Silicosis is an incurable occupational disease associated with inflammation, fibroblast proliferation and the accumulation of extracellular matrix in lung tissues. The dysregulation of lncRNAs and miRNAs has been implicated in many complex diseases; however, the current understanding of their roles in fibrotic lung diseases, especially silicosis, remains limited. Our previous microRNA (miRNA, miR) microarray data have indicated decreased expression levels of miR-489 in lung tissues of silica-induced pulmonary fibrosis. Here, we further explored the role of miR-489 in a mouse model of silicosis. Interestingly, miR-489 levels were reduced in both macrophages that were exposed to silica and fibroblasts that were exposed to TGF-β1. Additionally, the overexpressed miR-489 carried out its anti-fibrotic role by attenuating inflammation and fibrotic progression in vivo. Our molecular study further demonstrated that miR-489 inhibited silica-induced pulmonary fibrosis primarily by repressing its target genes MyD88 and Smad3. Moreover, the up-regulated lncRNA cardiac hypertrophy-related factor (CHRF) reversed the inhibitory effect of miR-489 on MyD88 and Smad3 and then triggered the inflammation and fibrotic signaling pathways. Overall, our data indicate that the CHRF-miR-489-MyD88 Smad3 signaling axis exerts key functions in silica-induced pulmonary fibrosis and may represent a therapeutic target for silicosis.

Silicosis is a kind of chronic, progressive and incurable lung fibrotic diseases with largely unknown and complex pathogenesis and molecular mechanisms. Mounting evidence suggests that microRNAs (miRNAs, miRs) are involved in the pathogenesis of silicosis. Our previous study based on miRNA microarray had shown that the expression levels of miR-503 were down-regulated in mouse lung tissues of silica-induced pulmonary fibrosis. Here, we validated the decreased expression of miR-503 in the fibrotic mouse lung tissues, human bronchial epithelial cells (HBE) and human lung adenocarcinoma A549 cells which were exposed to silica. In addition, overexpressed miR-503 inhibited silica-induced pulmonary fibrosis by attenuating the severity and the distribution of lesions in vivo and limiting the process of epithelial-mesenchymal transition (EMT) in vitro. Our molecular study further demonstrated that PI3K p85 is one of the target genes of miR-503 and the downstream molecules (Akt, mTOR and Snail) are tightly associated with EMT. Furthermore, the up-regulated lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), acted as a competing endogenous RNA (ceRNA), can directly bound to miR-503, which indicated that lncRNA MALAT1 may modulate the expression of miR-503 thus triggering the activation of downstream fibrotic signaling pathways. Taken together, our data suggested that MALAT1-miR-503-PI3K/Akt/mTOR/Snail pathway plays critical roles in silica-induced pulmonary fibrosis.Silicosis, a kind of interstitial lung fibrotic disease, is incurable and irreversible, and usually caused by occupational exposure to silica dust 1, 2 . Alveolar epithelial cell injury and hyperplasia, persistent inflammation, extracellular matrix deposition and subsequent aberrant wound healing are common characteristics of silicosis 3 . In the process of pulmonary fibrosis, epithelial cells and macrophages are stimulated by the silica particles, secreting large amount of cytokines and inflammatory mediators, thus promoting epithelial cells transform to myofibroblasts through epithelial metaplasia, apoptosis, fibrocyte recruitment and EMT 4 . However, the molecular mechanisms underlying pulmonary fibrosis are still unclear.Epithelial-mesenchymal transition (EMT) means a process that polar adjacent epithelial cells transform to non-polar mesenchymal cells which lack cell-cell contacts and increase cell mobility 5 . EMT plays an important role in the development of pulmonary fibrosis and has been proved to be a valuable incident which occurs in the alveolar type II epithelial cells 6 . Myofibroblasts accumulate and secrete large amount of collagen during the formation of fibrosis, which lead to the failure of lung function. Studies have shown that pulmonary fibrosis is a process undergoing the activation of interstitial fibroblasts that convert to myofibroblasts to form the fibrotic collagen network 7 . Moreover, a population of the fibroblasts involved in the fibrotic process is thought to originate from the transition of the epithelial cel...

