McGillick Erin V, Orgeig Sandra, Allison Beth J, Brain Kirsty L, Niu Youguo, Itani Nozomi, Skeffington Katie L, Kane Andrew D, Herrera Emilio A, Giussani Dino A, Morrison Janna L
Early Origins of Adult Health Research Group, School of Pharmacy & Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
Molecular and Evolutionary Physiology of the Lung Laboratory, School of Pharmacy & Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
J Physiol. 2017 Jul 1;595(13):4329-4350. doi: 10.1113/JP273842. Epub 2017 May 7.
Chronic fetal hypoxaemia is a common pregnancy complication associated with intrauterine growth restriction that may influence respiratory outcome at birth. We investigated the effect of maternal chronic hypoxia for a month in late gestation on signalling pathways regulating fetal lung maturation and the transition to air-breathing at birth using isobaric hypoxic chambers without alterations to maternal food intake. Maternal chronic hypoxia in late gestation increases fetal lung expression of genes regulating hypoxia signalling, lung liquid reabsorption and surfactant maturation, which may be an adaptive response in preparation for the successful transition to air-breathing at birth. In contrast to other models of chronic fetal hypoxaemia, late gestation onset fetal hypoxaemia promotes molecular regulation of fetal lung maturation. This suggests a differential effect of timing and duration of fetal chronic hypoxaemia on fetal lung maturation, which supports the heterogeneity observed in respiratory outcomes in newborns following exposure to chronic hypoxaemia in utero.
Chronic fetal hypoxaemia is a common pregnancy complication that may arise from maternal, placental and/or fetal factors. Respiratory outcome of the infant at birth likely depends on the duration, timing and severity of the hypoxaemic insult. We have isolated the effect of maternal chronic hypoxia (MCH) for a month in late gestation on fetal lung development. Pregnant ewes were exposed to normoxia (21% O ) or hypoxia (10% O ) from 105 to 138 days of gestation (term ∼145 days). At 138 days, gene expression in fetal lung tissue was determined by quantitative RT-PCR. Cortisol concentrations were determined in fetal plasma and lung tissue. Numerical density of surfactant protein positive cells was determined by immunohistochemistry. MCH reduced maternal PaO2 (106 ± 2.9 vs. 47 ± 2.8 mmHg) and fetal body weight (4.0 ± 0.4 vs. 3.2 ± 0.9 kg). MCH increased fetal lung expression of the anti-oxidant marker CAT and decreased expression of the pro-oxidant marker NOX-4. MCH increased expression of genes regulating hypoxia signalling and feedback (HIF-3α, KDM3A, SLC2A1, EGLN-3). There was no effect of MCH on fetal plasma/lung tissue cortisol concentrations, nor genes regulating glucocorticoid signalling (HSD11B-1, HSD11B-2, NR3C1, NR3C2). MCH increased expression of genes regulating sodium (SCNN1-B, ATP1-A1, ATP1-B1) and water (AQP-4) movement in the fetal lung. MCH promoted surfactant maturation (SFTP-B, SFTP-D, ABCA3) at the molecular level, but did not alter the numerical density of surfactant positive cells in lung tissue. MCH in late gestation promotes molecular maturation of the fetal lung, which may be an adaptive response in preparation for the successful transition to air-breathing at birth.
慢性胎儿低氧血症是一种常见的妊娠并发症，与宫内生长受限相关，可能影响出生时的呼吸结局。我们使用等压缺氧舱，在不改变母体食物摄入量的情况下，研究了妊娠晚期母体慢性缺氧一个月对调节胎儿肺成熟及出生时向呼吸转变的信号通路的影响。妊娠晚期母体慢性缺氧会增加胎儿肺中调节缺氧信号、肺液重吸收和表面活性剂成熟的基因表达，这可能是一种适应性反应，为出生时成功向呼吸转变做准备。与其他慢性胎儿低氧血症模型不同，妊娠晚期开始的胎儿低氧血症促进胎儿肺成熟的分子调节。这表明胎儿慢性低氧血症的时间和持续时间对胎儿肺成熟有不同影响，这支持了在子宫内暴露于慢性低氧血症后新生儿呼吸结局中观察到的异质性。
慢性胎儿低氧血症是一种常见的妊娠并发症，可能由母体、胎盘和/或胎儿因素引起。婴儿出生时的呼吸结局可能取决于低氧损伤的持续时间、时间和严重程度。我们分离出了妊娠晚期母体慢性缺氧（MCH）一个月对胎儿肺发育的影响。怀孕母羊在妊娠105至138天（足月约145天）期间暴露于常氧（21% O₂）或低氧（10% O₂）环境。在138天时，通过定量RT-PCR测定胎儿肺组织中的基因表达。测定胎儿血浆和肺组织中的皮质醇浓度。通过免疫组织化学测定表面活性蛋白阳性细胞的数值密度。MCH降低了母体动脉血氧分压（106 ± 2.9 vs. 47 ± 2.8 mmHg）和胎儿体重（4.0 ± 0.4 vs. 3.2 ± 0.9 kg）。MCH增加了胎儿肺中抗氧化标志物CAT的表达，并降低了促氧化标志物NOX-4的表达。MCH增加了调节缺氧信号和反馈的基因（HIF-3α、KDM3A、SLC2A1、EGLN-3）的表达。MCH对胎儿血浆/肺组织皮质醇浓度以及调节糖皮质激素信号的基因（HSD11B-1、HSD11B-2、NR3C1、NR3C2）没有影响。MCH增加了胎儿肺中调节钠（SCNN1-B、ATP1-A1、ATP1-B1）和水（AQP-4）转运的基因的表达。MCH在分子水平上促进了表面活性剂成熟（SFTP-B、SFTP-D、ABCA3），但没有改变肺组织中表面活性物质阳性细胞的数值密度。妊娠晚期的MCH促进了胎儿肺的分子成熟，这可能是一种适应性反应，为出生时成功向呼吸转变做准备。
