Activation of NF-kappaB transcription factor in the preterm ovine brain and placenta after acute LPS exposure.
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.
Briscoe
T
T
Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia.
Duncan
J
J
Cock
M
M
Choo
J
J
Rice
G
G
Harding
R
R
Scheerlinck
J-P Y
JP
Rees
S
S
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
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