Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease
Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease
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DOI：
10.1164/rccm.200804-535oc
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发表时间：
2009-01-15
影响因子：
24.7
通讯作者：
Kleeberger, Steven R.
中科院分区：
文献类型：
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作者：
Cho, Hye-Youn;Imani, Farhad;Kleeberger, Steven R.
理由：呼吸道合胞病毒 (RSV) 是婴幼儿严重下呼吸道疾病的最常见原因，但其发病机制尚不完全清楚。转录因子 Nrf2 通过抗氧化反应元件 (ARE) 介导的基因诱导来保护肺部免受氧化损伤和炎症。目的：本研究旨在确定 Nrf2 介导的细胞保护机制在小鼠气道 RSV 疾病中的作用。方法：Nrf2 缺陷型 (Nrf 2(-/-)) 和野生型 (Nrf 2(-/-)) 2(+/+))小鼠鼻内滴注RSV或媒介物。在另一项研究中，Nrf 2(+/+) 和 Nrf2(-/-) 小鼠在 RSV 感染前口服萝卜硫素（一种 Nrf 2-ARE 诱导剂）或磷酸盐缓冲盐水。测量和主要结果：RSV 诱导的支气管肺炎症、上皮损伤、粘液细胞化生以及鼻上皮损伤 Nrf2(-/-) 小鼠显着高于 Nrf2(+/+) 小鼠。与 Nrf2(+/+) 小鼠相比，Nrf2(-/-) 小鼠对 RSV 的反应显着减弱病毒清除和 IFN-γ、体重减轻、蛋白质/脂质氧化增强和 AP-1/NF-κ B 活性以及抑制抗氧化诱导。萝卜硫素预处理显着限制了 Nrf2(+/+) 小鼠的肺 RSV 复制和病毒诱导的炎症，但在 Nrf2(-/-) 小鼠中则不然。结论：本研究的结果支持氧化应激与 RSV 发病机制的关联以及 Nrf 2-ARE 途径在宿主抵抗 RSV 中的关键作用。
Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of significant lower respiratory illness in infants and young children, but its pathogenesis is not fully understood. The transcription factor Nrf2 protects lungs from oxidative injury and inflammation via antioxidant response element (ARE)-mediated gene induction.Objectives: The current study was designed to determine the role of Nrf2-mediated cytoprotective mechanisms in murine airway RSV disease.Methods: Nrf2-deficient (Nrf 2(-/-)) and wild-type (Nrf 2(+/+)) mice were intranasally instilled with RSV or vehicle. In a separate study, Nrf 2(+/+) and Nrf2(-/-) mice were treated orally with sulforaphane (an Nrf 2-ARE inducer) or phosphate-buffered saline before RSV infection.Measurements and Main Results: RSV-induced bronchopulmonary inflammation, epithelial injury, and mucus cell metaplasia as well as nasal epithelial injury were significantly greater in Nrf2(-/-) mice than in Nrf2(+/+) mice. Compared with Nrf2(+/+) mice, significantly attenuated viral clearance and IFN-gamma, body weight loss, heightened protein/lipid oxidation, and AP-1/NF-kappa B activity along with suppressed antioxidant induction was found in Nrf2(-/-) mice in response to RSV. Sulforaphane pretreatment significantly limited lung RSV replication and virus-induced inflammation in Nrf2(+/+) but not in Nrf2(-/-) mice.Conclusions: The results of this study support an association of oxidant stress with RSV pathogenesis and a key role for the Nrf 2-ARE pathway in host defense against RSV.