Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells
Abstract
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.
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From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Kode et al., 2008
In C. elegans, resveratrol, metformin, and rapamycin activate Nrf2 signaling as part of their mechanism of lifespan extension.
“in C. elegans, drugs believed to be ‘calorie restriction mimetics’ (resveratrol, metformin, and rapamycin) activate the Nrf2 signaling pathway as part of their mechanism of lifespan extension”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Kode et al., 2008
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- Authors
- Kode, A., Rajendrasozhan, S., Caito, S., Yang, S.-R., Megson, I. L., & Rahman, I.
- Affiliations
- University of Rochester Medicine (US)
- Venue
- American Journal of Physiology-Lung Cellular and Molecular Physiology
- Publisher
- American Physiological Society
- Published
- 2008-03
- Volume
- 294
- Issue
- 3
- Pages
- L478-L488
- ISSN
- 1040-0605 (ISSN-L)
- 1522-1504
- OpenAlex
- W2138420210
- Cited by
- 447
- References
- 59
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 13 · 2023: 26 · 2022: 10 · 2021: 32 · 2020: 25 · 2019: 28 · 2018: 21 · 2017: 33 · 2016: 27 · 2015: 28 · 2014: 36 · 2013: 30 · 2012: 25
- FWCI
- 9.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Lung Cellular and Molecular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL085613)
- National Institute of Environmental Health Sciences (ES-01247, ES 07026, P30ES001247)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- resveratrol, Nrf2, glutathione synthesis, gamma-glutamylcysteine synthetase, cigarette smoke extract, oxidative stress, alveolar epithelial cells, small airway epithelial cells, reactive oxygen species, Nrf2 nuclear translocation, antioxidant signaling, chronic obstructive pulmonary disease, dietary antioxidants
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Resveratrol, Antioxidants, Cells, Cultured, Epithelial Cells, Glutamate-Cysteine Ligase, Glutathione, Humans, Lung, Smoking, Stilbenes, Down-Regulation, Reactive Oxygen Species, Oxidative Stress, Protein Transport, RNA, Small Interfering, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2
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