Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells

• Published in: American journal of physiology. Lung cellular and molecular physiology 2008-03, Vol.294 (3), p.L478-L488
• Main Authors: Kode, Aruna, Rajendrasozhan, Saravanan, Caito, Samuel, Yang, Se-Ran, Megson, Ian L, Rahman, Irfan
• Format: Article
• Language: English
• Subjects: Antioxidants; Antioxidants - pharmacology; Cells; Cells, Cultured; Chronic obstructive pulmonary disease; Cigarettes; Down-Regulation; Epithelial Cells - physiology; Genes; Glutamate-Cysteine Ligase - biosynthesis; Glutathione - biosynthesis; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Kelch-Like ECH-Associated Protein 1; Lung - cytology; Lung - physiology; Lungs; NF-E2-Related Factor 2 - physiology; Oxidation; Oxidative Stress - drug effects; Protein Transport - drug effects; Reactive Oxygen Species - metabolism; RNA, Small Interfering - metabolism; Smoking - physiopathology; Stilbenes - pharmacology; Tobacco smoke
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00361.2007

1 Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York; and 2 Free Radical Research Laboratory, UHI Millennium Institute, Inverness, Scotland, United Kingdom Submitted 3 September 2007 ; accepted in final form 21 December 2007 Nuclear erythroid-related factor 2 (Nrf2), a redox-sensitive transcription factor, is involved in transcriptional regulation of many antioxidant genes, including glutamate-cysteine ligase (GCL). Cigarette smoke (CS) is known to cause oxidative stress and deplete glutathione (GSH) levels in alveolar epithelial cells. We hypothesized that resveratrol, a polyphenolic phytoalexin, has antioxidant signaling properties by inducing GSH biosynthesis via the activation of Nrf2 and protects lung epithelial cells against CS-mediated oxidative stress. Treatment of human primary small airway epithelial and human alveolar epithelial (A549) cells with CS extract (CSE) dose dependently decreased GSH levels and GCL activity, effects that were associated with enhanced production of reactive oxygen species. Resveratrol restored CSE-depleted GSH levels by upregulation of GCL via activation of Nrf2 and also quenched CSE-induced release of reactive oxygen species. Interestingly, CSE failed to induce nuclear translocation of Nrf2 in A549 and small airway epithelial cells. On the contrary, Nrf2 was localized in the cytosol of alveolar and airway epithelial cells due to CSE-mediated posttranslational modifications such as aldehyde/carbonyl adduct formation and nitration. On the other hand, resveratrol attenuated CSE-mediated Nrf2 modifications, thereby inducing its nuclear translocation associated with GCL gene transcription, as demonstrated by GCL-promoter reporter and Nrf2 small interfering RNA approaches. Thus resveratrol attenuates CSE-mediated GSH depletion by inducing GSH synthesis and protects epithelial cells by reversing CSE-induced posttranslational modifications of Nrf2. These data may have implications in dietary modulation of antioxidants in treatment of chronic obstructive pulmonary disease. glutamate-cysteine ligase; 4-hydroxy-2-nonenal; chronic obstructive pulmonary disease; polyphenols; reactive oxygen species Address for reprint requests and other correspondence: I. Rahman, Dept. of Environmental Medicine, Univ. of Rochester Medical Center, Box 850,601 Elmwood Ave., Rochester, NY 14642 (e-mail: irfan_rahman{at}urmc.rochester.edu )