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Long non-coding RNAs (lncRNAs) are important signal transduction regulators that act by various patterns. However, little is known about the molecular mechanisms of lncRNA related pathways in occupational lung fibrosis. Our previous study found that epithelial-mesenchymal transition (EMT) was one of the key events in silica-induced pulmonary fibrosis. This study showed that the lncRNA-ATB promoted EMT by acting as a miR-200c sponge. miR-200c was identified by miRNA array as a potential target of lncRNA-ATB and verified by dual luciferase reporter gene together with RNA pull-down assays. Moreover, our findings demonstrated that lncRNA-ATB is abundantly expressed during EMT of lung epithelial cells, which contributes to decreased levels of miR-200c. miR-200c targeted ZEB1 to relief silicosis by blocking EMT in vivo and in vitro. The results also suggested M2 macrophages secreted transforming growth factor-β1 (TGF-β1) to induce EMT process by activating lncRNA-ATB in epithelial cells. Collectively, silica-stimulated macrophages secreted TGF-β1 to induce lncRNA-ATB in epithelia cells, promoting EMT by binding with miR-200c and releasing ZEB1. These observations provide further understanding of the regulatory network of silica-induced pulmonary fibrosis and identify new therapeutic targets hopefully.

MiR-449a expression was decreased in fibrotic lungs and activated fibroblasts. Autophagy was inhibited in fibrotic lung tissues and TGF-β1-treated fibroblasts. MiR-449a had an antifibrotic effect in silica-induced lung fibrosis. MiR-449a upregulated autophagic activity in vitro. Bcl2 is the autophagy-related target of miR-449a.

Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons, Autophagy,

Silicosis is one of the typical forms of pneumoconiosis characterized by abnormal proliferation of fibroblasts and deposition of extracellular matrix. Recent findings have shown that microRNAs and circular RNAs (circRNAs) are implicated in many diseases. However, the function of noncoding RNAs in pulmonary fibrosis remain to be elucidated. Here, miR-7 was found significantly decreased in silica-treated pulmonary epithelial cells as well as in fibrotic lung tissues of mice. Elevated expression of miR-7 via agomir injection relieved lung fibrosis in vivo. Further molecular study showed that miR-7 played its role against pulmonary fibrosis by blocking epithelial-mesenchymal transition (EMT) progression of human bronchial epithelial cells and A549 cells. Notably, transforming growth factor beta receptor 2 (TGFBR2) was identified as a target gene of miR-7 with bioinformatics tools, which was verified by dual luciferase receptor gene assay in human bronchial epithelial cells and A549 cells. Silica induced elevation of TGFBR2 could be abolished by exogenous expression of miR-7. Furthermore, bioinformatics software indicated that circRNA CDR1as had several binding sites for miR-7. The inhibitory effects of miR-7 on EMT and its target TGFBR2 were suppressed by circRNA CDR1as, which contributed to pulmonary fibrosis. Our studies also revealed overexpressed miR-7 could repress fibrogenesis of lung fibroblasts induced by TGF-β1. Collectively, circRNA CDR1as stimulated by silica could sponge miR-7 to release TGFBR2, plays an important role during pulmonary fibrosis by promoting EMT process. These results indicated that the interaction between miR-7 and circRNA CDR1as may exert important functions and provide potential therapeutic targets in lung fibrotic diseases.

Silicosis is a kind of irreversible pulmonary fibrosis induced by the long-term inhalation of silica particles. The therapeutic strategy based on the microRNAs might be an effective way for the treatment of silicosis. Our previous miRNA microarray data indicated that miR-326 was decreased in the mouse lung tissues of silica-induced pulmonary fibrosis. However, the specific functions of miR-326 on silica-induced pulmonary fibrosis remain unclear. The objective was to determine the expression and the biological effects of miR-326 in silica-induced pulmonary fibrosis. Methods included mouse models of silica-induced pulmonary fibrosis and miR-326 intervention that were established separately to explore the effect of miR-326 in vivo. The cell models of SiO2-treated lung epithelial cells (HBE and A549) and TGF-β1-stimulated lung fibroblast cells (MRC-5 and NIH/3T3) were used to investigate the mechanism of miR-326 in vitro. Hematoxylin and eosin staining was used to evaluate the severity and distribution of fibrosis of mouse lung tissues. Western blot and immunofluorescence assays were performed to measure the downstream molecules of miR-326. Transmission electron microscopy pictures showed the autophagy activity. The results showed miR-326 is down-regulated in the fibrotic lung tissues of silica-treated mice, while increased expression of miR-326 attenuates silica-induced pulmonary fibrosis in vivo. Tumor necrosis factor superfamily-14 (TNFSF14) and polypyrimidine tract-binding protein 1 (PTBP1) are identified as the targets of miR-326. MiR-326 dampens pulmonary inflammation through targeting TNFSF14 and promotes autophagy activity of fibroblasts through targeting PTBP1. LncRNA HOTAIR facilitates inflammation via sponging miR-326. In conclusion, we demonstrate that miR-326 inhibits inflammation and promotes autophagy activity by targeting TNFSF14 and PTBP1 separately to alleviate silica-induced pulmonary fibrosis. Our results might shed new light on the therapeutic strategies for silica-induced pulmonary fibrosis.