Nitsos Ilias, Rees Sandra M, Duncan Jhodie, Kramer Boris W, Harding Richard, Newnham John P, Moss Timothy J M
School of Women's and Infants' Health, The University of Western Australia, Crawley, Western Australia, Australia.
J Soc Gynecol Investig. 2006 May;13(4):239-47. doi: 10.1016/j.jsgi.2006.02.011.
Fetal brain injury is associated with chorioamnionitis, which is often present without signs of overt infection or fetal compromise. We aimed to determine if prolonged exposure to intrauterine inflammation caused by intra-amniotic infusion of lipopolysaccharide (LPS) would affect the fetal brain.
At 80 days of pregnancy ewes bearing singletons had osmotic pumps implanted intra-amniotically to infuse Escherichia coli LPS (055:B5; n = 8) or saline (n = 7) for 28 days. At delivery (110 days), umbilical arterial blood and chorioamnion were assessed for inflammation; cytokine concentrations (interleukin [IL]-6 and IL-8) in amniotic fluid and fetal and maternal plasma were measured. The fetal cerebral hemispheres were examined for gross anatomical changes and the number of activated microglia/macrophages, astrocytes, and oligodendrocytes estimated after immunohistochemical staining.
Intra-amniotic administration of LPS caused chorioamnionitis, fetal leucocytosis, and a moderate to extensive infiltration of activated microglia/macrophages in the subcortical white matter in six of eight fetuses; the remaining two fetuses were less affected. Within these focal regions of damage there was an attenuation of astrocytic processes, axonal injury, and a reduction in the number of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) immunoreactive oligodendrocytes in areas of extensive focal damage. In control fetuses there was mild (3/7) or no infiltration of activated microglia/macrophages in the subcortical white matter. Overall the infiltration of activated microglia/macrophages in the white matter was significantly greater in LPS-exposed fetuses compared to controls. In regions devoid of injury, the number of oligodendrocytes and astrocytes was not different between groups, nor was there a difference in the volume of cerebral white matter or density of blood vessels within the white matter. Amniotic fluid IL-6 and IL-8, and maternal plasma IL-8 concentrations were significantly increased by LPS infusion.
An increase in inflammatory cells and axonal disruption in the subcortical white matter of the fetal brain can accompany chorioamnionitis induced by intra-amniotic administration of LPS, but cystic lesions do not occur. Thus, the effect on the fetal brain is milder than that reported from animal models of acute fetal/intrauterine infection.
胎儿脑损伤与绒毛膜羊膜炎有关，而绒毛膜羊膜炎常无明显感染迹象或胎儿窘迫表现。我们旨在确定羊膜腔内注入脂多糖（LPS）导致的宫内炎症长期暴露是否会影响胎儿大脑。
妊娠80天时，对怀有单胎的母羊进行羊膜腔内植入渗透泵，以注入大肠杆菌LPS（055:B5；n = 8）或生理盐水（n = 7），持续28天。分娩时（110天），评估脐动脉血和绒毛膜羊膜的炎症情况；测量羊水、胎儿和母体血浆中的细胞因子浓度（白细胞介素[IL]-6和IL-8）。检查胎儿脑半球的大体解剖变化，并在免疫组织化学染色后估计活化的小胶质细胞/巨噬细胞、星形胶质细胞和少突胶质细胞的数量。
羊膜腔内给予LPS导致绒毛膜羊膜炎、胎儿白细胞增多，8只胎儿中有6只在皮质下白质出现中度至广泛的活化小胶质细胞/巨噬细胞浸润；其余2只胎儿受影响较小。在这些局部损伤区域，星形胶质细胞突起减少、轴突损伤，在广泛局部损伤区域2',3'-环核苷酸3'-磷酸二酯酶（CNPase）免疫反应性少突胶质细胞数量减少。在对照胎儿中，皮质下白质有轻度（3/7）或无活化小胶质细胞/巨噬细胞浸润。总体而言，与对照组相比，暴露于LPS的胎儿白质中活化小胶质细胞/巨噬细胞的浸润明显更多。在无损伤区域，两组之间少突胶质细胞和星形胶质细胞的数量无差异，脑白质体积或白质内血管密度也无差异。注入LPS后，羊水IL-6和IL-8以及母体血浆IL-8浓度显著升高。
羊膜腔内给予LPS诱导的绒毛膜羊膜炎可伴有胎儿脑皮质下白质炎症细胞增加和轴突破坏，但不发生囊性病变。因此，对胎儿脑的影响比急性胎儿/宫内感染动物模型报道的要轻。
