Nuclear Thioredoxin-1 Overexpression Attenuates Alcohol-Mediated Nrf2 Signaling and Lung Fibrosis.
Alcohol Clin Exp Res
; 40(9): 1846-56, 2016 09.
Article
em En
| MEDLINE
| ID: mdl-27436123
ABSTRACT
BACKGROUND:
Alcohol abuse, which impairs antioxidant defenses and promotes acute lung injury, increases Nrf2 nuclear translocation but nevertheless inhibits its activation of the antioxidant response element (ARE). Thioredoxin-1 (Trx1) is required for optimal Nrf2 binding and activation of the ARE, and we hypothesized that its inhibition contributes to impaired Nrf2-ARE signaling in the alcoholic lung.METHODS:
Lung tissue and primary lung fibroblasts (PLFs) were isolated from C57/BL6 wild-type (WT) and transgenic mice overexpressing the human Trx1 gene with a nuclear localizing sequence (NLS-Tg); some mice consumed alcohol in water prior to lung tissue and PLF isolation; in some mice, acute lung injury was induced with intratracheal bleomycin. In other experiments, PLFs were isolated from WT and NLS-Tg mice and then exposed to alcohol. Finally, PLF isolated from WT mice were transfected with Trx1 expression vector containing either a cytosolic localized sequence (NES) or a nuclear localized sequence (NLS) prior to alcohol exposure.RESULTS:
Alcohol treatment in vivo or in vitro decreased Trx1 expression, and bleomycin-treated alcohol-fed mice had fibrotic disrepair in their lungs. In parallel, whereas alcohol exposure in vitro increased TGFß1 expression and decreased Nrf2-ARE activity in PLF from WT mice, these effects were not observed in PLF from NLS-Tg mice. Finally, selective overexpression of Trx1 in the nucleus but not in the cytosol preserved Nrf2-ARE activity during alcohol exposure.CONCLUSIONS:
Although alcohol-induced redox stress actually promotes Nrf2 nuclear translocation, the coincident suppression of Trx1 impairs Nrf2-ARE activity within the nuclear compartment. Nuclear overexpression of Trx1 restored Nrf2-ARE activity and attenuated alcohol-induced TGFß1 expression and alcohol-induced exaggerate response to bleomycin-induced acute lung injury.Palavras-chave
Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fibrose Pulmonar
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Tiorredoxinas
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Transdução de Sinais
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Núcleo Celular
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Etanol
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Fator 2 Relacionado a NF-E2
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article