ApoAl. Morphological changes and expression of EN/If-related markers, including E-cadherin, N-cadherin, and alpha-smooth muscle actin were evaluated. Expressions of Salad and non-Smad mediators and TGF-beta 1 receptor type I (T beta RI) and type 2 (T beta RII) were measured. The silica-induced lung fibrosis model was established using ApoA1 overexpressing transgenic mice. Results: TGF-beta 1-treated A549 cells were changed to the mesenchymal morphology with less E-cadherin and more N-cadherin expression. The addition of ApoA1 inhibited the TGF-beta 1-induced change of the EMT phenotype. ApoA1 inhibited the TGF-beta 1-induced increase in the phosphorvlation of Smad2 and 3 as well as that of ERK and p38 mitogen-activated protein kinase mediators. In addition, ApoA1 reduced the TGF-beta 1-induced increase in T beta RI and T beta RII expression. In a mouse model of silica-induced lung fibrosis, ApoA1 overexpression reduced the silica-mediated effects, which were increased N-cadherin and decreased E-cadherin expression in the alveolar epithelium. Conclusion: Our data demonstrate that ApoA1 inhibits TGFT-beta 1-induced EMT in experimental lung fibrosis.