Chronic endotoxin exposure causes brain injury in the ovine fetus in the absence of hypoxemia

OBJECTIVE: Intrauterine infection has been linked to brain injury in human infants, although the mechanisms are not fully understood. We recently showed that repeated acute exposure of preterm fetal sheep to bacterial endotoxin (lipopolysaccharide [LPS]) results in fetal hypoxemia, hypotension, increased systemic proinflammatory cytokines, and brain damage, including white matter injury. However, it is not clear whether this injury is caused by reduced cerebral oxygen delivery or inflammatory pathways independent of hypoxia. The aim of the present study was to determine the effects on the fetal brain and placenta of a chronic intrauterine inflammatory state, induced by LPS infusion into the fetal circluation, a model that did not cause hypoxia. METHODS: At 0.65 of term, eight catheterized fetal sheep received intravenous infusions of LPS (5 to 15 mu g) over 5 days; control fetuses received saline. Fetal physiologic responses were monitored throughout the infusion. Fetal brain and placental tissues were examined histologically 6 days after the conclusion of the infusion. RESULTS: LPS infusions did not result in physiologically significant alterations to fetal blood gases or mean arterial pressure; however, plasma proinflammatory cytokine levels were elevated. Following LPS exposure there was no difference in fetal body or brain weights (P > .05); placental weight was reduced (P < .05), consistent with reduced placentome cross-sectional area (P < .05). In the cerebral hemispheres subcortical white matter injury was present in six LPS-exposed fetuses and included axonal damage, microgliosis, oligodendrocyte injury, and increased beta amyloid precursor protein (beta-APP) expression. CONCLUSIONS: Chronic, systemic exposure of the fetus to LPS resulted in fetal brain damage in the absence of hypoxemia or hypotension, although the resulting injury was less severe than following repeated acute exposure.