Abstract
Pulmonary fibrosis is a progressive fibrotic lung disease of persisting lung injury and ineffective wound repair, with poor prognosis. Epithelial–mesenchymal transition (EMT) of alveolar epithelia cells is an early event in the development of pulmonary fibrosis, and transforming growth factor β (TGF-β) is an acknowledged inducer of EMT. Epidemiological studies demonstrated that serum levels of 25-hydroxy-vitamin D were associated with the presence of fibrosis diseases. We investigated whether vitamin D attenuated TGF-β-induced pro-fibrotic effects through inhibiting EMT in human alveolar epithelia A549 cells. A549 cells were cultured with TGF-β alone or in combination with 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). TGF-β increased the expression of the mesenchymal markers (N-cadherin and Vimentin), and decreased the expression of epithelial markers (E-cadherin). 1α,25(OH)2D3 attenuated these TGF-β-induced alterations. Furthermore, the EMT-related transcription factors (Snail and β-catenin) and the extracellular matrix genes (Collagen I and fibronectin) were inhibited by 1α,25(OH)2D3, while the expression of vitamin D receptor (VDR) was elevated. In addition, 1α,25(OH)2D3 alleviated the cell migration and the invasion abilities in TGF-β-stimulated A549 cells, determined by the scratch wound healing and transwell assays. Our findings suggested that 1α,25(OH)2D3 inhibited the pro-fibrotic phenotype of lung epithelial cells under TGF-β stimulation and provided new clues in the clinical management of pulmonary fibrosis.
Highlights
Pulmonary fibrosis is a highly heterogeneous and lethal pathological process with limited therapeutic options [1]
epithelial–mesenchymal transition (EMT) is a complex process in which epithelial cells are converted into mesenchymal cell phenotype with enhancing migration and invasion capacity [3], which has been proved to play an important role in the pathogenesis of fibrotic disease occurring in kidneys, the liver, intestines and lungs [4,5,6,7]
Based on Ramirez’s work, we further examined the role of 1α,25(OH)2 D3 in inhibiting cell migration and invasion abilities induced by Transforming growth factor β (TGF-β) in human alveolar epithelia A549 cells, and investigated the potential mechanisms involved
Summary
Pulmonary fibrosis is a highly heterogeneous and lethal pathological process with limited therapeutic options [1]. Pulmonary fibrosis is characterized by the accumulation of myofibroblasts and excessive deposition of the extracellular matrix. Myofibroblasts are derived from a variety of sources including resident mesenchymal cells, bone marrow progenitors ( called as fibrocytes), and epithelial cells undergone epithelial–mesenchymal transition (EMT) [1]. EMT is a complex process in which epithelial cells are converted into mesenchymal cell phenotype with enhancing migration and invasion capacity [3], which has been proved to play an important role in the pathogenesis of fibrotic disease occurring in kidneys, the liver, intestines and lungs [4,5,6,7].
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