title: Activation of NF-kappaB transcription factor in the preterm ovine brain and placenta after acute LPS exposure.
abstract: Intrauterine infection may be causally related to inflammation and injury of the fetal brain, however the mechanisms by which this occurs are unclear. We have investigated whether nuclear factor (NF)-kappaB, a transcription factor for proinflammatory cytokines, is activated in the fetal brain after acute LPS-exposure. At 95 days of gestation (term = approximately 147 days), 5 fetuses received a single intravenous bolus dose of LPS (1 microg/kg); 6 fetuses served as controls. Fetal blood samples were taken hourly for 6 hr post LPS-exposure to assess physiological status. Ewes and fetuses were then euthanased, placental and brain tissue examined histologically, and NF-kappaB activation assessed in several regions of the fetal brain using an electromobility shift assay (EMSA). Oxidative stress was measured using lipid peroxidation and 8-isoprostane biochemical assays and brain cytokine concentrations analysed by enzyme linked immunosorbent assay (ELISA). LPS-exposed fetuses (relative to controls) were hypoxemic and the haematocrit and lactate levels had increased. In the brains of LPS-exposed fetuses compared to controls, NF-kappaB binding activity was elevated in the hippocampus and the thalamus/basal ganglia; 8-isoprostane levels were elevated overall (P < 0.05) in the parietal/occipital/temporal lobes and thalamus/basal ganglia. TNF-alpha and IL-6 concentrations were not elevated, however, there was a tendency for an elevation of IFN-gamma concentrations in the thalamus/basal ganglia. IFN-gamma concentration was elevated (P < 0.05) in the plasma 4 hr after LPS-exposure. In the placenta, NF-kappaB binding activity was increased (P < 0.05). We conclude that acute systemic administration of LPS leads to increased binding activity of NF-kappaB subunits in specific regions of the fetal brain and in the placenta, but that there is no clear-cut relationship between this elevation and vulnerability to endotoxic damage.
authors.affiliation: Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Briscoe
authors.forename: J
authors.initials: J
authors.lastname: Duncan
authors.forename: M
authors.initials: M
authors.lastname: Cock
authors.forename: J
authors.initials: J
authors.lastname: Choo
authors.forename: G
authors.initials: G
authors.lastname: Rice
authors.forename: R
authors.initials: R
authors.lastname: Harding
authors.forename: J-P Y
authors.initials: JP
authors.lastname: Scheerlinck
authors.forename: S
authors.initials: S
authors.lastname: Rees
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology* / Q000633:toxicity*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010920:Placenta / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D012756:Sheep; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C075750:8-epi-prostaglandin F2alpha; D007371:Interferon-gamma; D015237:Dinoprost