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

Abstract

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.

Recent advances in the mechanisms of lung alveolarization and the pathogenesis of bronchopulmonary dysplasia

“…These data support the idea of activating sGC as a management strategy in hyperoxia-induced lung injury. Along similar lines, McKenna and coworkers (231) demonstrated that sustained NF-B activation, through overexpression of the NF-B inhibitor-␤ (I-B␤), protected mice against the deleterious effects of hyperoxia (95% O 2 ) on alveolarization (assessed by MLI and RAC), suggesting that the potentiation of NF-B activity may also represent a management strategy in hyperoxia-induced lung injury.…”

5-aza-2′-deoxycytidine Inhibits the Proliferation of Lung Fibroblasts in Neonatal Rats Exposed to Hyperoxia

“…Hyperoxia is a significant cause of lung injury and contributes to the pathogenesis of BPD. 14,15 The hallmark features of BPD are a decreased number of alveoli, increased variability in alveolar size, and lung interstitial fibrosis. 3,16 There is evidence from animal models that exposure of the developing lung to hyperoxia leads to the development of a simplified lung structure that resembles human BPD.…”

“…3,16 There is evidence from animal models that exposure of the developing lung to hyperoxia leads to the development of a simplified lung structure that resembles human BPD. 15 A Figure 3 Growth curve of 5-aza-CdR-treated LFs (n Z 5).…”

Pathogenesis of bronchopulmonary dysplasia: when inflammation meets organ development

“…However, the therapeutic potential of NF-kB inhibition is limited by its essential role in physiologic lung development, mediating both alveologenesis and vasculogenesis. Furthermore, a disease-limiting function of NF-kB in inflammation was attributed to the suppression of macrophage inflammatory protein 2 [ 50 – 53 ]. The physiologic functions of NF-kB in the developing lung are even more complex as it is ubiquitously expressed; controls diverse cellular functions including apoptosis, survival, proliferation, and immune regulation; and exerts simultaneously pro- and anti-inflammatory actions.…”