Gussenhoven Ruth, Ophelders Daan R M G, Kemp Matthew W, Payne Matthew S, Spiller Owen B, Beeton Michael L, Stock Sarah J, Cillero-Pastor Bertha, Barré Florian P Y, Heeren Ron M A, Kessels Lilian, Stevens Bas, Rutten Bart P, Kallapur Suhas G, Jobe Alan H, Kramer Boris W, Wolfs Tim G A M
Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.
Dev Neurosci. 2017;39(6):472-486. doi: 10.1159/000479021. Epub 2017 Aug 29.
Chorioamnionitis is associated with adverse neurodevelopmental outcomes in preterm infants. Ureaplasma spp. are the microorganisms most frequently isolated from the amniotic fluid of women diagnosed with chorioamnionitis. However, controversy remains concerning the role of Ureaplasma spp. in the pathogenesis of neonatal brain injury. We hypothesize that reexposure to an inflammatory trigger during the perinatal period might be responsible for the variation in brain outcomes of preterms following Ureaplasma-driven chorioamnionitis. To investigate these clinical scenarios, we performed a detailed multimodal study in which ovine neurodevelopmental outcomes were assessed following chronic intra-amniotic Ureaplasma parvum (UP) infection either alone or combined with subsequent lipopolysaccharide (LPS) exposure. We show that chronic intra-amniotic UP exposure during the second trimester provoked a decrease in astrocytes, increased oligodendrocyte numbers, and elevated 5-methylcytosine levels. In contrast, short-term LPS exposure before preterm birth induced increased microglial activation, myelin loss, elevation of 5-hydroxymethylcytosine levels, and lipid profile changes. These LPS-induced changes were prevented by chronic preexposure to UP (preconditioning). These data indicate that chronic UP exposure has dual effects on preterm brain development in utero. On the one hand, prolonged UP exposure causes detrimental cerebral changes that may predispose to adverse postnatal clinical outcomes. On the other, chronic intra-amniotic UP exposure preconditions the brain against a second inflammatory hit. This study demonstrates that microbial interactions and the timing and duration of the inflammatory insults determine the effects on the fetal brain. Therefore, this study helps to understand the complex and diverse postnatal neurological outcomes following UP driven chorioamnionitis.
绒毛膜羊膜炎与早产儿不良神经发育结局相关。解脲脲原体是从诊断为绒毛膜羊膜炎的女性羊水样本中最常分离出的微生物。然而，解脲脲原体在新生儿脑损伤发病机制中的作用仍存在争议。我们推测，围产期再次暴露于炎症触发因素可能是解脲脲原体引发绒毛膜羊膜炎后早产儿脑结局存在差异的原因。为了研究这些临床情况，我们进行了一项详细的多模式研究，评估了羊在单独慢性羊膜内感染微小脲原体（UP）或联合随后暴露于脂多糖（LPS）后的神经发育结局。我们发现，孕中期慢性羊膜内暴露于UP会导致星形胶质细胞减少、少突胶质细胞数量增加以及5-甲基胞嘧啶水平升高。相反，早产前短期暴露于LPS会导致小胶质细胞激活增加、髓鞘丢失、5-羟甲基胞嘧啶水平升高以及脂质谱改变。慢性预先暴露于UP（预处理）可预防这些LPS诱导的变化。这些数据表明，慢性UP暴露对子宫内早产儿脑发育具有双重影响。一方面，长时间暴露于UP会导致有害的脑部变化，可能使新生儿易出现不良临床结局。另一方面，慢性羊膜内暴露于UP可使大脑对第二次炎症刺激产生预处理作用。这项研究表明，微生物相互作用以及炎症损伤的时间和持续时间决定了对胎儿脑的影响。因此，本研究有助于理解解脲脲原体引发绒毛膜羊膜炎后复杂多样的新生儿神经学结局。
