Enhanced Pulmonary Vascular and Alveolar Development via Prenatal Administration of a Slow-Release Synthetic Prostacyclin Agonist in Rat Fetal Lung Hypoplasia.
Enhanced Pulmonary Vascular and Alveolar Development via Prenatal Administration of a Slow-Release Synthetic Prostacyclin Agonist in Rat Fetal Lung Hypoplasia.
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DOI：
10.1371/journal.pone.0161334
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Okuyama H
中科院分区：
文献类型：
--
作者：
Umeda S;Miyagawa S;Fukushima S;Oda N;Saito A;Sakai Y;Sawa Y;Okuyama H
肺发育不良和肺动脉高压是新生儿先天性膈疝（CDH）死亡的主要原因。虽然前列腺素途径在肺发育中起着关键作用，但报告的出生后前列腺素激动剂治疗的疗效并不理想。我们假设，产前治疗ONO-1301 SR，一种缓释形式的新型合成前列环素激动剂与血栓素抑制活性，可能会提高肺发育不全的胎儿期。在胚胎（E）9.5天，对妊娠Sprague-Dawley大鼠给予除草醚以建立CDH相关肺发育不全模型，而正常大鼠仅接受溶媒。同一天，也随机给予ONO-1301 SR或安慰剂。在E21.5，分析正常组和表现出CDH的胎儿。产前ONO-1301 SR给药对硝苯酰草醚诱导的CDH的发生率没有影响。CDH+ONO组的肺/体重比大于CDH组。组织学上，CDH+ONO组的内侧壁比CDH组薄三分之二。此外，CDH+ONO组中Ttf-1阳性细胞数量和毛细血管密度是CDH组的1.5倍以上，这种增加与CDH+ONO组中血管内皮生长因子和基质细胞衍生因子的表达增加有关，表明肺泡和毛细血管网络的发育增强。因此，产前ONO-1301 SR对与硝苯酰草醚诱导的大鼠模型中CDH相关的肺发育不全的进展具有保护作用，表明这种治疗对表现出肺发育不全的病理的潜力。
Lung hypoplasia and pulmonary hypertension are the major causes of mortality in neonates with congenital diaphragmatic hernia (CDH). Although the prostaglandin pathway plays a pivotal role in lung development, the reported efficacy of postnatal prostaglandin agonist treatment is suboptimal. We hypothesized that prenatal treatment with ONO-1301SR, a slow-release form of a novel synthetic prostacyclin agonist with thromboxane inhibitory activity, might enhance the development of lungs exhibiting hypoplasia in the fetal period. On embryonic day (E) 9.5, nitrofen was given to pregnant Sprague-Dawley rats to establish a CDH-related lung hypoplasia model, whereas normal rats received the vehicle only. The same day, either ONO-1301SR or a placebo was also randomly administered. On E21.5, the fetuses of the normal group and those exhibiting CDH were analyzed. Prenatal ONO-1301SR administration had no influence on the incidence of nitrofen-induced CDH. The lung-to-body weight ratio in the CDH+ONO group was greater than that in the CDH group. Histologically, the medial wall in the CDH+ONO group was two-thirds thinner than that in the CDH group. In addition, the number of Ttf-1-positive cells and the capillary density were ≥1.5 times greater in the CDH+ONO group than in the CDH group, and this increase was associated with higher expression of vascular endothelial growth factor and stromal cell-derived factor in the CDH+ONO group, suggesting enhanced development of the alveolar and capillary networks. Thus, prenatal ONO-1301SR was protective against the progression of lung hypoplasia associated with CDH in a nitrofen-induced rat model, indicating the potential of this treatment for pathologies exhibiting lung hypoplasia.