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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/L296    most recent 90499.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Wright, C. J. Articles by Dennery, P. A. Search for Related Content PubMed PubMed Citation Articles by Wright, C. J. Articles by Dennery, P. A.

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

¹Division of Neonatology, Children's Hospital of Philadelphia, and ²Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Submitted 22 September 2008 ; accepted in final form 11 December 2008

NF-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 IB could account for differences in NF-B activation in hyperoxia-exposed fetal and adult lung fibroblasts. After exposure to hyperoxia (>95% O₂), nuclear NF-B binding increased in fetal, but not adult, lung fibroblasts. Unique to fetal cells, phosphorylation of IB on tyrosine 42, rather than serine 32/36 as seen in TNF--exposed cells, preceded NF-B nuclear translocation. In fetal cells stably transfected with an NF-B-driven luciferase reporter, hyperoxia significantly suppressed reporter activity, in contrast to increased reporter activity after TNF- incubation. Targeted gene profiling analysis showed that hyperoxia resulted in decreased expression of multiple genes, including proapoptotic factors. Transfection with a dominant-negative IB (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-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.

IB; apoptosis