Hyperoxia-induced NF-κB activation occurs via a maturationally sensitive atypical pathway

Wright CJ, Zhuang T, La P, Yang G, Dennery PA. Hyperoxia-induced NF-kappa B activation occurs via a maturationally sensitive atypical pathway. Am J Physiol Lung Cell Mol Physiol 296: L296-L306, 2009. First published December 12, 2008; doi: 10.1152/ajplung.90499.2008. NF-kappa B activation is exaggerated in neonatal organisms after oxidant and inflammatory insults, but the reason for this and the downstream effects are unclear. We hypothesized that specific phosphorylation patterns of I kappa B alpha could account for differences in NF-kappa B activation in hyperoxia-exposed fetal and adult lung fibroblasts. After exposure to hyperoxia (> 95% O-2), nuclear NF-kappa B binding increased in fetal, but not adult, lung fibroblasts. Unique to fetal cells, phosphorylation of I kappa B alpha on tyrosine 42, rather than serine 32/36 as seen in TNF-alpha-exposed cells, preceded NF-kappa B nuclear translocation. In fetal cells stably transfected with an NF-kappa B-driven luciferase reporter, hyperoxia significantly suppressed reporter activity, in contrast to increased reporter activity after TNF-alpha incubation. Targeted gene profiling analysis showed that hyperoxia resulted in decreased expression of multiple genes, including proapoptotic factors. Transfection with a dominant-negative I kappa B alpha (Y42F), which cannot be phosphorylated on tyrosine 42, resulted in upregulation of multiple proapoptotic genes. In support of this finding, caspase-3 activity and DNA laddering were specifically increased in fetal lung fibroblasts expressing Y42F after exposure to hyperoxia. These data demonstrate a unique pathway of NF-kappa B activation in fetal lung fibroblasts after exposure to hyperoxia, whereby these cells are protected against apoptosis. Activation of this pathway in fetal cells may prevent the normal pattern of fibroblast apoptosis necessary for normal lung development, resulting in aberrant lung morphology in vivo.