XAV-939 inhibits epithelial-mesenchymal transformation in pulmonary fibrosis induced by crystalline silica via the Wnt signaling pathway.

Silicosis is an occupational lung disease that results from long-term inhalation of free silica dust, the expression is sustained inflammation response, fibroblast hyperplasia, and excessive collagen deposit, bringing about pulmonary interstitial fibrosis. Wnt signaling pathway exists in various kinds of eukaryotic cells, is a highly conservative signaling pathway in biological evolution, and participates in cell proliferation, differentiation, migration, and polarity of physiological activity, such as in embryonic development, organ morphology, and tumor. In addition, it plays an important role in the progress of fibrosis disease. At present, studies related to silicosis are increasing, but the pathogenesis of silicosis still is not clear. In recent years, more and more studies have suggested that the Wnt signaling pathway could participate in the pathogenesis of silicosis fibrosis. In the study, we explored the mechanism of the Wnt signaling pathway in the pathogenesis of silicosis fibrosis and evaluated the effect of XAV-939 treatment epithelial-mesenchymal transformation (EMT) induced by silica. In addition, the results showed that EMT and activation of the Wnt signaling pathway would occur after stimulation of silica or TGF-ß1. However, after treatment with the Wnt signaling pathway inhibitor XAV-939, EMT was reversed and the expression of the ß-catenin decreased. These results suggested that the Wnt signaling pathway is associated with EMT induced by silica and it could be a potential target for the treatment of silicosis.

Echistatin/BYL-719 impedes epithelial-mesenchymal transition in pulmonary fibrosis induced by silica through modulation of the Integrin ß1/ILK/PI3K signaling pathway.

Silicosis is a chronic fibroproliferative lung disease caused by long-term inhalation of crystalline silica dust, characterized by the proliferation of fibroblasts and pulmonary interstitial fibrosis. Currently, there are no effective treatments available. Recent research suggests that the Integrin ß1/ILK/PI3K signaling pathway may be associated with the pathogenesis of silicosis fibrosis. In this study, we investigated the effects of Echistatin (Integrin ß1 inhibitor) and BYL-719 (PI3K inhibitor) on silicosis rats at 28 and 56 days after silica exposure. Histopathological analysis of rat lung tissue was performed using H&E staining and Masson staining. Immunohistochemistry, Western blotting, and qRT-PCR were employed to assess the expression of markers associated with epithelial-mesenchymal transition (EMT), fibrosis, and the Integrin ß1/ILK/PI3K pathway in lung tissue. The results showed that Echistatin, BYL 719 or their combination up-regulated the expression of E-cadherin and down-regulated the expression of Vimentin and extracellular matrix (ECM) components, including type I and type III collagen. The increase of Snail, AKT and ß-catenin in the downstream Integrin ß1/ILK/PI3K pathway was inhibited. These results indicate that Echistatin and BYL 719 can inhibit EMT and pulmonary fibrosis by blocking different stages of Integrinß1 /ILK/PI3K signaling pathway. This indicates that the Integrin ß1/ILK/PI3K signaling pathway is associated with silica-induced EMT and may serve as a potential therapeutic target for silicosis.

Inhibition of the ITGB1 gene attenuates crystalline silica-induced pulmonary fibrosis via epithelial-mesenchymal transformation.

Silicosis is a systemic disease caused by long-term exposure to high concentrations of free silica dust particles in the workplace. It is characterized by a persistent inflammatory response, fibroblast proliferation, and excessive collagen deposition, leading to pulmonary interstitial fibrosis. Epithelial interstitial transformation (EMT) can cause epithelial cells to lose their tight junctions, cell polarity, and epithelial properties, thereby enhancing the properties of interstitial cells, which can lead to the progression of fibrosis and the formation of scar tissue. Integrin 1 (ITGB1) is considered an important factor for promoting EMT and tumor invasion in a variety of tumors and also plays an important role in the progression of fibrotic diseases. Therefore, ITGB1 can be used as a potential target for the treatment of silicosis. In this study, we found that silica exposure induced epithelial-mesenchymal transformation in rats and that the expression of integrin ITGB1 was elevated along with the EMT. We used CRISPR/Cas9 technology to construct integrin ITGB1 knockdown cell lines for in vitro experiments. We compared the expression of the EMT key proteins E-cadherin and vimentin in the ITGB1 knockdown cells and wild-type cells simultaneously stimulated by silica and detected the aggregation point distribution of E-cadherin and vimentin in the cells using laser confocal microscopy. Our results showed that ITGB1 knockout inhibited the ITGB1/ILK/Snail signaling pathway and attenuated the EMT occurrence compared to control cells. These results suggested that ITGB1 is associated with silica-induced EMT and may be a potential target for the treatment of silicosis.