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Cytokine. 2014 Jan;65(1):4-9. doi: 10.1016/j.cyto.2013.09.021. Epub 2013 Oct 17.

Transcriptional responses of neonatal mouse lung to hyperoxia by Nrf2 status.

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Department of Pediatrics, Division of Pediatric Pulmonary, Johns Hopkins School of Medicine, Baltimore, MD, United States. Electronic address:


Hyperoxia exposure can inhibit alveolar growth in the neonatal lung through induction of p21/p53 pathways and is a risk factor for the development of bronchopulmonary dysplasia (BPD) in preterm infants. We previously found that activation of nuclear factor erythroid 2 p45-related factor (Nrf2) improved survival in neonatal mice exposed to hyperoxia likely due to increased expression of anti-oxidant response genes. It is not known however, whether hyperoxic induced Nrf2 activation attenuates the growth impairment caused by hyperoxia in neonatal lung. To determine if Nrf2 activation modulates cell cycle regulatory pathway genes associated with growth arrest we examined the gene expression in the lungs of Nrf2(-/-) and Nrf2(+/+) neonatal mice at one and 3days of hyperoxia exposure.


Microarray analysis was performed in neonatal Nrf2(+/+) and Nrf2(-/-) lungs exposed to one and 3days of hyperoxia. Sulforaphane, an inducer of Nrf2 was given to timed pregnant mice to determine if in utero exposure attenuated p21 and IL-6 gene expression in wildtype neonatal mice exposed to hyperoxia.


Cell cycle regulatory genes were induced in Nrf2(-/-) lung at 1day of hyperoxia. At 3days of hyperoxia, induction of cell cycle regulatory genes was similar in Nrf2(+/+) and Nrf2(-/-) lungs, despite higher inflammatory gene expression in Nrf2(-/-) lung.


p21/p53 pathways gene expression was not attenuated by Nrf2 activation in neonatal lung. In utero SUL did not attenuate p21 expression in wildtype neonatal lung exposed to hyperoxia. These findings suggest that although Nrf2 activation induces expression of anti-oxidant genes, it does not attenuate alveolar growth arrest caused by exposure to hyperoxia.


Alveolar growth inhibition; CLDP; Cell cycle regulatory genes; Chronic lung disease of prematurity; Hyperoxia; Inflammation; Nrf2; chronic lung disease of prematurity; nuclear factor erythroid 2 p45-related factor

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