Resveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the Nrf2 pathway

Details

• Personal Author:
  Bi Y ; He X ; Ma Q ; Szklarz G ; Wang L
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Antibodies Antioxidants Cells, Cultured Cytotoxins DNA Genetics Growth Hazardous Substances Herbicides Immune System Lung Occupational Health Respiratory System Safety

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• Keywords:
  Antibody-response Antioxidation Author Keywords: Antioxidants Cell-cultures Cell-damage Cellular-reactions Cytotoxicity DNA-damage Dose-response Fibroblasts Fibrogenicity Genes Growth-factors Immune-reaction Lung-cells Lung-fibrosis Lung-function Molecular-biology Oxidation-reduction-reactions Oxidative-processes Oxidative Stress Pharmacodynamics Pulmonary-function Pulmonary-system Regulation Of Gene Expression Respiratory Toxicants Therapeutic-agents Toxic-effects Toxic-materials

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• ISSN:
  0022-3565
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  81-90
• Volume:
  342
• Issue:
  1
• NIOSHTIC Number:
  nn:20040737
• Citation:
  J Pharmacol Exp Ther 2012 Jul; 342(1):81-90
• Contact Point Address:
  Q. Ma, Mailstop 3014, 1095 Willowdale Road, Morgantown, WV 26505
• Email:
  qam1@cdc.gov
• CAS Registry Number:
  Methyl viologen (CAS RN 1910-42-5) ; Resveratrol (CAS RN 501-36-0)
• Federal Fiscal Year:
  2012
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Pharmacology and Experimental Therapeutics
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:76f355eb219a00d4e310135ef092d1efa9b08c1d8a6cd8c9f3615c59dc76578ea2787ba7f0a841ae463da2344733e6bde2dd6c0759369ccbbf702c7bd2e90afb
• Download URL:
  https://stacks.cdc.gov/view/cdc/193498/cdc_193498_DS1.pdf
• File Type:
  [PDF - 995.87 KB ]