Abstract
Silicosis is a very serious occupational disease and it features pathological manifestations of inflammatory infiltration, excessive proliferation of fibroblasts and massive depositions of the extracellular matrix in the lungs. Recent studies described the roles of a variety of microRNAs (miRNAs) in fibrotic diseases. Here, we aimed to explore the potential mechanism of miR-542-5p in the activation of lung fibroblasts. To induce a pulmonary fibrosis mouse model, silica suspension and the miR-542-5p agomir were administered to mice by intratracheal instillation and tail vein injection. We found that miR-542-5p was significantly decreased in mouse fibrotic lung tissues and up-regulation of miR-542-5p visually attenuated a series of fibrotic lesions, including alveolar structural damage, alveolar interstitial thickening and silica-induced nodule formation. The down-regulation of miR-542-5p was also observed in mouse fibroblast (NIH-3T3) treated with transforming growth factor β1 (TGF-β1). The proliferation and migration ability of NIH-3T3 cells were also inhibited by the transfection of miR-542-5p mimic. Integrin α6 (Itga6), reported as a cell surface protein associated with fibroblast proliferation, was confirmed to be a direct target of miR-542-5p. The knockdown of Itga6 significantly inhibited the phosphorylation of FAK/PI3K/AKT. In conclusion, miR-542-5p has a potential function for reducing the proliferation of fibroblasts and inhibiting silica-induced pulmonary fibrosis, which might be partially realized by directly binding to Itga6. Our data suggested that miR-542-5p might be a new therapeutic target for silicosis or other pulmonary fibrosis.
Highlights
Silicosis is a progressive, disabling and incurable disease that is characterized by the aberrant proliferation of fibroblasts and the deposition of the extracellular matrix (ECM) [1,2]
We investigated the role of miR-542-5p, in silica-induced pulmonary fibrosis and the activation of pulmonary fibroblasts. miRNA microarray analysis in our previous study has shown a decrease of miR-542-5p in silica-induced mouse lung fibrosis [15]
Silicosis is a major type of pneumoconiosis and it is characterized by the destruction of alveolar structure, excessive deposition of the extracellular matrix and aberrant fibroblast proliferation
Summary
Silicosis is a progressive, disabling and incurable disease that is characterized by the aberrant proliferation of fibroblasts and the deposition of the extracellular matrix (ECM) [1,2]. It is reported that miR-1343 suppressed the TGF-β signaling pathway to attenuate lung fibrosis by directly targeting the 3 -UTRs of TGFBR1 and TGFBR2 [10]. Our previous study revealed that miR-449a had an antifibrotic effect on silica-induced lung fibrosis by targeting autophagy-related Bcl mRNA [11]. Chen et al reported that miR-497-5p promoted pulmonary fibrogenesis via the induction of the differentiation of lung resident mesenchymal stem cells into myofibroblasts [14]. All of these studies showed that miRNAs might participate in the occurrence and development of fibrosis in different ways. Further identification of specific miRNAs and a detailed clarification of their potential roles in mediating silicosis are critical for developing efficient therapies
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