Stojanovska Vanesa, Atta John, Kelly Sharmony B, Zahra Valerie A, Matthews-Staindl Eva, Nitsos Ilias, Moxham Alison, Pham Yen, Hooper Stuart B, Herlenius Eric, Galinsky Robert, Polglase Graeme R
The Ritchie Center, Hudson Institute of Medical Research, Melbourne, VIC, Australia.
Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia.
Front Physiol. 2022 Mar 3;13:841229. doi: 10.3389/fphys.2022.841229. eCollection 2022.
Preterm newborns commonly experience apnoeas after birth and require respiratory stimulants and support. Antenatal inflammation is a common antecedent of preterm birth and inflammatory mediators, particularly prostaglandin E2 (PGE), are associated with inhibition of vital brainstem respiratory centers. In this study, we tested the hypothesis that exposure to antenatal inflammation inhibits fetal breathing movements (FBMs) and increases inflammation and PGE levels in brainstem respiratory centers, cerebrospinal fluid (CSF) and blood plasma.
Chronically instrumented late preterm fetal sheep at 0.85 of gestation were randomly assigned to receive repeated intravenous saline ( = 8) or lipopolysaccharide (LPS) infusions (experimental day 1 = 300 ng, day 2 = 600 ng, day 3 = 1200 ng, = 8). Fetal breathing movements were recorded throughout the experimental period. Sheep were euthanized 4 days after starting infusions for assessment of brainstem respiratory center histology.
LPS infusions increased circulating and cerebrospinal fluid PGE levels, decreased arterial oxygen saturation, increased the partial pressure of carbon dioxide and lactate concentration, and decreased pH ( < 0.05 for all) compared to controls. LPS infusions caused transient reductions in the % of time fetuses spent breathing and the proportion of vigorous fetal breathing movements ( < 0.05 vs. control). LPS-exposure increased PGE expression in the RTN/pFRG ( < 0.05 vs. control) but not the pBÖTC ( < 0.07 vs. control) of the brainstem. No significant changes in gene expression were observed for PGE enzymes or caspase 3. LPS-exposure reduced the numbers of GFAP-immunoreactive astrocytes in the RTN/pFRG, NTS and XII of the brainstem ( < 0.05 vs. control for all) and increased microglial activation in the RTN/pFRG, preBÖTC, NTS, and XII brainstem respiratory centers ( < 0.05 vs. control for all).
Chronic LPS-exposure in late preterm fetal sheep increased PGE levels within the brainstem, CSF and plasma, and was associated with inhibition of FBMs, astrocyte loss and microglial activation within the brainstem respiratory centers. Further studies are needed to determine whether the inflammation-induced increase in PGE levels plays a key role in depressing respiratory drive in the perinatal period.
早产新生儿出生后常出现呼吸暂停，需要呼吸兴奋剂和支持。产前炎症是早产的常见先兆，炎症介质，尤其是前列腺素E2（PGE），与抑制重要的脑干呼吸中枢有关。在本研究中，我们检验了以下假设：产前炎症暴露会抑制胎儿呼吸运动（FBMs），并增加脑干呼吸中枢、脑脊液（CSF）和血浆中的炎症和PGE水平。
将妊娠0.85期的慢性植入仪器的晚期早产胎羊随机分为两组，分别接受重复静脉注射生理盐水（n = 8）或脂多糖（LPS）输注（实验第1天 = 300 ng，第2天 = 600 ng，第3天 = 1200 ng，n = 8）。在整个实验期间记录胎儿呼吸运动。在开始输注4天后对绵羊实施安乐死，以评估脑干呼吸中枢组织学。
与对照组相比，LPS输注使循环和脑脊液中的PGE水平升高，动脉血氧饱和度降低，二氧化碳分压和乳酸浓度升高，pH值降低（所有均P < 0.05）。LPS输注导致胎儿呼吸时间百分比和剧烈胎儿呼吸运动比例短暂降低（与对照组相比P < 0.05）。LPS暴露使脑干的延髓头端腹外侧网状核/面神经后核（RTN/pFRG）中的PGE表达增加（与对照组相比P < 0.05），但脑桥臂旁外侧核（pBÖTC）中的PGE表达未增加（与对照组相比P < 0.07）。未观察到PGE酶或半胱天冬酶3的基因表达有显著变化。LPS暴露使脑干的RTN/pFRG、孤束核（NTS）和舌下神经核（XII）中胶质纤维酸性蛋白（GFAP）免疫反应性星形胶质细胞数量减少（所有均与对照组相比P < 0.05），并使RTN/pFRG、脑桥臂旁外侧核前区（preBÖTC）、NTS和XII脑干呼吸中枢中的小胶质细胞活化增加（所有均与对照组相比P < 0.05）。
晚期早产胎羊长期暴露于LPS会使脑干、CSF和血浆中的PGE水平升高，并与抑制FBMs、脑干呼吸中枢内星形胶质细胞丢失和小胶质细胞活化有关。需要进一步研究以确定炎症诱导的PGE水平升高是否在围产期抑制呼吸驱动中起关键作用。
