title: The NF-κB inhibitory proteins IκBα and IκBβ mediate disparate responses to inflammation in fetal pulmonary endothelial cells.
abstract: Exposure to intrauterine inflammation impairs lung growth but paradoxically protects the neonatal pulmonary vasculature from hyperoxic injury. The mechanisms mediating these contradictory effects are unknown. The objective is to identify the role of NF-κB in mediating cytoprotective and proinflammatory responses to inflammation in the fetal pulmonary endothelium. In newborn rats exposed to intra-amniotic LPS, we found increased expression of the NF-κB target gene manganese superoxide dismutase (MnSOD) in the pulmonary endothelium. Supporting these in vivo findings, LPS induced NF-κB activation and MnSOD expression in isolated fetal pulmonary arterial endothelial cells. In addition, LPS exposure caused apoptosis and suppressed cellular growth and induced P-selectin expression. LPS-induced NF-κB activation that proceeded through specific isoforms of the inhibitory protein IκB mediated these diverse responses; NF-κB signaling through IκBα degradation resulted in MnSOD upregulation and preserved cell growth, whereas NF-κB signaling through IκBβ degradation mediated apoptosis and P-selectin expression. These findings suggest that selective inhibition of NF-κB activation that results from IκBβ degradation preserves the enhanced antioxidant defense and protects the developing pulmonary vascular endothelium from ongoing inflammatory injury.
authors: Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors: Jen-Ruey
authors: JR
authors: Tang
authors: Katherine A
authors: KA
authors: Michaelis
authors: Eva
authors: E
authors: Nozik-Grayck
authors: Gregory J
authors: GJ
authors: Seedorf
authors: Marlena
authors: M
authors: Hartman-Filson
authors: Steven H
authors: SH
authors: Abman
authors: Clyde J
authors: CJ
authors: Wright
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D005333:Fetus / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D051550:I-kappa B Kinase / Q000502:physiology*; D020672:I-kappa B Proteins / Q000502:physiology*; D018836:Inflammation Mediators / Q000502:physiology*; D008168:Lung / Q000098:blood supply / Q000201:enzymology / Q000276:immunology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000975:Antioxidants; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha; D013482:Superoxide Dismutase; D051550:I-kappa B Kinase