Sustained hyperoxia-induced NF-κB activation improves survival and preserves lung development in neonatal mice

Oxygen toxicity contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Neonatal mice exposed to hyperoxia develop a simplified lung structure that resembles BPD. Sustained activation of the transcription factor NF-κB and increased expression of protective target genes attenuate hyperox...

Full description

Saved in:
Bibliographic Details
Published in:American journal of physiology. Lung cellular and molecular physiology 2014-06, Vol.306 (12), p.L1078-L1089
Main Authors: McKenna, Sarah, Michaelis, Katherine A, Agboke, Fadeke, Liu, Thanh, Han, Kristie, Yang, Guang, Dennery, Phyllis A, Wright, Clyde J
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Gene Expression Regulation - physiology
Hyperoxia - metabolism
Hyperoxia - mortality
I-kappa B Proteins - genetics
I-kappa B Proteins - metabolism
Lung - growth & development
Lung - pathology
Lung Injury - metabolism
Lung Injury - mortality
Mice
Mice, Inbred ICR
NF-kappa B - metabolism
Signal Transduction - physiology
Vascular Endothelial Growth Factor Receptor-2 - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Oxygen toxicity contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Neonatal mice exposed to hyperoxia develop a simplified lung structure that resembles BPD. Sustained activation of the transcription factor NF-κB and increased expression of protective target genes attenuate hyperoxia-induced mortality in adults. However, the effect of enhancing hyperoxia-induced NF-κB activity on lung injury and development in neonatal animals is unknown. We performed this study to determine whether sustained NF-κB activation, mediated through IκBβ overexpression, preserves lung development in neonatal animals exposed to hyperoxia. Newborn wild-type (WT) and IκBβ-overexpressing (AKBI) mice were exposed to hyperoxia (>95%) or room air from day of life (DOL) 0-14, after which all animals were kept in room air. Survival curves were generated through DOL 14. Lung development was assessed using radial alveolar count (RAC) and mean linear intercept (MLI) at DOL 3 and 28 and pulmonary vessel density at DOL 28. Lung tissue was collected, and NF-κB activity was assessed using Western blot for IκB degradation and NF-κB nuclear translocation. WT mice demonstrated 80% mortality through 14 days of exposure. In contrast, AKBI mice demonstrated 60% survival. Decreased RAC, increased MLI, and pulmonary vessel density caused by hyperoxia in WT mice were significantly attenuated in AKBI mice. These findings were associated with early and sustained NF-κB activation and expression of cytoprotective target genes, including vascular endothelial growth factor receptor 2. We conclude that sustained hyperoxia-induced NF-κB activation improves neonatal survival and preserves lung development. Potentiating early NF-κB activity after hyperoxic exposure may represent a therapeutic intervention to prevent BPD.
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00001.2014