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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 SiO 2 -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.

Silicosis is an occupational pulmonary fibrosis caused by inhalation of silica (SiO 2 ) and there are no ideal drugs to treat this disease. Earthworm extract (EE), a natural nutrient, has been reported to have anti-inflammatory, antioxidant, and anti-apoptosis effects. The purpose of the current study was to test the protective effects of EE against SiO 2 -induced pulmonary fibrosis and to explore the underlying mechanisms using both in vivo and in vitro models. We found that treatment with EE significantly reduced lung inflammation and fibrosis and improved lung structure and function in SiO 2 -instilled mice. Further mechanistic investigations revealed that EE administration markedly inhibited SiO 2 -induced oxidative stress, mitochondrial apoptotic pathway, and epithelial-mesenchymal transition in HBE and A549 cells. Furthermore, we demonstrate that Nrf2 activation partly mediates the interventional effects of EE against SiO 2 -induced pulmonary fibrosis. Our study has identified EE to be a potential anti-oxidative, anti-inflammatory, and anti-fibrotic drug for silicosis.

Inhalation and deposition of crystalline silica particles in the lung can cause pulmonary fibrosis, then leading to silicosis. Given the paucity of effective drugs for silicosis, new insights for understanding the mechanisms of silicosis, including lung fibroblast activation and myofibroblast differentiation, are essential to explore therapeutic strategies. Our previous research showed that the up‐regulation of miR‐503 alleviated silica‐induced pulmonary fibrosis in mice. In this study, we investigated whether miR‐503 can regulate the TGF‐β1‐induced effects in lung fibroblasts. Mimic‐based strategies aiming at up‐regulating miR‐503 were used to discuss the function of miR‐503 in vivo and in vitro. We found that the expression level of miR‐503 was decreased in fibroblasts stimulated by TGF‐β1, and the up‐regulation of miR‐503 reduced the release of fibrotic factors and inhibited the migration and invasion abilities of fibroblasts. Combined with the up‐regulation of miR‐503 in a mouse model of silica‐induced pulmonary fibrosis, we revealed that miR‐503 mitigated the TGF‐β1‐induced effects in fibroblasts by regulating VEGFA and FGFR1 and then affecting the MAPK/ERK signalling pathway. In conclusion, miR‐503 exerted protective roles in silica‐induced pulmonary fibrosis and may represent a novel and potent candidate for therapeutic strategies in silicosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Highlights • Post-translational of epigenetic plays a key role in lung fibroblast activation and silica-induced fibrosis. • MiR-125a-3p regulates lung fibroblast activation and silica-induced fibrosis by targeting Fyn. • MiR-125a-3p/Fyn/STAT3signaling pathway is a potential therapeutic approach for pulmonary fibrosis. Abstract Various miRNAs are dysregulated during initiation and progression of pulmonary fibrosis. However, their function remains limited in silicosis. Here, we observed that miR-125a-3p was downregulated in silica-induced fibrotic murine lung tissues. Ectopic miR-125a-3p expression with chemotherapy attenuated silica-induced pulmonary fibrosis. Further in vitro experiments revealed that TGF-β1 effectively decreased miR-125a-3p expression in fibroblast lines (NIH/3T3 and MRC-5). Overexpression of miR-125a-3p blocked fibroblast activation stimulated by TGF-β1. Mechanistically, miR-125a-3p could bind to the 3′-untranslated region of Fyn and inhibit its expression in both mRNA and protein levels, thus causing inactivation of Fyn downstream effector STAT3. Fyn and p-STAT3, as opposed to miR-125a-3p expression, were elevated in silica-induced fibrotic murine lung tissues and TGF-β1-treated fibroblast lines. Furthermore, Fyn knockdown or p-STAT3 suppression effectively attenuated fibroblast activation and ECM production. Taken together, miR-125a-3p is involved in fibrosis pathogenesis by fibroblast activation, suggesting that targeting miR-125a-3p/Fyn/STAT3 signaling pathway could be a potential therapeutic approach for pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]