Background: Perinatal hypoxia-ischemia (HI) and exposure to infection/inflammation are associated with neurodevelopmental impairment after preterm birth. Experimentally, insults interact such that exposure to inflammation can confer tolerance or sensitization to subsequent HI. We have previously shown that acute-on-chronic lipopolysaccharide (LPS) exposure followed by HI reduced white matter injury compared to either LPS or HI alone in preterm fetal sheep. However, the impact on grey matter injury is unclear.
Methods: Fetal sheep at 0.7 gestation were randomized to saline-sham (n = 8), LPS-sham (n = 8), saline-HI (n = 9) and LPS-saline (n = 8) groups. LPS groups received a continuous LPS infusion at 100 ng/kg for 24 hours, then 250 ng/kg/24 hours for 96 hours. Boluses of 1 μg LPS were given at 48, 72, and 96 hours or the same volume of saline for saline groups. Four hours after the last bolus, HI was induced by complete umbilical cord occlusion or sham occlusion for 15 minutes. Sheep were killed 10 days after the start of infusions and brain histology was assessed.
Results: LPS-sham was associated with a reduction in neuronal number and increased caspase-3 positive cells in the parasagittal cortex, hippocampus and striatum compared to saline-sham. Saline-HI and LPS-HI were not associated with significant neuronal loss. However, saline-HI but not LPS-HI had increased numbers of caspase-3 positive cells, compared to saline-sham. Saline-HI and LPS-sham were associated with increased microglia and TNF-α positive cells in the parasagittal cortex and striatum, whereas LPS-HI had similar microglial and TNF-α positive cell numbers to saline-sham.
Conclusions: By contrast with the sensitization to HI often seen after acute LPS injections, the combination of acute-on-chronic LPS with HI reduced neuronal loss compared to LPS exposure alone, and reduced inflammation and apoptosis in the grey matter after 5 days recovery compared to either LPS or HI.