- Neonatal surgery and fetal diagnosis and treatment
- Minimally invasive surgery (laparoscopic surgery, thorascopic surgery, etc.)
- Organ transplantation (liver, small intestine) and regenerative medicine (trachea, esophagus)
- Surgical metabolism and nutrition
- Solid tumors (Wilms’ tumor, neuroblastomas, hemangioma, etc.)
Novel fetal therapies using synthetic prostacyclin agonist for lung hypoplasia in congenital diaphragmatic hernia
"Congenital diaphragmatic hernia (CDH) has high mortality and is marked by lung hypoplasia and pulmonary hypertension. Currently, 75% of CDH cases in Japan involve the fetus, demanding new fetal therapies. Recent studies have shown the positive effects of VEGF (vascular endothelial cell growth factor) and sildenafil (Sildenafil) on lung development and pulmonary hypertension in CDH rat models.
ONO-1301 is a prostacyclin (PGI2) agonist that inhibits thromboxane synthesis, thus giving it a vasodilative effect. It also promotes angiogenesis through VEGF/HGF/SDF-1 signaling. In addition, this molecule has been reported to reduce pulmonary arterial thickening and improve pulmonary hypertension in rat models. Furthermore, a polylactic-co-glycolic acid copolymer-polymerized microsphere form of ONO-1301 (ONO-1301SR) has been enabled to provid a sustained ONO-1301 effect. PGI2 agonists have already been clinically applied for pulmonary hypertension in CDH neonates. We are currently investigating the effects of ONO-1301 in our CDH rat model.
A CDH model was prepared by orally administering Nitrofen (100 mg/body) to Sprague-Dawley rats on the 9th day of pregnancy (E9.5). On the same day, ONO-1301 SR (30 mg/kg) or placebo was randomly given to pregnant model rats. The fetus was removed on E21.5, and the following evaluation was made among the three groups (control, CDH, CDH + ONO).
(1) The expression of prostacyclin receptor (IPR) in fetal lung was examined by immunohistochemical staining. The incidence of CDH was examined, and the lung-to-body weight ratio (LW/BW (%)) was measured as an indicator of fetal lung hypoplasia.
(2) Sections stained with hematoxylin and eosin (H&E) were used for pulmonary airspace assessment by measuring the mean linear intercept (Lm). Medial wall thickness was calculated by Elastica van Gieson staining, and pulmonary artery media thickening was quantitatively evaluated.
(3) RNA was taken from the excised lung, and the gene expressions of VEGF, HGF and SDF-1 were examined by qRT-PCR.
(1) Immunostaining showed IPR was localized in the fetal pulmonary artery smooth muscle (Fig. 1). There was no change in the incidence of CDH with ONO-1301 administration. In the CDH + ONO group, the lung-to-body weight ratio was significantly increased compared to the CDH group.
(2) Also in the CDH + ONO group, the mean linear intercept values remarkably increased compared to the CDH group. In the CDH + ONO group, the thickening of the pulmonary artery significantly improved compared with the CDH group (Fig. 2).
(3) The expressions of VEGF and SDF-1 were significantly increased in the CDH + ONO group compared with the CDH group, suggesting enhanced development of the alveolar and capillary networks.
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."