Inhibitory Activities of Ononin on Particulate Matter-induced Oxidative Stress

Exposure to high levels of atmospheric particulate matter (PM) with an aerodynamic diameter of less than 2.5 µm (PM_2.5) is associated with increased risk of respiratory injury, hospitalization, and respiratory death. The mechanism underlying the correlation between PM_2.5 exposure and adverse health effects has not been fully elucidated, but oxidative stress due to PM_2.5 appears to be an important molecular mechanism in PM_2.5-mediated toxicity. The aim of this study was to determine the effects of ononin, a major isoflavone, on PM_2.5-induced oxidative stress, and the mechanisms underlying these effects. Human pulmonary artery endothelial cells (HPAECs) were treated with PM_2.5 and then ononin. Exposure to PM_2.5 decreased cell viability in HPAECs in a time- and dose-dependent manner, possibly due to increased release of extracellular lactate dehydrogenase and generation of intracellular reactive oxygen species. PM_2.5-induced oxidative damage was observed to occur via alterations to superoxide dismutase and catalase activities. Serum- and glucocorticoid-inducible kinase 1 (SGK1), a crucial cell survival factor, was downregulated by PM_2.5. However, ononin treatment increased cell viability, decreased oxidative stress, and recovered the expression of SGK1 cell survival genes. Additionally, ononin increased the phosphorylation of mammalian target of rapamycin (mTOR) and dramatically suppressed the PM_2.5-induced expression of toll-like receptor 4, MyD88, and the autophagy-related proteins LC3 II and Beclin 1. These findings indicate that ononin exhibits pulmonary protective effects against PM_2.5-induced lung injury via inhibition of oxidative stress and mTOR-dependent autophagy pathways and is thus a potential therapeutic agent for PM_2.5-induced lung injury.