Assessment of Protection Offered By the NRF2 Pathway Against Hyperoxia-Induced Acute Lung Injury in NRF2 Knockout Rats.
Assessment of Protection Offered By the NRF2 Pathway Against Hyperoxia-Induced Acute Lung Injury in NRF2 Knockout Rats.
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DOI：
10.1097/shk.0000000000001882
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发表时间：
2022-02-01
期刊：
影响因子：
--
通讯作者：
Clough AV
中科院分区：
文献类型：
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作者：
Audi SH;Jacobs ER;Taheri P;Ganesh S;Clough AV
核因子红系2相关因子(Nrf2)是一种氧化还原敏感的转录因子，通过Nrf2-抗氧化剂反应元件(ARE)信号通路激活关键抗氧化剂和细胞保护酶的表达来响应氧化应激。我们的目的是研究高氧诱导的Nrf2基因敲除(KO)大鼠急性肺损伤(HALI)的特征，以阐明这一途径在HALI中的作用。成年Nrf2野生型(WT)和KO大鼠暴露于室内空气(常氧)或>；95%O2(高氧)48h后，在体内和体外测量选定的损伤和功能终点。结果表明，Nrf2-ARE信号通路对HALI有一定的保护作用，表现为KO和WT大鼠高氧诱导的组织学损伤和更高的肺内皮细胞滤过系数。我们观察到，与KO大鼠相比，WT大鼠在高氧诱导下肺组织谷胱甘肽合成酶、3-硝基酪氨酸(氧化应激指数)和白细胞介素1β的表达增加，并在体内摄取对GSH敏感的SPECT生物标志物99mTC-HMPAO。高氧还引起WT和KO大鼠肺组织髓过氧化物酶表达增加，但WT和KO之间无差异。高氧对抗凋亡蛋白Bcl2和过氧化还蛋白1的表达无明显影响。这些结果表明，Nrf2-ARE途径对HALI的保护作用部分是通过调节GSH氧化还原途径实现的。据我们所知，这是第一次使用大鼠Nrf2基因敲除模型来评估Nrf2-ARE信号通路在预防HALI中的作用。
Nuclear factor erythroid 2-related factor (Nrf2) is a redox-sensitive transcription factor that responds to oxidative stress by activating expressions of key antioxidant and cytoprotective enzymes via the Nrf2-antioxidant response element (ARE) signaling pathway. Our objective was to characterize hyperoxia-induced acute lung injury (HALI) in Nrf2 knock-out (KO) rats to elucidate the role of this pathway in HALI. Adult Nrf2 wildtype (WT) and KO rats were exposed to room air (normoxia) or > 95% O2 (hyperoxia) for 48 hours, after which selected injury and functional endpoints were measured in vivo and ex vivo. Results demonstrate that the Nrf2-ARE signaling pathway provides some protection against HALI, as reflected by greater hyperoxia-induced histological injury and higher pulmonary endothelial filtration coefficient in KO versus WT rats. We observed larger hyperoxia-induced increases in lung expression of glutathione (GSH) synthetase, 3-nitrotyrosine (index of oxidative stress), and interleukin-1β, and in vivo lung uptake of the GSH-sensitive SPECT biomarker 99mTc-HMPAO in WT compared to KO rats. Hyperoxia also induced increases in lung expression of myeloperoxidase in both WT and KO rats, but with no difference between WT and KO. Hyperoxia had no effect on expression of Bcl-2 (anti-apoptotic protein) or peroxiredoxin-1. These results suggest that the protection offered by the Nrf2-ARE pathway against HALI is in part via its regulation of the GSH redox pathway. To the best of our knowledge, this is the first study to assess the role of the Nrf2-ARE signaling pathway in protection against HALI using a rat Nrf2 knockout model.