Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice

被引:156
作者
Athale, Janhavi [1 ]
Ulrich, Allison [2 ]
MacGarvey, Nancy Chou [1 ]
Bartz, Raquel R. [2 ,3 ]
Welty-Wolf, Karen E. [1 ,4 ]
Suliman, Hagir B. [2 ]
Piantadosi, Claude A. [1 ,2 ,4 ,5 ]
机构
[1] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Dept Anesthesiol, Durham, NC 27710 USA
[3] Durham VA Med Ctr, Dept Anesthesiol, Durham, NC 27710 USA
[4] Durham VA Med Ctr, Dept Med, Durham, NC 27710 USA
[5] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA
关键词
Acute lung injury; IL-10; Inflammation; Mitochondria; Oxidative stress; NRF-1; Nrf2; Free radicals; TRANSCRIPTION FACTOR NRF2; HEME OXYGENASE-1 GENE; CYTOKINE RELEASE; ACTIVATION; ALPHA; INFLAMMATION; DISRUPTION; EPITHELIUM; COMMUNITY; SURVIVAL;
D O I
10.1016/j.freeradbiomed.2012.08.009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
Acute lung injury (ALI) initiates protective responses involving genes downstream of the Nrf2 (Nfe212) 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 x 10(8) 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-alpha, IL-1 beta, and CCL2 and, especially in AT2 cells, higher anti-inflammatory IL-10 and suppressor of cytokine signaling-3 than Nrj2(-/-) mice. In the alveolar region. WT but not Nrf2(-/-) mice showed strongly induced nuclear respiratory factor-1, PGC-1 alpha, 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. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:1584 / 1594
页数:11
相关论文
共 55 条
[1]
Involvement of PPARγ co-activator-1, nuclear respiratory factors 1 and 2, and PPARα in the adaptive response to endurance exercise [J].
Baar, K .
PROCEEDINGS OF THE NUTRITION SOCIETY, 2004, 63 (02) :269-273
[2]
Oxidative stress targets in pulmonary emphysema: focus on the Nrf2 pathway [J].
Boutten, A. ;
Goven, D. ;
Boczkowski, J. ;
Bonay, M. .
EXPERT OPINION ON THERAPEUTIC TARGETS, 2010, 14 (03) :329-346
[3]
Mitochondrial biogenesis in the pulmonary vasculature during inhalational lung injury and fibrosis [J].
Carraway, Martha S. ;
Suliman, Hagir B. ;
Kliment, Corrine ;
Welty-Wolf, Karen E. ;
Oury, Tim D. ;
Piantadosi, Claude A. .
ANTIOXIDANTS & REDOX SIGNALING, 2008, 10 (02) :269-275
[4]
Identification of novel modulators of mitochondrial function by a genome-wide RNAi screen in Drosophila melanogaster [J].
Chen, Jian ;
Shi, Xiaoying ;
Padmanabhan, Ranjani ;
Wang, Qiong ;
Wu, Zhidan ;
Stevenson, Susan C. ;
Hild, Marc ;
Garza, Dan ;
Li, Hao .
GENOME RESEARCH, 2008, 18 (01) :123-136
[5]
Lipopolysaccharide induces apoptotic insults to human alveolar epithelial A549 cells through reactive oxygen species-mediated activation of an intrinsic mitochondrion-dependent pathway [J].
Chuang, Chi-Yuan ;
Chen, Ta-Liang ;
Cherng, Yih-Giun ;
Tai, Yu-Tyng ;
Chen, Tyng-Guey ;
Chen, Ruei-Ming .
ARCHIVES OF TOXICOLOGY, 2011, 85 (03) :209-218
[6]
Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice [J].
Chung, Su Wol ;
Liu, Xiaoli ;
Macias, Alvaro A. ;
Baron, Rebecca M. ;
Perrella, Mark A. .
JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (01) :239-247
[7]
Role of claudin interactions in airway tight junctional permeability [J].
Coyne, CB ;
Gambling, TM ;
Boucher, RC ;
Carson, JL ;
Johnson, LG .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2003, 285 (05) :L1166-L1178
[8]
DEMLING RH, 1995, ANNU REV MED, V46, P193
[9]
Transcriptional mechanisms of acute lung injury [J].
Fan, J ;
Ye, RD ;
Malik, AB .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2001, 281 (05) :L1037-L1050
[10]
Defining mitochondrial targets to combat the pleiotropic effects of toxic oxidative stress [J].
Fariss, MW ;
Chan, CB ;
Patel, M ;
Van Houten, B ;
Orrenius, S .
MOLECULAR INTERVENTIONS, 2005, 5 (02) :94-111