Inhibition of paraquat-induced oxidative stress, proinflammatory cytokine expression, and fibroblast-tomyofibroblast transformation by resveratrol via the Nrf2 pathway.
He-X; Wang-L; Szklarz-G; Ma-Q
Toxicologist 2012 Mar; 126(Suppl 1):462
Paraquat (PQ) is a most widely used herbicide in the world. PQ selectively accumulates in the lungs and induces lung injury and fibrosis in humans. Redox cycling has been linked with PQ pulmonary toxicity but no effective antidote is available. Resveratrol (Res) is a natural phytoalexin with multiple functions including antioxidant, anti-inflammatory in animals and humans. In this study, we found that Res at pharmacological doses effectively attenuated PQ-induced cell toxicity and fibrogenic response in human lung cells. PQ dose-dependently caused toxicity in normal human bronchial epithelium BEAS-2B cells including increased cell death, oxidative stress, and loss of mitochondrial inner membrane potential. Res at 10 to 20 uM markedly inhibited PQ toxicity. PQ at 10 uM induced transformation of normal human lung fibroblast WI-38 cells into myofibroblasts, as shown by the de nova synthesis of a-smooth muscle actin, and heightened production of inflammatory cytokines TNFa and IL-6 and growth factor TGFb1. On the other hand, pre- or cotreatment with Res blocked the fibrogenic reactions to PQ. Mechanistic analyses revealed that Res activated the oxidant/antioxidant-activated receptor Nrf2 to induce cytoprotective genes. Nrf2 was required for normal defense against PQ toxicity and fibrogenic reactions as loss of Nrf2 significantly increased PQ toxicity, myofibroblast transformation, and cytokine expression. Finally, Nrf2 mediated the protective response to PQ by Res because protection was lost in Nrf2-deficient cells. The study demonstrated that Res prevents PQ-induced ROS production, inflammation, and fibrogenic reactions in cultured cells by activating Nrf2 signaling. The findings provide new insights into the understanding and chemoprotection of PQ lung toxicity and potential intervention through Nrf2-based mechanisms.
Oxidation-reduction-reactions; Cytotoxicity; Herbicides; Pulmonary-function; Pulmonary-system; Lung-function; Lung-fibrosis; Antioxidants; Pharmacodynamics; Fibrogenicity; Toxic-effects; Toxic-materials; Cell-damage; Cellular-reactions; Lung-cells; Dose-response; Oxidative-processes; Cytotoxicity; Growth-factors; Genes; Cell-cultures
The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California