IκBβ-Mediated NF-κB Activation Confers Protection against Hyperoxic Lung Injury

Supplemental oxygen is frequently used in an attempt to improve oxygen delivery; however, prolonged exposure results in damage to the pulmonary endothelium and epithelium. Although NF-kappa B has been identified as a redox-responsive transcription factor, whether NF-kappa B activation exacerbates or attenuates hyperoxic lung injury is unclear. We determined that sustained NF-kappa B activity mediated by I kappa B beta attenuates lung injury and prevents mortality in adult mice exposed to greater than 95% O-2. Adult wild-type mice demonstrated evidence of alveolar protein leak and 100% mortality by 6 days of hyperoxic exposure, and showed NF-kappa B nuclear translocation that terminated after 48 hours. Furthermore, these mice showed increased expression of NF-kappa B-regulated proinflammatory and proapoptotic cytokines. In contrast, mice overexpressing the NF-kappa B inhibitory protein, I kappa B beta (AKBI), demonstrated significant resistance to hyperoxic lung injury, with 50% surviving through 8 days of exposure. This was associated with NF-kappa B nuclear translocation that persisted through 96 hours of exposure. Although induction of NF-kappa B-regulated proinflammatory cytokines was not different between wild-type and AKBI mice, significant up-regulation of antiapoptotic proteins (BCL-2, BCL-XL) was found exclusively in AKBI mice. We conclude that sustained NF-kappa B activity mediated by I kappa B beta protects against hyperoxic lung injury through increased expression of antiapoptotic genes.