Activation of NF-κB 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.

Reducing Peripheral Inflammation with Infliximab Reduces Neuroinflammation and Improves Cognition in Rats with Hepatic Encephalopathy

“…A similar activation of NF-kB has been observed in ovine hippocampus following LPS-induced peripheral inflammation (Hang et al, 2004; Briscoe et al, 2006) and in cortex of rats with traumatic brain injury, which was also associated with increased TNF-a levels (Hang et al, 2004). …”

Increased Number of Cerebellar Granule Cells and Astrocytes in the Internal Granule Layer in Sheep Following Prenatal Intra-amniotic Injection of Lipopolysaccharide

“…Although in our model the mechanisms causing fetal cerebellar changes in the fetus remain unidentified, it is generally known that LPS, a pyrogenic component of Gram-negative bacteria, induces a downstream cascade of inflammatory responses via the toll-like receptor 4 (TLR4) and NF-κB activation stimulating macrophages to produce large amounts of cytokines [60–63]. Work by Kallapur and Kramer already demonstrated that an intra-amniotic LPS injection causes chorioamnionitis, which was quantified by an increased number of granulocytes in the amniotic fluid and the accumulation of inflammatory cells in the chorion/amnion [42, 64].…”

The Anti-Inflammatory Agent N-Acetyl Cysteine Exacerbates Endotoxin-Induced Hypoxemia and Hypotension and Induces Polycythemia in the Ovine Fetus

“…In vivo models of LPS-induced inflammation have shown elevated binding activity of the transcription factor nuclear factor B [5] , increased concentrations of the proinflammatory cytokines interleukin (IL)-6 [6] and tumor necrosis factor (TNF)-␣ [7] , and increased concentrations of the oxidative stress marker 8-isoprostane [5] and oxygen free radicals [8] . We have recently shown that repeated intravenous administration of LPS to the immature ovine fetus at 0.67 of term induces hypoxemia, acidemia, hyperlactemia and hypotension and causes cerebral white matter injury including diffuse changes and focal periventricular lesions [6] typical of white matter injury seen in preterm infants [9][10][11] .…”