Genetic ablation of the Bach1 gene reduces hyperoxic lung injury in mice: Role of IL-6
Genetic ablation of the Bach1 gene reduces hyperoxic lung injury in mice: Role of IL-6
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DOI：
10.1016/j.freeradbiomed.2009.01.017
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发表时间：
2009-04-15
影响因子：
7.4
通讯作者：
Kohno, Nobuoki
中科院分区：
文献类型：
--
作者：
Tanimoto, Takuya;Hattori, Noboru;Kohno, Nobuoki
Bach1是血红素氧合酶(HO)-1基因的转录抑制因子。据报道，Bach1缺失(Bach1(-/-))小鼠可以免受心肌缺血/再灌注损伤；然而，Bach1中断对另一种高氧性肺损伤氧化应激模型的影响尚未确定。为探讨Bach1在高氧性肺损伤中的作用，将Bach1(-/-)小鼠和野生型(WT)小鼠暴露于90%O-2中。在高氧暴露期间，Bach1(-/-)小鼠的存活时间明显长于WT小鼠。然而，给予锌原卟啉，一种HO-1活性的抑制剂，并没有改变这两只小鼠的死亡率。因此，这一保护作用不是通过在Bach1(-/-)小鼠中过表达HO-1来实现的。Bach1(-/-)组小鼠肺损伤指数低于WT组，但Bach1(-/-)组小鼠肺泡灌洗液中IL-6水平显著高于WT组。有趣的是，肺内注射针对IL-6的小干扰RNA可以降低BAL液中IL-6的水平，并缩短Bach1(-/-)小鼠在高氧暴露期间的存活时间。此外，染色质免疫沉淀分析显示，Bach1与IL-6启动子结合，并在氧化应激后脱落。考虑到先前的观察结果，过量表达IL-6的转基因小鼠对高氧性肺损伤具有保护作用，因此这些结果表明，IL-6介导了高氧暴露下Bach1(-/-)小鼠的存活增加。(C)2009 Elsevier Inc.保留所有权利。
Bach1 is a transcriptional repressor of the heme oxygenase (HO)-1 gene. Bach1-null (Bach1(-/-)) mice are reported to be protected from myocardial ischemia/reperfusion injury; however, the effect of Bach1 disruption on another oxidative stress model of hyperoxic lung injury has yet to be determined. To investigate the role of Bach1 in hyperoxic lung injury, Bach1(-/-) mice and wild-type (WT) mice were exposed to 90% O-2. During hyperoxic exposure, the survival of Bach1(-/-) mice was significantly longer than that of WT mice. However, the administration of zinc protoporphyrin, an inhibitor of HO-1 activity, did not change the mortality in either of the mice. thus suggesting that this protective effect was not mediated by an HO-1 overexpression in Bach1(-/-) mice. The indices of lung injury in the lungs of Bach1(-/-) mice were lower than those of WT mice; unexpectedly, however, the levels of IL-6 in bronchoalveolar lavage (BAL) fluid from Bach1(-/-) mice were significantly higher than those of WT mice. Interestingly, the intrapulmonary administration of small interfering RNA against IL-6 was shown to reduce the IL-6 levels in BAL fluids and shorten the survival in Bach1(-/-) mice during hyperoxic exposure. In addition, a chromatin immunoprecipitation analysis revealed the binding of Bach1 to the IL-6 promoter and its detachment after oxidative stress. Considering the previous observation that the transgenic mice overexpressing IL-6 are protected from hyperoxic lung injury, these results therefore indicate that IL-6 mediates an increased survival in Bach1(-/-) mice during hyperoxic exposure. (C) 2009 Elsevier Inc. All rights reserved.