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• W2478531111 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 ( PLF s) were isolated from C57/ BL 6 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, PLF s 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 TGF β 1 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 TGF β 1 expression and alcohol‐induced exaggerate response to bleomycin‐induced acute lung injury." @default.
• W2478531111 created "2016-08-23" @default.
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• W2478531111 date "2016-07-20" @default.
• W2478531111 modified "2023-10-16" @default.
• W2478531111 title "Nuclear Thioredoxin‐1 Overexpression Attenuates Alcohol‐Mediated Nrf2 Signaling and Lung Fibrosis" @default.
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• W2478531111 doi "https://doi.org/10.1111/acer.13148" @default.
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