Journal
PEDIATRIC RESEARCH
Volume 82, Issue 6, Pages 1064-1072Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/pr.2017.182
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Funding
- NIH [R01HL132941]
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BACKGROUND: The pro-inflammatory consequences of IL1 beta expression contribute to the pathogenesis of bronchopulmonary dysplasia. Selectively targeting Lipopolysaccharide (LPS)-induced I kappa B beta/NF kappa B signaling attenuates IL1 beta mRNA expression in macrophages. Whether targeting I kappa B beta/NF kappa B signaling affects the anti-apoptotic gene expression, a known consequence of global LPS-induced NF kappa B inhibition, is unknown. METHODS: Macrophages (RAW 264.7, bone marrow-derived macrophage) were assessed for LPS-induced IL1 beta mRNA/protein expression, anti-apoptotic gene expression, cell viability (trypan blue exclusion), and activation of apoptosis (caspase-3 and PARP cleavage) following pharmacologic and genetic attenuation of I kappa B beta/NF kappa B signaling. Expressions of IL1 beta and anti-apoptotic genes were assessed in endotoxemic newborn mice (P0) with intact (WT), absent (I kappa B beta KO), and attenuated (I kappa B beta overexpressing) I kappa B beta/NF kappa B signaling. RESULTS: In cultured macrophages, pharmacologic and genetic inhibition of LPS-induced I kappa B beta/NF kappa B signaling significantly attenuated IL1 beta mRNA and protein expression. Importantly, targeting I kappa B beta/NF kappa B signaling did not attenuate LPS-induced expression of anti-apoptotic genes or result in cell death. In endotoxemic neonatal mice, targeting LPS-induced I kappa B beta/NF kappa B signaling significantly attenuated pulmonary IL1 beta expression without affecting the anti-apoptotic gene expression. CONCLUSION: Targeting I kappa B beta/NF kappa B signaling prevents LPS-induced IL1 beta expression without inducing apoptosis in cultured macrophages and in the lungs of endotoxemic newborn mice. Inhibiting this pathway may prevent inflammatory injury without affecting the protective role of NF kappa B activity in the developing lung.
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