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

Abstract

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.

Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function

“…The role of Nrf2 as a critical mediator of the antioxidant response has been well studied. Previous studies demonstrate that Nrf2 deficiency exacerbates inflammation and oxidative stress in a variety of disease models, including emphysema (38), COPD exacerbations (13), acute lung injury (31,42), pulmonary fibrosis (6,22), and sepsis (53). Alternatively, activation of Nrf2 in these disease models reduces oxidative stress and inflammation (24,43,49).…”

Superoxide Dismutase 3 Dysregulation in a Murine Model of Neonatal Lung Injury

“…Although most studies with a recovery phase demonstrate persistent changes in lung architecture and function (4,(24)(25)(26), data are limited on surveys of contemporaneous inflammatory, apoptotic, proliferative, and oxidative stress profile in a murine model of BPD and especially in describing the attendant antioxidant profile (17,33). In a study by Auten and colleagues, hyperoxia markedly impaired bronchiolar and alveolar epithelial proliferation at postnatal day 3 and 5, as measured by 5-bromo-29-deoxyuridine uptake or Ki67 labeling (15).…”

Hyperoxia inhibits protein synthesis and increases eIF2α phosphorylation in the newborn rat lung

“…On translocation to the nucleus, Nrf2 binds the promoters of NAD(P)H-quinone oxidoreductase, glutathione S-transferases, and heme oxygenase 1, leading to increased expression of these important antioxidant enzymes (13). Hyperoxia-induced Nrf2 protein expression has been found to be cytoprotective in type II alveolar epithelial cells and to ameliorate O 2 -induced lung injury in mice (18). Accordingly, the integrated activation of mTOR and eIF2␣ phosphorylation during hyperoxia may be adaptive.…”