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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/L565    most recent 90487.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McGrath-Morrow, S. Articles by Biswal, S. Search for Related Content PubMed PubMed Citation Articles by McGrath-Morrow, S. Articles by Biswal, S.

Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia

¹Department of Pediatric Pulmonary, Johns Hopkins School of Medicine, Baltimore, Maryland; ²Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York; and ³Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, and ⁴Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland

Submitted 16 September 2008 ; accepted in final form 30 December 2008

Increased oxidative stress is associated with perinatal asphyxia and respiratory distress in the newborn period. Induction of nuclear factor erythroid 2 p45-related factor (Nrf2) has been shown to decrease oxidative stress through the regulation of specific gene pathways. We hypothesized that Nrf2 attenuates mortality and alveolar growth inhibition in newborn mice exposed to hyperoxia. Nrf2^+/+ and Nrf2^–/– newborn mice were exposed to hyperoxia at 24 h. Survival was significantly less in Nrf2^–/– mice exposed to 72 h of hyperoxia and returned to room air (P < 0.0001) and in Nrf2^–/– mice exposed to hyperoxia for 8 continuous days (P < 0.005). To determine the response of Nrf2 target genes to hyperoxia, glutathione peroxidase 2 (Gpx2) and NAD(P)H:quinone oxidoreductase (NQO1) expression was measured from lung of newborn mice using real-time PCR. In the Nrf2^+/+ mice, significant induction of lung Gpx2 and NQO1 above room air controls was found with hyperoxia. In contrast, Nrf2^–/– mice had minimal induction of lung Gpx2 and NQO1 with hyperoxia. Expression of p21 and IL-6, genes not regulated by Nrf2, were also measured. IL-6 expression in Nrf2^–/– lung was markedly induced by 72 h of hyperoxia in contrast to the Nrf2^+/+ mice. p21 was induced in both Nrf2^+/+ and Nrf2^–/– lung by hyperoxia. Mean linear intercept (MLI) and mean chord length (MCL) were significantly increased in 14-day-old Nrf2^–/– mice previously exposed to hyperoxia compared with Nrf2^+/+ mice. The percentage of surfactant protein C (Sp-c⁺) type 2 alveolar cells in 14-day-old Nrf2^–/– mice exposed to neonatal hyperoxia was also significantly less than Nrf2^+/+ mice (P < 0.02). In summary, these findings indicate that Nrf2 increases survival in newborn mice exposed to hyperoxia and that Nrf2 may help attenuate alveolar growth inhibition caused by hyperoxia exposure.

oxidative stress; Gpx2; interleukin-6; developing lung