Abstract
Silicosis is associated with fibroblast proliferation and extracellular matrix deposition in lung tissues. The dysregulation of miR-1224-5p has been implicated in several human cancers; however, the expression and function of miR-1224-5p in silicosis is unknown. The mitochondrial dysfunctions play critical roles in some diseases, but how these processes are regulated in silicosis remains limited. Here, we explored the role of miR-1224-5p in a mouse model of silicosis. We showed that the expression of miR-1224-5p is increased both in lung tissues of silica-induced pulmonary fibrosis and fibroblasts exposed to TGF-β1. Repression of miR-1224-5p expression attenuated silica-induced fibrotic progression in vivo and TGF-β1-induced myofibroblast differentiation in vitro. Additionally, we demonstrated that miR-1224-5p facilitated silica-induced pulmonary fibrosis primarily by repressing one of target genes, BECN1, thereby blocking PARK2 translocation to mitochondria and inducing the accumulation of damaged mitochondria. Furthermore, the activation of PDGFR signal mediated by mitochondrial damage and insufficient mitophagy resulted in myofibroblast differentiation. Collectively, these data indicated that miR-1224-5p exerts key functions in silica-induced pulmonary fibrosis and may represent a potential therapeutic target for silicosis.
Highlights
Silicosis, caused by prolonged exposure to silica dust, is one of the serious types of pneumoconiosis
Mitophagy appears to be involved in the development of several lung diseases, such as idiopathic pulmonary fibrosis (IPF) [4,5], chronic obstructive pulmonary disease (COPD) [6], and pulmonary hypertension (PH) [7]
It is possible that aberrant mitochondria and mitophagy activity participate in the pathogenesis of silicosis, but the exact mechanisms by which mitophagy is modulated under silica exposure remains unknown
Summary
Silicosis, caused by prolonged exposure to silica dust, is one of the serious types of pneumoconiosis. It is possible that aberrant mitochondria and mitophagy activity participate in the pathogenesis of silicosis, but the exact mechanisms by which mitophagy is modulated under silica exposure remains unknown. Further attentions are warranted to focus on the changes of miRNA expression in silica induced pulmonary fibrosis. We confirmed that miR-1224-5p expression was increased in mouse lung tissues of silica-induced pulmonary fibrosis compared with the mouse saline lung tissues. Repression of miR-1224-5p expression attenuated silica-induced pulmonary fibrosis both in vivo and in vitro by regulating its one of the target genes, BECN1, which is critical mediator in the PARK2 translocation to mitochondria and the degradation of damaged mitochondria. This study firstly reported that miR-1224-5p participates in silica-induced pulmonary fibrosis by directly repressing BECN1, thereby impairing mitochondria. Repression of miR-1224-5p expression might provide a novel therapeutic target of the silicosis
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