Prevention of pulmonary hypoplasia and pulmonary vascular remodeling by antenatal simvastatin treatment in nitrofen-induced congenital diaphragmatic hernia

Abstract

Congenital diaphragmatic hernia (CDH) has a high mortality rate mainly due to lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). Simvastatin has been shown to prevent the development of pulmonary hypertension (PH) in experimental models of PH. We, therefore, hypothesized that antenatal simvastatin would attenuate PPHN in nitrofen-induced CDH in rats. The efficacy of antenatal simvastatin was compared with antenatal sildenafil, which has already been shown to improve pathological features of PPHN in nitrofen-induced CDH. On embryonic day (E) 9.5, nitrofen or vehicle was administered to pregnant Sprague-Dawley rats. On E11, nitrofen-treated rats were randomly assigned to antenatal simvastatin (20 mg·kg(-1)·day(-1) orally), antenatal sildenafil (100 mg·kg(-1)·day(-1) orally), or placebo administration from E11 to E21. On E21, fetuses were delivered by cesarean section, killed, and checked for left-sided CDH. Lung tissue was then harvested for further pathobiological evaluation. In nitrofen-induced CDH, simvastatin failed to reduce the incidence of nitrofen-induced CDH in the offspring and to increase the body weight, but improved the lung-to-body weight ratio and lung parenchyma structure. Antenatal simvastatin restored the pulmonary vessel density and external diameter, and reduced the pulmonary arteriolar remodeling compared with nitrofen-induced CDH. This was associated with decreased lung expression of endothelin precursor, endothelin type A and B receptors, endothelial and inducible nitric oxide synthase, together with restored lung activation of apoptotic processes mainly in the epithelium. Antenatal simvastatin presented similar effects as antenatal therapy with sildenafil on nitrofen-induced CDH. Antenatal simvastatin improves pathological features of lung hypoplasia and PPHN in experimental nitrofen-induced CDH.

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia

“…We focused primarily on the physiological effects of antenatal sildenafil treatment in DH lambs, so our study is limited by the absence of histological evidence to confirm the morphological and biochemical features underlying the observed physiology. However, the effects of sildenafil on pulmonary vascular development have been well described in other animal models of CDH and correlate well with our current findings. Interestingly, fetal plasma sildenafil concentrations in our lambs immediately prior to delivery (2–5 ng/mL) were similar to those obtained in rats by Mous et al ,.…”

“…Furthermore, antenatal treatment with the PDE‐5 inhibitor sildenafil has been shown to attenuate pulmonary vascular abnormalities in both a nitrofen‐induced CDH rodent model and a surgery‐induced CDH rabbit model, which is more clinically relevant in terms of lung development. In these animal studies, antenatal sildenafil treatment increased cGMP and vascular endothelial growth factor expression in lung tissue, increased distal pulmonary vessel density, decreased pulmonary vascular muscularization, reduced right ventricular wall thickness and increased distal airway complexity. However, it is unclear if these improvements in pulmonary vascular structure and biochemistry translate to improved pulmonary hemodynamics after birth.…”

Pulmonary vascular development in congenital diaphragmatic hernia

“…We and others have performed some studies on the antenatal use of the phosphodiesterase-5 inhibitor sildenafil in different animal models of CDH, showing improvement in alveolarisation and pulmonary vascular development [57][58][59][60][61]. However, the pulmonary pathology in these treated animals did not show complete reversal to the normal lung histology.…”

Effects of Simvastatin on Fetal Cardiac Impairment in the Diaphragmatic Experimental Hernia Model

“…Mous et al [12] demonstrated that prenatal sildenafil started at a clinically relevant time point decreases lung hypoplasia and attenuates vascular remodeling in nitrofen-induced CDH in rats. Makanga et al [17] reported that antenatal simvastatin presented similar effects as antenatal therapy with sildenafil, improving the pathological features of lung hypoplasia and PH.…”

“…In animal models, prenatal treatment with sildenafil results in improved pulmonary morphology and increased vessel density associated with evidence of decreased PH [12-16]. Similarly, antenatal maternal administration of simvastatin in experimental nitrofen-induced CDH improves the pathological features of lung hypoplasia and PH, promoting improved lung parenchyma architecture and decreased pulmonary arteriolar remodeling [17]. …”