Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice
Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice
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DOI：
10.1016/j.freeradbiomed.2018.10.400
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发表时间：
2018-12-01
影响因子：
7.4
通讯作者：
Hizawa, Nobuyuki
中科院分区：
文献类型：
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作者：
Sakurai, Hirofumi;Morishima, Yuko;Hizawa, Nobuyuki
香烟烟雾和其他环境污染物引起的氧化应激导致难治性哮喘。为了更好地了解吸烟在哮喘中的作用，我们研究了香烟烟雾对小鼠过敏性呼吸道反应的影响，并检测了核因子-E2相关因子-2(Nrf2)及其下游因子的表达，因为Nrf2已知在抗氧化反应中发挥关键作用。卵子致敏和激发的BALB/c小鼠暴露在香烟烟雾中，然后用地塞米松、萝卜硫醚(Nrf2的激活剂)或它们的组合进行治疗。当暴露在香烟烟雾中时，Nrf2及其相关转录本在氧化应激反应中上调，哮喘反应是类固醇抵抗的。在OVA致敏和激发的小鼠中，暴露在香烟烟雾中并用萝卜硫素治疗的小鼠，Nrf2介导的抗氧化反应在更大程度上被上调，哮喘反应的类固醇敏感性恢复。此外，在香烟烟雾暴露的小鼠中，类固醇反应性的关键调节因子组蛋白脱乙酰基酶2(HDAC2)的表达和活性降低，但经萝卜硫素处理后恢复。没有观察到萝卜硫素对Nrf2缺陷小鼠的影响。这些结果表明，香烟烟雾可诱导哮喘气道类固醇无反应，萝卜硫素通过上调Nrf2和增强HDAC2的表达和活性来恢复类固醇敏感性。因此，Nrf2可能成为香烟烟雾相关性难治性哮喘激素治疗耐药的潜在分子靶点。
Oxidative stress induced by cigarette smoke and other environmental pollutants contributes to refractory asthma. To better understand the role of smoking in asthma, we investigated the effects of cigarette smoke on allergic airway responses in mice and examined expression of nuclear factor-E2-related factor-2 (Nrf2) and its downstream factors, because Nrf2 is known to play a pivotal role in antioxidant responses. OVA-sensitized and challenged BALB/c mice were exposed to cigarette smoke and then treated with dexamethasone, sulforaphane (an activator of Nrf2), or their combination. Upon exposure to cigarette smoke, Nrf2 and associated transcripts were upregulated in response to oxidative stress, and asthmatic responses were steroid resistant. In OVA-sensitized and challenged mice exposed to cigarette smoke and treated with sulforaphane, Nrf2-mediated antioxidant responses were upregulated to a greater extent, and steroid sensitivity of asthmatic responses was restored. Moreover, the expression and activity of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness, was reduced in mice exposed to cigarette smoke, but restored by sulforaphane treatment. No effects of sulforaphane were observed in Nrf2-deficient mice. These findings indicate that cigarette smoke induces steroid unresponsiveness in asthmatic airways, and that sulforaphane restores steroid sensitivity via upregulation of Nrf2 and enhancement of HDAC2 expression and activity. Thus, Nrf2 may serve as a potential molecular target for cigarette smoke-related refractory asthma resistant to steroid therapy.