Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice
Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice
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DOI：
10.1164/rccm.200907-1047oc
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发表时间：
2010-07-01
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;Gladwell, Wesley;Kleeberger, Steven R.
基本原理：NF-E2相关因子2（Nrf 2）-抗氧化反应元件（ARE）通路对于保护免受氧化损伤和炎症包括高氧诱导的急性肺损伤是必不可少的。微阵列表达谱显示，与野生型（Nrf 2（+/+））小鼠相比，高氧敏感性Nrf 2缺陷（Nrf 2（-/-））小鼠的肺过氧化物酶体增殖物激活受体γ（PPAR γ）诱导受到抑制。目的：验证PPARgamma是Nrf 2调节肺对高氧反应性的重要决定因素的假设。方法：应用计算生物信息学方法筛选Pparg启动子中与Nrf 2结合的潜在战神。通过体外启动子分析研究了潜在ARE的功能作用。通过经鼻内递送PPAR-y特异性干扰RNA暂时沉默PPART和通过给予小鼠PPAR-y配体15-脱氧-Delta（12，14）前列腺素J（2）来确定PPAR-y在高氧诱导的急性肺损伤中的作用。潜在ARE跨越-784/-764序列的缺失或定点突变显著减弱高氧-在过表达Nrf 2的气道上皮细胞中增加Pparg启动子活性，表明-784/-764 ARE对于Nrf 2调节的PPAR γ表达至关重要。通过特异性干扰RNA治疗降低肺PPAR γ的小鼠显著增加了高氧诱导的肺部炎症和损伤。15脱氧-δ（12，14）-前列腺素J（2）给药显著降低了Nrf 2（+/+）小鼠高氧诱导的肺部炎症和水肿，但在Nrf 2（-/-）小鼠中没有。结论：结果首次表明，Nrf 2驱动的PPAR γ诱导在肺氧化损伤中具有重要的保护作用。我们的观察结果提供了新的见解的治疗潜力的过氧化物酶体增殖物激活受体γ在气道氧化炎症性疾病。
Rationale: The NF-E2 related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is essential for protection against oxidative injury and inflammation including hyperoxia-induced acute lung injury. Microarray expression profiling revealed that lung peroxisome proliferator activated receptor gamma (PPAR gamma) induction is suppressed in hyperoxia-susceptible Nrf2-deficient (Nrf2(-/-)) mice compared with wild-type (Nrf2(+/+)) mice. PPAR gamma has pleiotropic beneficial effects including antiinflammation in multiple tissues.Objectives: We tested the hypothesis that PPAR gamma is an important determinant of pulmonary responsivity to hyperoxia regulated by Nrf2.Methods: A computational bioinformatic method was applied to screen potential AREs in the Pparg promoter for Nrf2 binding. The functional role of a potential ARE was investigated by in vitro promoter analysis. A role for PPAR gamma in hyperoxia-induced acute lung injury was determined by temporal silencing of PPART via intranasal delivery of PPAR-y-specific interference RNA and by administration of a PPAR gamma ligand 15-deoxy-Delta(12,14) prostaglandin J(2) in mice.Measurements and Main Results: Deletion or site-directed mutagenesis of a potential ARE spanning -784/-764 sequence significantly attenuated hyperoxia-increased Pparg promoter activity in airway epithelial cells overexpressing Nrf2, indicating that the -784/-764 ARE is critical for Nrf2-regulated PPAR gamma expression. Mice with decreased lung PPAR gamma by specific interference RNA treatment had significantly augmented hyperoxia-induced pulmonary inflammation and injury. 15 Deoxy-Delta(12,14)- prostaglandin J(2) administration significantly reduced hyperoxia-induced lung inflammation and edema in Nrf2(+/+), but not in Nrf2(-/-) mice.Conclusions: Results indicate for the first time that Nrf2-driven PPAR gamma induction has an essential protective role in pulmonary oxidant injury. Our observations provide new insights into the therapeutic potential of PPAR gamma in airway oxidative inflammatory disorders.