Department of Neonatology, Heidelberg University Children's Hospital, 69120, Heidelberg, Germany.
Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Pediatr Res. 2018 Nov;84(5):757-764. doi: 10.1038/s41390-018-0030-z. Epub 2018 Aug 22.
A pro-inflammatory intrauterine milieu accounts for increased perinatal morbidity and mortality. We asked how maternal inflammation as seen in endotoxemia affects fetal leukocyte recruitment in vivo during late gestation.
Inflammation was induced in pregnant LysEGFP-mice by intraperitoneal LPS injection between gestational day 14 and 18 (E14-E18). After 20 h, intravital fluorescence microscopy was performed on fetal yolk sac venules to examine leukocyte rolling (number of rolling cells/min) and adhesion (>30 s). Infiltration of neutrophils into chorion/amnion, lung, and kidney were quantified by immunofluorescence microscopy.
At high doses (2 × 1 mg/kg), LPS triggered preterm birth (PTB) and intrauterine fetal death (IUFD), with early gestations at high risk of IUFD and late gestations prone to PTB. Lower LPS dosing (2 × 0.25 mg/kg) did not induce labor, but promoted maternal and fetal cytokine production, as well as neutrophilic infiltration of fetal membranes, as seen in chorioamnionitis (CAM). Baseline fetal leukocyte recruitment increased throughout gestation, and maternal inflammation further augmented adhesion at E16-E18. Enhanced leukocyte recruitment ultimately translated into prominent infiltration of fetal lung and kidney.
LPS-induced maternal endotoxemia promotes IUFD, PTB, and fetal leukocyte recruitment depending on gestational age. Our proposed model may serve as a platform to test novel perinatal immune modulators.
促炎的子宫内环境导致围产期发病率和死亡率增加。我们想知道内毒素血症引起的母体炎症如何影响晚期妊娠胎儿白细胞在体内的募集。
在妊娠 LysEGFP 小鼠中，通过腹腔内 LPS 注射在妊娠第 14 天至 18 天（E14-E18）期间诱导炎症。20 小时后，对胎儿卵黄囊静脉进行活体荧光显微镜检查，以检查白细胞滚动（每分钟滚动细胞数）和黏附（>30 秒）。通过免疫荧光显微镜定量分析绒毛膜/羊膜、肺和肾的中性粒细胞浸润。
高剂量（2×1mg/kg）LPS 引发早产（PTB）和宫内胎儿死亡（IUFD），高剂量妊娠早期 IUFD 风险高，晚期妊娠易发生 PTB。较低剂量的 LPS（2×0.25mg/kg）不会引起分娩，但会促进母体和胎儿细胞因子的产生，以及胎儿膜中的中性粒细胞浸润，如绒毛膜羊膜炎（CAM）。基线胎儿白细胞募集在整个妊娠期间增加，母体炎症进一步增加了 E16-E18 时的黏附。增强的白细胞募集最终导致胎儿肺和肾的明显浸润。
LPS 诱导的母体内毒素血症会根据胎龄导致 IUFD、PTB 和胎儿白细胞募集。我们提出的模型可以作为测试新型围生期免疫调节剂的平台。
