Abstract
Background:
BTB and CNC homology 1 (Bach1) is a transcriptional repressor of heme oxygenase (HO)-1. The effects of Bach1 disruption on hyperoxic lung injury in newborn mice have not been determined. We aimed to investigate the role of Bach1 in the newborns exposed to hyperoxia.
Methods:
Bach1−/− and WT newborn mice were exposed to 21% or 95% oxygen for 4 d and were then allowed to recover in room air. Lung histology was assessed and lung Bach1, HO-1, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 mRNA levels were evaluated using RT-PCR. Lung inflammatory cytokine levels were determined using cytometric bead arrays.
Results:
After 10 d recovery from neonatal hyperoxia, Bach1−/− mice showed improved lung alveolarization compared with WT. HO-1, IL-6, and MCP-1 mRNA levels and IL-6 and MCP-1 protein levels were significantly increased in the Bach1−/− lungs exposed to neonatal hyperoxia. Although an increase in apoptosis was observed in the Bach1−/− and WT lungs after neonatal hyperoxia, there were no differences in apoptosis between these groups.
Conclusion:
Bach1−/− newborn mice were well-recovered from hyperoxia-induced lung injury. This effect is likely achieved by the antioxidant/anti-inflammatory activity of HO-1 or by the transient overexpression of proinflammatory cytokines.
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References
Jobe AH, Kallapur SG. Long term consequences of oxygen therapy in the neonatal period. Semin Fetal Neonatal Med 2010;15:230–5.
Vogel ER, Britt RD Jr, Trinidad MC, et al. Perinatal oxygen in the developing lung. Can J Physiol Pharmacol 2015;93:119–27.
Maeda Y, Davé V, Whitsett JA. Transcriptional control of lung morphogenesis. Physiol Rev 2007;87:219–44.
Berger J, Bhandari V. Animal models of bronchopulmonary dysplasia. The term mouse models. Am J Physiol Lung Cell Mol Physiol 2014;307:L936–47.
Warner BB, Stuart LA, Papes RA, Wispé JR. Functional and pathological effects of prolonged hyperoxia in neonatal mice. Am J Physiol 1998;275(1 Pt 1):L110–7.
Yee M, Chess PR, McGrath-Morrow SA, et al. Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity. Am J Physiol Lung Cell Mol Physiol 2009;297:L641–9.
Yang G, Biswasa C, Lin QS, et al. Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: role of β-catenin/hnRNPK signaling. Redox Biol 2013;1:234–43.
Namba F, Go H, Murphy JA, et al. Expression level and subcellular localization of heme oxygenase-1 modulates its cytoprotective properties in response to lung injury: a mouse model. PLoS One 2014;9:e90936.
Bender AT, Ostenson CL, Wang EH, Beavo JA. Selective up-regulation of PDE1B2 upon monocyte-to-macrophage differentiation. Proc Natl Acad Sci USA 2005;102:497–502.
Fox S, Leitch AE, Duffin R, Haslett C, Rossi AG. Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease. J Innate Immun 2010;2:216–27.
van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am J Pathol 2007;170:818–29.
Leor J, Rozen L, Zuloff-Shani A, et al. Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart. Circulation 2006;114(1 Suppl):I94–100.
Jang HS, Kim J, Park YK, Park KM. Infiltrated macrophages contribute to recovery after ischemic injury but not to ischemic preconditioning in kidneys. Transplantation 2008;85:447–55.
Vandivier RW, Henson PM, Douglas IS. Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 2006;129:1673–82.
Igarashi K, Hoshino H, Muto A, et al. Multivalent DNA binding complex generated by small Maf and Bach1 as a possible biochemical basis for beta-globin locus control region complex. J Biol Chem 1998;273:11783–90.
Sun J, Hoshino H, Takaku K, et al. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J 2002;21:5216–24.
Sun J, Brand M, Zenke Y, Tashiro S, Groudine M, Igarashi K. Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network. Proc Natl Acad Sci USA 2004;101:1461–6.
Ishikawa M, Numazawa S, Yoshida T. Redox regulation of the transcriptional repressor Bach1. Free Radic Biol Med 2005;38:1344–52.
Suzuki H, Tashiro S, Sun J, Doi H, Satomi S, Igarashi K. Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene. J Biol Chem 2003;278:49246–53.
Omura S, Suzuki H, Toyofuku M, Ozono R, Kohno N, Igarashi K. Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury. Genes Cells 2005;10:277–85.
Yano Y, Ozono R, Oishi Y, et al. Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice. Genes Cells 2006;11:791–803.
Tanimoto T, Hattori N, Senoo T, et al. Genetic ablation of the Bach1 gene reduces hyperoxic lung injury in mice: role of IL-6. Free Radic Biol Med 2009;46:1119–26.
Hsia CC, Hyde DM, Ochs M, Weibel ER ; ATS/ERS Joint Task Force on Quantitative Assessment of Lung Structure. An official research policy statement of the American Thoracic Society/European Respiratory Society: standards for quantitative assessment of lung structure. Am J Respir Crit Care Med 2010;181:394–418.
Yang G, Hinson MD, Bordner JE, et al. Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 2011;301:L187–96.
Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 1997 30:10925–30.
Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 1997;94:10919–24.
Duckers HJ, Boehm M, True AL, et al. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med 2001;7:693–8.
Anyanwu AC, Bentley JK, Popova AP, et al. Suppression of inflammatory cell trafficking and alveolar simplification by the heme oxygenase-1 product carbon monoxide. Am J Physiol Lung Cell Mol Physiol 2014;306:L749–63.
Fernandez-Gonzalez A, Alex Mitsialis S, Liu X, Kourembanas S. Vasculoprotective effects of heme oxygenase-1 in a murine model of hyperoxia-induced bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2012;302:L775–84.
Suttner DM, Dennery PA. Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron. FASEB J 1999;13:1800–9.
Ward NS, Waxman AB, Homer RJ, et al. Interleukin-6-induced protection in hyperoxic acute lung injury. Am J Respir Cell Mol Biol 2000;22:535–42.
Choo-Wing R, Nedrelow JH, Homer RJ, Elias JA, Bhandari V. Developmental differences in the responses of IL-6 and IL-13 transgenic mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol 2007;293:L142–50.
Vozzelli MA, Mason SN, Whorton MH, Auten RL Jr . Antimacrophage chemokine treatment prevents neutrophil and macrophage influx in hyperoxia-exposed newborn rat lung. Am J Physiol Lung Cell Mol Physiol 2004;286:L488–93.
Okuma T, Terasaki Y, Sakashita N, et al. MCP-1/CCR2 signaling pathway regulates hyperoxia-induced acute lung injury via nitric oxide production. Int J Exp Pathol 2006;87:475–83.
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Ito, M., Nagano, N., Arai, Y. et al. Genetic ablation of Bach1 gene enhances recovery from hyperoxic lung injury in newborn mice via transient upregulation of inflammatory genes. Pediatr Res 81, 926–931 (2017). https://doi.org/10.1038/pr.2017.17
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DOI: https://doi.org/10.1038/pr.2017.17
