产前母体给予磷酸二酯酶 5 抑制剂可使先天性膈疝胎儿羊模型中 eNOS 的表达正常化。
Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia.
机构信息
Department of Surgery, Division of Pediatric Surgery and Fetal Treatment Center, University of California, San Francisco, San Francisco, CA.
Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
出版信息
J Pediatr Surg. 2014 Jan;49(1):39-45; discussion 45. doi: 10.1016/j.jpedsurg.2013.09.024. Epub 2013 Oct 5.
PURPOSE
Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH.
METHODS
CDH was created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis.
RESULTS
Mean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82%±12% in Normal-Placebo, 61%±5% in CDH-Placebo, 116%±6% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Normalized expression of β-sGC was 105%±15% in Normal-Placebo, 82%±3% in CDH-Placebo, 158%±16% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Endothelial NOS and β-sGC were significantly decreased in CDH (p=0.0007 and 0.01 for eNOS and β-sGC, respectively), and tadalafil significantly increased eNOS expression (p=0.0002).
CONCLUSIONS
PDE5 inhibitors can cross the placental barrier. β-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH.
目的
肺动脉高压（pHTN）是先天性膈疝（CDH）患者生存的主要决定因素，源于宫内血管重塑。磷酸二酯酶 5 型（PDE5）抑制剂从未被用于治疗 pHTN。本研究旨在确定产前 PDE5 抑制剂是否能预防 CDH 胎儿模型中的 pHTN。
方法
在怀孕的母羊中建立 CDH。手术后，怀孕的母羊接受口服安慰剂或他达拉非（一种 PDE5 抑制剂）治疗，直至分娩。接近足月时，羔羊接受复苏，肺组织立即冷冻用于蛋白质分析。
结果
安慰剂治疗的胎儿羔羊平均 cGMP 水平为 0.53±0.11，他达拉非治疗的胎儿羔羊为 1.73±0.21（p=0.002）。正常情况下，eNOS 的表达归一化率为 82%±12%（Normal-Placebo），61%±5%（CDH-Placebo），116%±6%（Normal-Tadalafil）和 86%±8%（CDH-Tadalafil）。β-sGC 的表达归一化率为 105%±15%（Normal-Placebo），82%±3%（CDH-Placebo），158%±16%（Normal-Tadalafil）和 86%±8%（CDH-Tadalafil）。CDH 时内皮型一氧化氮合酶（eNOS）和β-sGC 显著降低（p=0.0007 和 0.01，分别为 eNOS 和 β-sGC），他达拉非显著增加 eNOS 表达（p=0.0002）。
结论
PDE5 抑制剂可以穿过胎盘屏障。CDH 胎儿中β-sGC 和 eNOS 表达下调。产前 PDE5 抑制剂可使 eNOS 正常化，并可能预防 CDH 中的宫内血管重塑。
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