背景:目前对有早产风险的妊娠的临床处理包括产妇产前皮质类固醇(ACS)治疗。ACS激活所有胎儿组织中的糖皮质激素受体(GR),以大脑发育受损为代价使肺部成熟,需要新的治疗方法。前药环索奈德(CIC)仅在通过特定酶转化为des-CIC时才激活GR,包括乙酰胆碱酯酶(ACHE)和羧酸酯酶1和2(CES1,CES2)。重要的是,人类胎盘表达ACHE和CES,并可能产生des-CIC,导致全身胎儿暴露和所有胎儿组织的GR激活。因此,我们研究了在妊娠中期(Tri2)收集的人胎盘中CES基因表达和CIC向des-CIC的转化,在早产和足月分娩时。
方法:在Tri2(n=27)中进行差异表达分析,早产(n=34),和使用DESeq2R包的足月(n=40)胎盘。使用功能测定在胎盘样品的子集(Tri2n=7,早产n=26,期限n=20)中测量CIC向des-CIC的转化。
结果:ACHEmRNA在Tri2雄性胎盘中的表达高于早产和足月雄性胎盘,而CES1mRNA在Tri2中的表达高于早产或足月胎盘。胎龄之间CIC到des-CIC的转换没有差异。
结论:人胎盘将CIC转化为des-CIC可能会阻止其作为一种新型GR激动剂用于先兆早产。需要进行体内研究以确认母体治疗后胎盘激活的程度。
BACKGROUND: Current clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development, creating a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only when converted to des-CIC by specific enzymes, including acetylcholinesterase (ACHE) and carboxylesterase 1 and 2 (CES1, CES2). Importantly, the human placenta expresses ACHE and CES, and could potentially produce des-CIC, resulting in systemic fetal exposure and GR activation in all fetal tissues. We therefore investigated CES gene expression and conversion of CIC to des-CIC in human placentae collected during the second trimester (Tri2), and at preterm and term birth.
METHODS: Differential expression analysis was performed in Tri2 (n = 27), preterm (n = 34), and term (n = 40) placentae using the DESeq2 R-package. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n = 7, preterm n = 26, term n = 20) using functional assays.
RESULTS: ACHE mRNA expression was higher in Tri2 male than preterm and term male placentae only, whereas CES1 mRNA expression was higher in Tri2 than preterm or term placentae of both sexes. Conversion of CIC to des-CIC did not differ between gestational ages.
CONCLUSIONS: Conversion of CIC to des-CIC by the human placenta may preclude its use as a novel GR-agonist in threatened preterm birth. In vivo studies are required to confirm the extent to which placental activation occurs after maternal treatment.