Abstract
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.
Highlights
Lung hypoplasia and pulmonary hypertension are the major causes of mortality in neonates with congenital diaphragmatic hernia (CDH)
Prostacyclin Agonist in Rat Fetal Lung Hypoplasia pulmonary hypertension varies, lung development in the fetal period is associated with the prostaglandin pathway, wherein prostacyclin regulates fetal pulmonary vascular tone and lung vessel development
This study demonstrated that maternally administered ONO-1301SR entered the fetal blood through the placenta to enhance both alveolar and vascular development of the fetal lungs in the nitrofen-induced CDH rat model
Summary
Lung hypoplasia and pulmonary hypertension are the major causes of mortality in neonates with congenital diaphragmatic hernia (CDH). Some possible prenatal treatments were previously tested using this model, which were found to decrease the pulmonary vasculature, including steroids [1], sildenafil citrate [2], and retinoic acid [3]. These previous reports for treating fetal lung hypoplasia required frequently repeated administration of the drugs, and clinical trials have not yet been realized. Of note, repeated administration of ONO-1301 attenuated pulmonary vascular remodeling and improved survival in a monocrotaline-induced pulmonary hypertension rat model [5], in association with upregulation of endogenous vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and stromal cell-derived factor (SDF)-1 [6]. We have developed a polylactic-co-glycolic acid copolymer-polymerized microsphere form of ONO1301 (ONO-1301SR), which provided a sustained ONO-1301 effect and attenuated monocrotaline-induced pulmonary hypertension in rats with a single injection [7]
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