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, Health and Biomedical Innovation, Adelaide, Australia.
UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
Pediatr Res. 2025 Feb 25. doi: 10.1038/s41390-025-03828-1.
Chronic hypoxemia is a common cause of fetal growth restriction and can have significant effects on the developing fetal lung. Maternal antioxidant treatment in hypoxic pregnancy protects against offspring cardiovascular dysfunction. The effects of antenatal antioxidants on lung development in the chronically hypoxic growth restricted fetus is unknown.
We investigated the effect of maternal daily Vitamin C (200 mg/kg i.v. vs. Saline) for a month in late gestation on molecular markers regulating lung maturation between normoxic normally grown and hypoxic growth-restricted fetal sheep. Chronic fetal hypoxia and fetal growth restriction were induced by exposure to maternal chronic hypoxia (10% O vs. Normoxia=21% O) from 105-138 d gestation (term=145 d).
The data show a differential effect of antenatal Vitamin C treatment on regulation of genes involved in surfactant maturation, sodium movement and hypoxia signaling. Limited responsiveness to antenatal Vitamin C exposure in the lung of the hypoxic fetus, compared to responsiveness to antenatal Vitamin C in the normoxic fetus, suggests a maximal upregulation of the molecular signaling pathways in response to the chronic hypoxic insult alone.
We provide molecular insight into the heterogeneity of antenatal Vitamin C treatment on development of the normoxic and growth restricted hypoxic fetal lung.
The effect of maternal Vitamin C on molecular markers of lung maturation between normoxic normally grown and hypoxic growth restricted fetal sheep was unknown. We show a differential effect of Vitamin C with a greater increase in molecular markers of lung maturation in normoxic compared with hypoxic fetuses. Limited responsiveness in the hypoxic fetal lung is likely due to maximal upregulation by the hypoxic insult alone, thus added exposure to Vitamin C is unable to upregulate the system further. The work highlights the need to understand differential effects of antenatal interventions in healthy and complicated pregnancy, prior to clinical translation.
慢性低氧血症是胎儿生长受限的常见原因，对发育中的胎儿肺可产生重大影响。缺氧妊娠时母体抗氧化剂治疗可预防子代心血管功能障碍。产前抗氧化剂对慢性低氧生长受限胎儿肺发育的影响尚不清楚。
我们研究了妊娠晚期母体每日静脉注射维生素C（200mg/kg，与生理盐水对照）一个月对正常氧合正常生长和低氧生长受限胎羊肺成熟相关分子标志物的影响。通过在妊娠105 - 138天（足月为145天）使母体处于慢性低氧环境（10%氧气，正常氧为21%氧气）来诱导胎儿慢性缺氧和生长受限。
数据显示产前维生素C治疗对参与表面活性剂成熟、钠转运和缺氧信号传导的基因调控有不同影响。与正常氧合胎儿对产前维生素C暴露的反应相比，低氧胎儿肺对产前维生素C暴露的反应有限，这表明仅慢性低氧损伤就使分子信号通路达到了最大上调。
我们为产前维生素C治疗对正常氧合和生长受限低氧胎儿肺发育的异质性提供了分子层面的见解。
母体维生素C对正常氧合正常生长和低氧生长受限胎羊肺成熟分子标志物的影响尚不清楚。我们发现维生素C有不同影响，与低氧胎儿相比，正常氧合胎儿肺成熟分子标志物的增加幅度更大。低氧胎儿肺反应有限可能是由于仅低氧损伤就使其达到了最大上调，因此额外暴露于维生素C无法进一步上调该系统。这项工作强调了在临床转化之前，了解产前干预在健康和复杂妊娠中的不同影响的必要性。
