Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice.
Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice.
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DOI：
10.1016/j.freeradbiomed.2012.08.009
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发表时间：
2012-10-15
影响因子：
7.4
通讯作者：
Piantadosi, Claude A.
中科院分区：
文献类型：
--
作者：
Athale, Janhavi;Ulrich, Allison;MacGarvey, Nancy Chou;Bartz, Raquel R.;Welty-Wolf, Karen E.;Suliman, Hagir B.;Piantadosi, Claude A.
急性肺损伤(ALI)启动保护性反应，涉及Nrf2(NFe2l2)转录因子下游的基因，包括血红素加氧酶-1(HO-1)，它刺激线粒体的生物生成和相关的抗炎过程。我们研究了小鼠金黄色葡萄球菌肺炎时线粒体的生物发生，以及Nrf2缺乏对肺线粒体生物发生和肺部炎症消退的影响。用线粒体报告基因(mt-cox8-gfp)小鼠、野生型(Wt)小鼠和NRF2−/−小鼠研究了经鼻注入活菌建立的金黄色葡萄球菌肺炎。分别于0、6、24、48h对小鼠进行肺泡灌洗、肺湿干比、实时荧光定量RT-−/−和Western分析、免疫组织化学和荧光显微镜检查。在mt-Cox8-GFP小鼠中，支气管和肺泡II型(AT2)上皮细胞线粒体荧光增强。与Nrf2−/−小鼠相比，WT小鼠HO-1迅速上调，促炎性肿瘤坏死因子-α、IL-1β和CCL_2水平降低，抗炎IL-10和细胞因子信号转导抑制因子-3水平升高，在AT_2细胞中尤为明显。在肺泡区，WT而不是NRF2−/−小鼠表现出强烈的核呼吸因子-1、pGC-1α、线粒体转录因子-A、SOD2、Bnip3、线粒体DNA拷贝数和柠檬酸合成酶。这些发现表明金黄色葡萄球菌肺炎在肺泡区诱导依赖于Nrf2的线粒体生物发生，主要是在AT2细胞。Nrf2的缺失抑制了肺泡线粒体生物发生和抗炎的转录网络，从而加重了ALI。这一发现将线粒体生物发生的氧化还原激活与ALI的解决联系起来。
Acute lung injury (ALI) initiates protective responses involving genes downstream of the Nrf2 (Nfe2l2) transcription factor, including heme oxygenase-1 (HO-1), which stimulates mitochondrial biogenesis and related anti-inflammatory processes. We examined mitochondrial biogenesis during Staphylococcus aureus pneumonia in mice and the effect of Nrf2 deficiency on lung mitochondrial biogenesis and resolution of lung inflammation. S. aureus pneumonia established by nasal insufflation of live bacteria was studied in mitochondrial reporter (mt-COX8-GFP) mice, wild-type (WT) mice, and Nrf2−/− mice. Bronchoalveolar lavage, wet/dry ratios, real-time RT-PCR and Western analysis, immunohistochemistry, and fluorescence microscopy were performed on the lung at 0, 6, 24, and 48 h. The mice survived S. aureus inoculations at 5 × 108 CFU despite diffuse lung inflammation and edema, but the Nrf2−/− lung showed increased ALI. In mt-COX8-GFP mice, mitochondrial fluorescence was enhanced in bronchial and alveolar type II (AT2) epithelial cells. WT mice displayed rapid HO-1 upregulation and lower proinflammatory TNF-α, IL-1β, and CCL2 and, especially in AT2 cells, higher anti-inflammatory IL-10 and suppressor of cytokine signaling-3 than Nrf2−/− mice. In the alveolar region, WT but not Nrf2−/− mice showed strongly induced nuclear respiratory factor-1, PGC-1α, mitochondrial transcription factor-A, SOD2, Bnip3, mtDNA copy number, and citrate synthase. These findings indicate that S. aureus pneumonia induces Nrf2-dependent mitochondrial biogenesis in the alveolar region, mainly in AT2 cells. Absence of Nrf2 suppresses the alveolar transcriptional network for mitochondrial biogenesis and anti-inflammation, which worsens ALI. The findings link redox activation of mitochondrial biogenesis to ALI resolution.
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影响因子：
3
作者：
Kimura, K;Miyazaki, S;Yamaguchi, K
通讯作者：
Yamaguchi, K
DOI：
10.1164/rccm.201102-0271oc
发表时间：
2011-10-15
影响因子：
24.7
作者：
Kong, Xiaoni;Thimmulappa, Rajesh;Biswal, Shyam
通讯作者：
Biswal, Shyam
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
DOI：
10.1161/atvbaha.110.204123
发表时间：
2010-08-01
影响因子：
8.7
作者：
Ichihara, Sahoko;Yamada, Yoshiji;Ichihara, Gaku
通讯作者：
Ichihara, Gaku
DOI：
10.1152/ajplung.00182.2003
发表时间：
2003-11-01
影响因子：
4.9
作者：
Coyne, CB;Gambling, TM;Johnson, LG
通讯作者：
Johnson, LG