Microglial activation, macrophage infiltration, and evidence of cell death in the fetal brain after uteroplacental administration of lipopolysaccharide in sheep in late gestation

OBJECTIVE: The purpose of this study was to determine whether uteroplacental delivery of endotoxin produces fetal systemic and central nervous system reactions that are suggestive of inflammation. STUDY DESIGN: Lipopolysaccharide (30 or 60 microg) was administered into the uterine artery of late gestation (135 +/- 0.3 days) pregnant sheep. Fetal blood was assayed to determine changes in levels of quinolinic acid, which is a metabolite of tryptophan that is produced by monocytes (macrophages, microglia). Fetal brains were collected after 72 hours and examined for the presence of activated microglia and parenchymal macrophages. RESULTS: The brains of treated fetuses showed microglial activation and macrophage infiltration, which varied between brain region and lipopolysaccharide dose. Cell death that had been determined by cresyl violet/acid fuchsin staining was observed in the external capsule. There was significant increase of quinolinic acid in the fetal circulation, but no lipopolysaccharide was detected. CONCLUSION: Uteroplacental inflammation results in significant microglial activation and macrophage infiltration without direct fetal exposure to endotoxin, which suggests that placental responses contribute to perinatal brain damage that is associated with infection during pregnancy.