母体西地那非与胎儿气管阻塞联合作用对先天性膈疝兔模型肺发育的改善作用。

Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia.

机构信息

Cluster Woman and Child, Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium.

Department of Obstetrics and Gynecology, University Hospitals of Leuven, Leuven, Belgium.

出版信息

Ann Surg. 2022 Mar 1;275(3):e586-e595. doi: 10.1097/SLA.0000000000003943.

DOI:10.1097/SLA.0000000000003943

PMID:33055583

Abstract

OBJECTIVE

To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH).

BACKGROUND

Although antenatal sildenafil administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, it only partially improves airway morphometry. We hypothesized that we could additionally stimulate lung growth by combining this medical treatment with fetal TO.

METHODS

CDH was created on gestational day (GD)23 (n=54). Does were randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and finally harvested for histological and molecular analyses. Unoperated littermates served as controls.

RESULTS

The lung-to-body-weight ratio was significantly reduced in sham-CDH fetuses either (1.2 ± 0.3% vs 2.3 ± 0.3% in controls, P=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses undergoing TO had a lung-to-body-weight ratio comparable to that of controls (2.5 ± 0.8%, P<0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ± 0.8 br/mm2 vs 3.5 ± 0.9 br/mm2, P=0.043) and lung mechanics (static elastance 61 ± 36 cmH2O /mL vs 113 ± 40 cmH2O/mL, P=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ± 0.8 br/mm2, P=0.001 and 31 ± 9 cmH2O/mL, P<0.0001 respectively). Both CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall thickness of peripheral pulmonary vessels (41.9 ± 2.9% and 41.8 ± 3.2%, vs 24.0 ± 2.9% in controls, P<0.0001). CDH fetuses treated with sildenafil, either with or without TO, had a medial thickness in the normal range (29.4% ± 2.6%). Finally, TO reduced gene expression of vascular endothelial growth factor and surfactant protein A and B, but this effect was counteracted by sildenafil.

CONCLUSION

In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.

摘要

目的

评估在先天性膈疝（CDH）兔模型中，产前西地那非联合胎儿气管阻塞（TO）对胎儿的治疗效果。

背景

虽然产前西地那非可改善 CDH 胎儿肺部的血管异常，但仅能部分改善气道形态计量学。我们假设，通过联合这种药物治疗和胎儿 TO，还可以进一步刺激肺生长。

方法

在妊娠第 23 天（GD23）建立 CDH 模型（n=54）。母兔从 GD24 到 GD30 每天接受 10mg/kg 的西地那非或安慰剂皮下注射。在 GD28，胎儿随机接受 TO 或假颈清扫术。在足月（GD30）时分娩胎儿，进行通气，最后进行组织学和分子分析。未手术的同窝仔兔作为对照。

结果

与对照组相比，假 CDH 胎儿的肺/体重比显著降低（1.2±0.3% vs 2.3±0.3%，P=0.0003）。西地那非对该参数没有影响，而接受 TO 的 CDH 胎儿的肺/体重比与对照组相当（2.5±0.8%，P<0.0001）。西地那非单独使用可改善终末细支气管密度（2.5±0.8 br/mm2 与 3.5±0.9 br/mm2，P=0.043）和肺力学（静态弹性 61±36 cmH2O/mL 与 113±40 cmH2O/mL，P=0.008），但在接受额外 TO 的胎儿中，这两种作用更为明显（2.1±0.8 br/mm2，P=0.001 和 31±9 cmH2O/mL，P<0.0001）。接受安慰剂治疗的 CDH-假和 CDH-TO 胎儿的肺外周血管壁中层厚度均增加（41.9±2.9%和 41.8±3.2%，与对照组 24.0±2.9%相比，P<0.0001）。接受西地那非治疗的 CDH 胎儿，无论是否接受 TO 治疗，其中层厚度均在正常范围内（29.4%±2.6%）。最后，TO 降低了血管内皮生长因子和表面活性剂蛋白 A 和 B 的基因表达，但西地那非可拮抗这种作用。