Acrolein causes transcriptional induction of phase II genes by activation of Nrf2 in human lung type II epithelial (A549) cells

Tirumalai, Radhakrishna S.; Kumar, T. R. Santhosh; Hue, K K; Biswal, Shyam

doi:10.1016/s0378-4274(02)00055-3

Cited by 100 publications

(71 citation statements)

References 34 publications

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“…The homogenates were centrifuged at 5000 g for 5 minutes at 4°C, and the supernatant fluid was used to measure GSH and GSSG per the manufacturer's instructions. Total GSH in MEFs was measured as previously described (45).…”

Section: Methodsmentioning

confidence: 99%

Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis

Thimmulappa

Lee

Rangasamy

et al. 2006

Journal of Clinical Investigation

925

696

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Host genetic factors that regulate innate immunity determine susceptibility to sepsis. Disruption of nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that regulates redox balance and stress response, dramatically increased the mortality of mice in response to endotoxin-and cecal ligation and puncture-induced septic shock. LPS as well as TNF-a stimulus resulted in greater lung inflammation in Nrf2-deficient mice. Temporal analysis of pulmonary global gene expression after LPS challenge revealed augmented expression of large numbers of proinflammatory genes associated with the innate immune response at as early as 30 minutes in lungs of Nrf2-deficient mice, indicating severe immune dysregulation. The expression profile indicated that Nrf2 has a global influence on both MyD88-dependent and -independent signaling. Nrf2-deficient mouse embryonic fibroblasts showed greater activation of NF-kB and interferon regulatory factor 3 in response to LPS and polyinosinic-polycytidylic acid [poly(I:C)] stimulus, corroborating the effect of Nrf2 on MyD88-dependent and -independent signaling. Nrf2's regulation of cellular glutathione and other antioxidants is critical for optimal NF-kB activation in response to LPS and TNF-a. Our study reveals Nrf2 as a novel modifier gene of sepsis that determines survival by mounting an appropriate innate immune response.

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Section: Methodsmentioning

confidence: 99%

Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis

Thimmulappa

Lee

Rangasamy

et al. 2006

Journal of Clinical Investigation

925

696

View full text Add to dashboard Cite

show abstract

“…Exposure of human lung epithelial (A549) cells to acrolein (150 fmol/cell for 1 h) first depleted 80% of the intracellular GSH pool and then increased the transcription of γ-glutamylcysteine synthetase at 6-12 h post-treatment, resulting in normalization of GSH levels. Acrolein treatment also activated the transcription of phase II genes, as indicated by an increase in mRNA coding for NAD(P)H:quinone oxidoreductase [110].…”

Section: Acrolein As An Inducer Of the Keap1-nrf2-dependent Are/epre mentioning

confidence: 99%

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Stevens

Maier

2008

Molecular Nutrition Food Res

630

634

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Acrolein (2-propenal) is ubiquitously present in (cooked) foods and in the environment. It is formed from carbohydrates, vegetable oils and animal fats, amino acids during heating of foods, and by combustion of petroleum fuels and biodiesel. Chemical reactions responsible for release of acrolein include heat-induced dehydration of glycerol, retro-aldol cleavage of dehydrated carbohydrates, lipid peroxidation of polyunsaturated fatty acids, and Strecker degradation of methionine and threonine. Smoking of tobacco products equals or exceeds the total human exposure to acrolein from all other sources. The main endogenous sources of acrolein are myeloperoxidase-mediated degradation of threonine and amine oxidase-mediated degradation of spermine and spermidine, which may constitute a significant source of acrolein in situations of oxidative stress and inflammation. Acrolein is metabolized by conjugation with glutathione and excreted in the urine as mercapturic acid metabolites. Acrolein forms Michael adducts with ascorbic acid in vitro, but the biological relevance of this reaction is not clear. The biological effects of acrolein are a consequence of its reactivity towards biological nucleophiles such as guanine in DNA and cysteine, lysine, histidine, and arginine residues in critical regions of nuclear factors, proteases, and other proteins. Acrolein adduction disrupts the function of these biomacromolecules which may result in mutations, altered gene transcription, and modulation of apoptosis.

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“…Newly identified Nrf2-modulated genes were validated with electrophoretic mobility shift assay (37,38). We incubated 10 μg of nuclear extract from small airway epithelium with a 32 P-labeled antioxidant response element oligonucleotide from NAD(P)H dehydrogenase, quinone 1 (NQO1), a known Nrf2-modulated gene (10,37).…”

Section: Validation Of Newly Identified Nrf2-modulated Genesmentioning

confidence: 99%

Coordinate Control of Expression of Nrf2-Modulated Genes in the Human Small Airway Epithelium Is Highly Responsive to Cigarette Smoking

Hübner

Schwartz

et al. 2009

Mol Med

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is an oxidant-responsive transcription factor known to induce detoxifying and antioxidant genes. Cigarette smoke, with its large oxidant content, is a major stress on the cells of small airway epithelium, which are vulnerable to oxidant damage. We assessed the role of cigarette smoke in activation of Nrf2 in the human small airway epithelium in vivo. Fiberoptic bronchoscopy was used to sample the small airway epithelium in healthy-nonsmoker and healthysmoker, and gene expression was assessed using microarrays. Relative to nonsmokers, Nrf2 protein in the small airway epithelium of smokers was activated and localized in the nucleus. The human homologs of 201 known murine Nrf2-modulated genes were identified, and 13 highly smoking-responsive Nrf2-modulated genes were identified. Construction of an Nrf2 index to assess the expression levels of these 13 genes in the airway epithelium of smokers showed coordinate control, an observation confirmed by quantitative PCR. This coordinate level of expression of the 13 Nrf2-modulated genes was independent of smoking history or demographic parameters. The Nrf2 index was used to identify two novel Nrf2-modulated, smoking-responsive genes, pirin (PIR) and UDP glucuronosyltransferase 1-family polypeptide A4 (UGT1A4). Both genes were demonstrated to contain functional antioxidant response elements in the promoter region. These observations suggest that Nrf2 plays an important role in regulating cellular defenses against smoking in the highly vulnerable small airway epithelium cells, and that there is variability within the human population in the Nrf2 responsiveness to oxidant burden.

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Acrolein causes transcriptional induction of phase II genes by activation of Nrf2 in human lung type II epithelial (A549) cells

Cited by 100 publications

References 34 publications

Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis

Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Coordinate Control of Expression of Nrf2-Modulated Genes in the Human Small Airway Epithelium Is Highly Responsive to Cigarette Smoking

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