Duncan Jhodie R, Cock Megan L, Suzuki Keiji, Scheerlinck Jean-Pierre Y, Harding Richard, Rees Sandra M
Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria, Australia.
J Soc Gynecol Investig. 2006 Feb;13(2):87-96. doi: 10.1016/j.jsgi.2005.12.003.
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 circulation, a model that did not cause hypoxia.
At 0.65 of term, eight catheterized fetal sheep received intravenous infusions of LPS (5 to 15 mug) 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.
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.
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.
宫内感染与人类婴儿脑损伤有关，但其机制尚未完全明确。我们最近发现，早产胎羊反复急性暴露于细菌内毒素（脂多糖 [LPS]）会导致胎儿低氧血症、低血压、全身促炎细胞因子增加以及脑损伤，包括白质损伤。然而，尚不清楚这种损伤是由脑氧输送减少还是独立于缺氧的炎症途径所致。本研究的目的是确定通过向胎儿循环中输注 LPS 诱导的慢性宫内炎症状态对胎儿脑和胎盘的影响，该模型不会导致缺氧。
在孕 0.65 期，八只插入导管的胎羊在 5 天内静脉输注 LPS（5 至 15 微克）；对照胎羊输注生理盐水。在整个输注过程中监测胎儿的生理反应。输注结束 6 天后对胎儿脑和胎盘组织进行组织学检查。
LPS 输注未导致胎儿血气或平均动脉压出现具有生理学意义的改变；然而，血浆促炎细胞因子水平升高。LPS 暴露后，胎儿体重和脑重无差异（P >.05）；胎盘重量减轻（P <.05），这与胎盘小叶横截面积减小一致（P <.05）。在大脑半球，六只暴露于 LPS 的胎羊出现皮质下白质损伤，包括轴突损伤、小胶质细胞增生、少突胶质细胞损伤以及β淀粉样前体蛋白（β-APP）表达增加。
胎儿长期全身性暴露于 LPS 会在无低氧血症或低血压的情况下导致胎儿脑损伤，尽管由此产生的损伤不如反复急性暴露后严重。
