Placental TNF-α Signaling in Illness-Induced Complications of Pregnancy
Placental TNF-α Signaling in Illness-Induced Complications of Pregnancy
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DOI：
10.1016/j.ajpath.2011.02.042
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发表时间：
2011-06-01
影响因子：
6
通讯作者：
Palmer, Theo D.
中科院分区：
文献类型：
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作者：
Carpentier, Pamela A.;Dingman, Andra L.;Palmer, Theo D.
孕产妇感染与妊娠期间的各种并发症有关，包括流产、早产和儿童神经发育障碍的风险增加。在本研究中，我们在小鼠身上发现，在妊娠早期，低剂量脂多糖即使是轻微的先天免疫激活也会导致胎盘出血，并增加妊娠丢失的风险。存活的胎儿表现为大脑缺氧和胎儿神经发生受损。母体toll样受体4信号是这一过程的关键中介，其激活伴随着胎盘中促炎细胞因子的升高。我们评估了肿瘤坏死因子- α (TNF- α)信号的作用，并表明TNF受体1 （TNFR1）在疾病引起的胎盘病理、伴随的胎儿缺氧和胎儿大脑神经增生性缺陷中是必要的。我们还表明，在母体TNFR1缺失的情况下，胎盘TNFR1足以导致胎盘病理的发展，并且临床相关的TNT-a拮抗剂可以防止胎盘病理和胎儿丢失。我们的观察结果表明，胎盘在妊娠早期对促炎信号高度敏感，而TNT-a是预防与疾病相关的胎盘缺陷以及对胎儿和胎儿大脑发育的相关风险的有效靶点。[J] .中华检验医学杂志，2011,38 (2):481 - 481；10.1016 / j.ajpath.2011.02.042)
Maternal infections are implicated in a variety of complications during pregnancy, including pregnancy loss, prematurity, and increased risk of neurodevelopmental disorders in the child. Here, we show in mice that even mild innate immune activation by low-dose lipopolysaccharide in early pregnancy causes hemorrhages in the placenta and increases the risk of pregnancy loss. Surviving fetuses exhibit hypoxia in the brain and impaired fetal neurogenesis. Maternal Toll-like receptor 4 signaling is a critical mediator of this process, and its activation is accompanied by elevated proinflammatory cytokines in the placenta. We evaluated the role of tumor necrosis factor-alpha (TNF-alpha) signaling and show that TNF receptor 1 (TNFR1) is necessary for the illnessinduced placental pathology, accompanying fetal hypoxia, and neuroproliferative defects in the fetal brain. We also show that placental TNFR1 in the absence of maternal TNFR1 is sufficient for placental pathology to develop and that a clinically relevant TNT-a antagonist prevents placental pathology and fetal loss. Our observations suggest that the placenta is highly sensitive to proinflammatory signaling in early pregnancy and that TNT-a is an effective target for preventing illness-related placental defects and related risks to the fetus and fetal brain development. (Am J Pathol 2011, 178:2802-2810; DOL. 10.1016/j.ajpath.2011.02.042)