Acute exposure to PM2.5 triggers lung inflammatory response and apoptosis in rat.

Severe haze events, especially with high concentration of fine particulate matter (PM2.5), are frequent in China, which have gained increasing attention among public. The purpose of our study was explored the toxic effects and potential damage mechanisms about PM2.5 acute exposure. Here, the diverse dosages of PM2.5 were used to treat SD rats and human bronchial epithelial cell (BEAS-2B) for 24 h, and then the bioassays were performed at the end of exposure. The results show that acute exposure to diverse dosages of PM2.5 could trigger the inflammatory response and apoptosis. The severely oxidative stress may contribute to the apoptosis. Also, the activation of Nrf2-ARE pathway was an important compensatory process of antioxidant damage during the early stage of acute exposure to PM2.5. Furthermore, the HO-1 was suppression by siRNA that promoted cell apoptosis triggered by PM2.5. In other words, enhancing the expression of HO-1 may mitigate the cell apoptosis caused by acute exposure to PM2.5. In summary, our findings present the first time that prevent or mitigate the damage triggered by PM2.5 through antioxidant approaches was a promising strategy.

Identification and validation of metformin protects against PM2.5-induced macrophages cytotoxicity by targeting toll like receptor pathway.

Fine particle matter (PM2.5) has been extensively reported to contribute to the pathogenesis of pulmonary diseases. Recently, metformin has been reported to attenuate PM2.5 associated respiratory and cardiovascular injury, but the underling mechanism has not been discovered. Here, we performed comprehensively bioinformatics analysis and fully validation experiment to investigate the protection role of metformin and underling mechanism with RNAseq profile in GEO database. A combination of various bioinformatics tools including edgeR, principal component analysis (PCA), K-Means clustering, Gene Set Enrichment Analysis (GSEA), GO and KEGG enrichment were performed to identify the TLRs/MyD88/NF-κB axis functional as the key signaling transduction during PM2.5 associated toxicity. PM2.5 activated TLRs/MyD88/NF-κB pathway and resulted in significantly generation of IL-6, TNF-α, mitochondrial damage, decreasing of cell viability and increased LDH activity in RAW264.7 cells. Metformin significantly attenuated the production of IL-6, mitochondrial damage, cell viability and LDH activity by limiting TLRs/MyD88/NF-κB pathway. The siRNA against AMPKα2 or negative control were transfected to RAW264.7 cells to identify whether metformin protects PM2.5-induced cytotoxicity in an AMPKα2-dependent manner. Pretreatment with metformin significantly attenuated PM2.5 induced decreasing of cell viability and increased LDH activity, as well as inhibited the TLRs/MyD88/NF-κB pathway in both siControl or siAMPKα2 cells. Taken together, our results indicate that metformin protects against PM2.5-induced mitochondrial damage and cell cytotoxicity by inhibiting TLRs/MyD88/NF-κB signaling pathway in an AMPKα2 independent manner.