Synergistic white matter protection with acute-on-chronic endotoxin and subsequent asphyxia in preterm fetal sheep

Abstract

BackgroundPerinatal asphyxia and exposure to intrauterine infection are associated with impaired neurodevelopment in preterm infants. Acute exposure to non-injurious infection and/or inflammation can either protect or sensitize the brain to subsequent hypoxia-ischemia. However, the effects of subacute infection and/or inflammation are unclear. In this study we tested the hypothesis that acute-on-chronic exposure to lipopolysaccharide (LPS) would exacerbate white matter injury after subsequent asphyxia in preterm fetal sheep.MethodsFetal sheep at 0.7 gestational age received a continuous LPS infusion at 100 ng/kg for 24 hours, then 250 ng/kg/24 hours for 96 hours, plus 1 μg boluses of LPS at 48, 72, and 96 hours or the same volume of saline. Four hours after the last bolus, complete umbilical cord occlusion or sham occlusion was induced for 15 minutes. Sheep were sacrificed 10 days after the start of infusions.ResultsLPS exposure was associated with induction of microglia and astrocytes and loss of total and immature and mature oligodendrocytes (n = 9) compared to sham controls (n = 9). Umbilical cord occlusion with saline infusions was associated with induction of microglia, astrogliosis, and loss of immature and mature oligodendrocytes (n = 9). LPS exposure before asphyxia (n = 8) was associated with significantly reduced microglial activation and astrogliosis and improved numbers of immature and mature oligodendrocytes compared to either LPS exposure or asphyxia alone.ConclusionsContrary to our initial hypothesis, the combination of acute-on-chronic LPS with subsequent asphyxia reduced neuroinflammation and white matter injury compared with either intervention alone.

Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

“…Interestingly, the lack of effect with ischemia 4 h after LPS is in contrast to our previous findings demonstrating reduced microglial activation and astrogliosis with acute or chronic administration of LPS before asphyxia induced by complete umbilical cord occlusion in preterm fetal sheep [68]. The reason for this difference is unknown but may reflect the use of asphyxia, or the much higher doses of repeated LPS (1,000 ng/bolus compared to 50/100 ng in the present study).…”

Human Amnion Epithelial Cells Modulate Ventilation-Induced White Matter Pathology in Preterm Lambs

“…We morphologically distinguished ramified microglia (presence of long branching processes) and amoeboid microglia (large, densely stained soma with retracted processes [27,28]). The percentage of amoeboid to total microglia was also determined.…”

A Critical Review of Models of Perinatal Infection

“…The precise reasons are unclear, although we may speculate that killing bacteria will release more inflammatory bacterial fragments. Infection/inflammation can also either dramatically exacerbate or alleviate neural damage from subsequent insults such as hypoxia-ischemia, hyperoxia and mechanical ventilation, depending on the precise timing and pattern of the insults [21,22,23,24]. Moreover, whereas brief hypoxia or low-dose Gram-negative lipopolysaccharide (LPS) exposure alone or in combination did not cause neural injury in very immature (postnatal day (P)1) rat pups, brief hyperthermia superimposed on combined hypoxia/LPS upregulated apoptosis and increased cell loss [25], illustrating the potential importance of multimodal injury.…”