Disruption of Nrf2 impairs the resolution of hyperoxia-induced acute lung injury and inflammation in mice.
Disruption of Nrf2 impairs the resolution of hyperoxia-induced acute lung injury and inflammation in mice.
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DOI：
10.4049/jimmunol.0804248
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发表时间：
2009-06-01
期刊：
影响因子：
--
通讯作者：
Reddy SP
中科院分区：
文献类型：
--
作者：
Reddy NM;Kleeberger SR;Kensler TW;Yamamoto M;Hassoun PM;Reddy SP
氧化剂介导的急性肺损伤（ALI）后的异常组织修复和持续性炎症可导致各种肺部疾病的发生和进展，但这些过程的机制尚不清楚。高氧被广泛用于肺部疾病的治疗，但这种氧化剂暴露对正在从ALI恢复的患者的影响尚不清楚。nrf 2已经成为一个重要的转录因子，通过诱导几种解毒酶和其他蛋白质来调节氧化应激。使用高氧诱导的ALI（HALI）的实验模型，我们研究了氧化应激在解决肺损伤和炎症中的作用。我们发现，当暴露于亚致死（72小时）高氧，Nrf 2缺陷，但不是野生型小鼠，在恢复过程中死亡。当两种基因型暴露于较短时间的HALI（48小时）时，Nrf 2缺陷小鼠在恢复期间的肺部表现出持续的细胞损伤、肺泡和内皮细胞再生受损以及巨噬细胞和淋巴细胞的持续细胞浸润。Nrf 2缺陷小鼠在高氧后立即补充GSH，以与野生型小鼠相似的方式显着恢复了其从高氧诱导的损伤中恢复的能力。因此，本研究的结果表明，Nrf 2调节的转录反应，特别是GSH的合成，是肺组织修复和体内炎症的决议是至关重要的，并表明，一个功能失调的Nrf 2-GSH通路可能会损害这些过程在体内。
Aberrant tissue repair and persistent inflammation following oxidant-mediated acute lung injury (ALI) can lead to the development and progression of various pulmonary diseases, but the mechanisms underlying these processes remain unclear. Hyperoxia is widely used in the treatment of pulmonary diseases, but the effects of this oxidant exposure in patients undergoing recovery from ALI are not clearly understood. Nrf2 has emerged as a crucial transcription factor that regulates oxidant stress through the induction of several detoxifying enzymes and other proteins. Using an experimental model of hyperoxia-induced ALI (HALI), we have examined the role of oxidant stress in resolving lung injury and inflammation. We found that when exposed to sub-lethal (72 h) hyperoxia, Nrf2-deficient, but not wild-type mice, succumbed to death during recovery. When both genotypes were exposed to a shorter period of HALI (48 h), the lungs of Nrf2-deficient mice during recovery exhibited persistent cellular injury, impaired alveolar and endothelial cell regeneration, and persistent cellular infiltration by macrophages and lymphocytes. GSH supplementation in Nrf2-deficient mice immediately after hyperoxia remarkably restored their ability to recover from hyperoxia-induced damage in a manner similar to that of wild-type mice. Thus, the results of the present study indicate that the Nrf2-regulated transcriptional response, and particularly GSH synthesis, is critical for lung tissue repair and the resolution of inflammation in vivo and suggests that a dysfunctional Nrf2-GSH pathway may compromise these processes in vivo.
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影响因子：
8
作者：
Reddy, N. M.;Kleeberger, S. R.;Reddy, S. P.
通讯作者：
Reddy, S. P.
影响因子：
4.4
作者：
Baleeiro, CEO;Wilcoxen, SE;Paine, R
通讯作者：
Paine, R
DOI：
10.1165/ajrcmb.26.1.4536
发表时间：
2002-01-01
影响因子：
6.4
作者：
Cho, HY;Jedlicka, AE;Kleeberger, SR
通讯作者：
Kleeberger, SR
DOI：
10.1513/pats.200604-097aw
发表时间：
2006-07-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Noble, Paul W;Jiang, Dianhua
通讯作者：
Jiang, Dianhua
DOI：
10.1152/ajplung.00299.2002
发表时间：
2003-02-01
影响因子：
4.9
作者：
O'Reilly, MA;Staversky, RJ;Keng, PC
通讯作者：
Keng, PC