miR-34a-5p Attenuates EMT through targeting SMAD4 in silica-induced pulmonary fibrosis.

Silicosis is an incurable occupational disease, and its pathological feature is diffuse pulmonary fibrosis. Pulmonary epithelial-mesenchymal transition (EMT) is one of the important events in the pathogenesis of silicosis. Previous studies found that abnormal expression of various microRNAs (miRNAs) involved in the development of lung fibrosis. However, their roles in silicosis have not been elucidated. To research the biological effects of miR-34a in EMT process in silica-induced lung fibrosis, we established the silicosis model in mouse and miR-34a intervention in a cell model of TGF-ß1 stimulated lung epithelial cells (A549). The results showed that miR-34a expression was down-regulated in the fibrotic lung tissue after silica treatment, and it was similarly expressed in A549 cells stimulated by TGF-ß1. Meanwhile, silica-induced EMT process can increase expression of two mesenchymal markers, α-SMA and vimentin. Furthermore, overexpression miR-34a markedly inhibited EMT stimulated by TGF-ß1. Mechanistically, SMAD4 was identified as the target of miR-34a. SMAD4 levels decreased in mRNA and protein levels in A549 cells upon miR-34a overexpression. In addition, the knockdown of SMAD4 blocked the EMT process. Taken together, miR-34a regulated EMT, which might be partially realized by targeting SMAD4. Our data might provide new insight into treatment targets for silica-induced pulmonary fibrosis.

Transcriptome analysis reveals a protective role of liver X receptor alpha against silica particle-induced experimental silicosis.

Silicosis, a severe and irreversible form of pulmonary fibrosis (PF) caused by long-term exposure to dust particles in production environments, is the biggest occupational health concern in China and most low-income countries. The transdifferentiation of pulmonary fibroblasts is the terminal event in silicosis, and specific transcription factors (TFs) play a crucial role in this condition. However, the relationship between TF-mediated regulation and silicosis remains unknown. We performed a transcriptomic analysis to elucidate this relationship, and our results revealed that two TFs, EGR2 and BHLHE40, were upregulated and five, i.e., TBX2, NR1H3 (LXRα), NR2F1, PPARG (PPARγ), and EPAS1, were downregulated in activated fibroblasts. Notably, PPARγ and LXRα expression was also decreased in an experimental mouse model of silicosis. The mechanism underlying these changes may involve TGF-ß1 secretion from silica-exposed alveolar macrophages, causing PPARγ and LXRα downregulation, which in turn would result in aberrant α-SMA transcription. Our results suggest that LXRα is a potential target for the prevention of silicosis and PF.