Genetic ablation of the Bach1 gene reduces hyperoxic lung injury in mice: Role of IL-6

Tanimoto Takuya

Hattori Noboru

Senoo Tadashi

Furonaka Makoto

Ishikawa Nobuhisa

Fujitaka Kazunori

Haruta Yoshinori

Yokoyama Akihito

Igarashi Kazuhiko

Kohno Nobuoki

Free Radical Biology and Medicine

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.

Bach1

Heme oxygenase-1

Hyperoxic lung injury

IL-6

Oxidative stress

Survival

Bronchoalveolar lavage

Small interfering RNA

Chromatin immunoprecipitation analysis

Free radicals

Medical sciences [ 490 ]

eng

Elsevier Science Inc

Copyright (c) 2009 Elsevier Inc.

[ISSN] 0891-5849

[DOI] 10.1016/j.freeradbiomed.2009.01.017

[NCID] AA10678845

[DOI] http://dx.doi.org/10.1016/j.freeradbiomed.2009.01.017