Ernst Linda M, Gonzalez Juan, Ofori Ella, Elovitz Michal
Department of Pathology and Laboratory Medicine, The Children's Hospital of Pennsylvania, and University of Pennsylvania, Philadelphia, PA, USA.
Pediatr Dev Pathol. 2010 Jul-Aug;13(4):273-81. doi: 10.2350/09-05-0649-OA.1.
The presence of intrauterine inflammation has been associated with adverse neurologic outcomes in preterm infants, but the precise mechanisms of fetal brain injury remain unclear. We sought to evaluate inflammatory cell trafficking, fetal organ damage, and molecular regulation in the fetoplacental unit using an established mouse model of preterm birth associated with intrauterine inflammation. Gestational sacs were harvested 6 hours after intrauterine infusion of saline or lipopolysaccharide (LPS). Histologic, immunohistochemical, and molecular investigations were performed to identify target organ damage and the cellular phenotype of inflammatory cells and to quantify circulating inflammatory and hematopoietic mediators within the placental and fetal tissue. There was widespread increase in fetal macrophages in LPS-exposed pups, including within the leptomeninges of the brain, associated with significantly higher of interleukin 6 levels in LPS-exposed pups. Although no specific central nervous system injury (necrosis or apoptosis) was documented, liver hematomas were seen significantly more frequently in LPS-exposed pups. Circulating nucleated fetal erythrocytes were also present more frequently with LPS exposure without significantly higher erythropoietin levels than saline-exposed mice. The presence of increased macrophages, increased circulating interleukin 6 levels, and increased circulating erythroid precursors in LPS-exposed pups suggests that these are significant factors associated with potential target organ damage, such as liver hematomas, associated with intrauterine inflammation and preterm birth. The role of macrophages within the fetal leptomeninges is unclear, but they may play an important role in inflammatory-mediated brain damage, and further investigation of their significance and potential as therapeutic targets is warranted.
宫内炎症的存在与早产儿不良神经学结局相关，但胎儿脑损伤的确切机制仍不清楚。我们试图使用一种已建立的与宫内炎症相关的早产小鼠模型，来评估胎儿-胎盘单位中的炎性细胞运输、胎儿器官损伤和分子调控。在宫内输注生理盐水或脂多糖（LPS）6小时后收集妊娠囊。进行组织学、免疫组织化学和分子研究，以确定靶器官损伤以及炎性细胞的细胞表型，并量化胎盘和胎儿组织内循环的炎性介质和造血介质。暴露于LPS的幼崽中胎儿巨噬细胞普遍增加，包括在脑软膜内，这与暴露于LPS的幼崽中白细胞介素6水平显著升高有关。尽管未记录到特异性中枢神经系统损伤（坏死或凋亡），但暴露于LPS的幼崽中肝血肿的出现频率明显更高。暴露于LPS时循环有核胎儿红细胞也更频繁出现，且促红细胞生成素水平并不比暴露于生理盐水的小鼠显著更高。暴露于LPS的幼崽中巨噬细胞增加、循环白细胞介素6水平升高以及循环红系前体细胞增加，表明这些是与潜在靶器官损伤相关的重要因素，如与宫内炎症和早产相关的肝血肿。胎儿软膜内巨噬细胞的作用尚不清楚，但它们可能在炎症介导的脑损伤中起重要作用，有必要进一步研究它们作为治疗靶点的意义和潜力。
