Resveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the Nrf2 pathway.
He-X; Wang-L; Szklarz-G; Bi-Y; Ma-Q
J Pharmacol Exp Ther 2012 Jul; 342(1):81-90
Nrf2 is an antioxidant-activated transcription factor that recently emerged as a critical regulator of cellular defense against oxidative and inflammatory lesions. Resveratrol (Res) is a natural phytoalexin that exhibits multiple therapeutic potentials including antioxidative and antiinflammatory effects in animals. Paraquat (PQ) is the second most widely used herbicide worldwide but selectively accumulates in human lungs to cause oxidative injury and fibrosis with high mortality. Here we analyzed the molecular mechanism of the fibrogenic response to PQ and its inhibition by Res and Nrf2. PQ dose-dependently caused toxicity in normal human bronchial epithelial cells (BEAS-2B) resulting in mitochondrial damage, oxidative stress, and cell death; Res at 10 microM markedly inhibited PQ toxicity. PQ at 10 microM stimulated production of inflammatory and profibrogenic factors (TNFalpha, IL-6, and TGFbeta1) and induced transformation of normal human lung fibroblasts (WI38-VA13) to myofibroblasts; both effects were inhibited by Res. Res strongly activated the Nrf2 signaling pathway and induced antioxidant response element-dependent cytoprotective genes. On the other hand, knockout or knockdown of Nrf2 markedly increased PQ-induced cytotoxicity, cytokine production, and myofibroblast transformation, and abolished protection by Res. The findings demonstrate that Res attenuates PQ-induced ROS production, inflammation, and fibrotic reactions by activating Nrf2 signaling. The study reveals a new pathway for molecular intervention against pulmonary oxidative injury and fibrosis.
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; Antibody-response; Immune-reaction; Antioxidation; Therapeutic-agents; Molecular-biology; DNA-damage;
Author Keywords: antioxidants; fibroblasts; oxidative stress; regulation of gene expression; respiratory toxicants
Q. Ma, Mailstop 3014, 1095 Willowdale Road, Morgantown, WV 26505
Journal of Pharmacology and Experimental Therapeutics