Prenatal tracheal ligation or intra-amniotic administration of surfactant or dexamethasone prevents some structural changes in the pulmonary arteries of surgically created diaphragmatic hernia in rabbits

Abstract

PURPOSE:Characterization of the structural changes occurring in the pulmonary arteries resulting from surgically produced congenital diaphragmatic hernia in rabbits, with particular emphasis on the preventive effects of prenatal tracheal ligation or administration of intra-amniotic dexamethasone or surfactant.METHODS: Twenty rabbit fetuses underwent surgical creation of a left-sided congenital diaphragmatic hernia on the 24th or 25th gestational day. They were divided according to the following procedures: congenital diaphragmatic hernia (n = 5), congenital diaphragmatic hernia plus tracheal ligation (n = 5), congenital diaphragmatic hernia plus intra-amniotic administration of dexamethasone 0.4 mg (n = 5) or surfactant (Curosurf 40 mg, n = 5). On gestational day 30, all the fetuses were delivered by caesarean section and killed. A control group consisted of five nonoperated fetuses. Histomorphometric analysis of medial thickness, cell nuclei density, and elastic fiber density of pulmonary arterial walls was performed.RESULTS: Arteries with an external diameter > 100 mm have a decreased medial thickness, lower cell nuclei density, and greater elastic fiber density when compared with arteries with external diameter £ 100 mm. Congenital diaphragmatic hernia promoted a significant decrease in medial thickness and an increase in cell nuclei density in artery walls with external diameter > 100 mm. Prenatal treatments with tracheal ligation or intra-amniotic administration of dexamethasone or surfactant prevented these changes. In arteries with external diameter £ 100 mm, congenital diaphragmatic hernia promoted a significant increase in medial thickness and in cell nuclei density and a decrease in elastic fiber density. The prenatal treatments with tracheal ligation or intra-amniotic administration of dexamethasone or surfactant prevented these changes, although no effect was observed in elastic fiber density in the congenital diaphragmatic hernia plus dexamethasone group.CONCLUSIONS: Congenital diaphragmatic hernia promoted different structural changes for large or small arteries. The prenatal intra-amniotic administration of dexamethasone or surfactant had positive effects on the lung structural changes promoted by congenital diaphragmatic hernia, and these effects were comparable to the changes induced by tracheal ligation. DESCRIPTORS: Congenital diaphragmatic hernia. Persistent pulmonary hypertension. Pulmonary hypoplasia. Surfactant. Glucocorticoid.Patients with congenital diaphragmatic hernia (CDH) have a high mortality rate, which has been attributed to pulmonary hypoplasia, pulmonary hypertension, and biochemical and structural immaturity of the lungs [1][2][3][4] . We have previously shown that fetal tracheal ligation (TL) reverses pulmonary hypoplasia in a rabbit model of CDH by accelerating fetal alveolar growth. In the same series of experiments, we also demonstrated that prenatal intraamniotic administration of surfactant or corticosteroids partially reverses the pulmonary hypoplasia of fetuses with CDH...

Heart hypoplasia in an animal model of congenital diaphragmatic hernia

“…These strategies consist of prenatal intra-amniotic administration of porcine surfactant or dexamethasone and prenatal tracheal ligation (TL), an invasive method that effectively treats or prevents pulmonary hypoplasia of CDH 1,2 . Based on functional, morphological, histomorphometric and biochemical studies, we proved that in this model, CDH is associated with hypoplastic lungs 3 , and the preventive effects of intra-amniotic administration of drugs on lung maturation were comparable to the changes induced by TL [4][5][6] . In addition to lung hypoplasia, pulmonary hypertension, biochemical and structural immaturity of CDH lungs, the hemodynamics of infants and animals with CDH are markedly altered 7,8 .…”

“…Despite all refinements of the current management, survival rates of patients with CDH remains frustratingly low because of pulmonary hypoplasia, biochemical immaturity of lungs, and arterial thickening and constriction with persistence of the fetal circulation pattern 6 . In addition, associated anomalies-primarily cardiac anomaliesaccount for many of the deaths.…”

Traqueo-oclusão intra-útero: técnica cirúrgica associada à corticoterapia promove aumento nos receptores de VEGF (Vascular Endothelial Growth Factor) em pulmões de fetos de ratas

“…O efeito maturador da TO parece residir, sobretudo, na ação mecânica que exerce no parênquima pulmonar, consoante ao demonstrado que a aceleração do crescimento celular está diretamente relacionada ao aumento da pressão intratraqueal 13,14,15 . Esse estímulo físico, além de recuperar o espaço pulmonar perdido pela herniação na HDC e restabelecer a arquitetura pulmonar, estimula processos moleculares, culminando com maior transcrição gênica, maior produção protéica e conseqüentemente desenvolvimento e diferenciação celular confluindo para acelerar a maturação pulmonar 7,16 . O VEGF pode ser localizado nos pulmões, rins e ossos, sendo secretado por células endoteliais e outras como espermatozóides e pneumócitos, sendo considerado um mediador parácrino e autócrino.…”

“…A TO pode atuar reduzindo alterações na produção de VEGF ou de seus receptores, na medida em que reverte mecanicamente o desarranjo da arquitetura pulmonar 6 bem como, pode aumentar a diferenciação dos pneumócitos II em tipo I e melhorar a hipoplasia pulmonar, especialmente quando associado ao aumento da produção de surfactante estimulada pelo corticóide 7,8 . A participação do VEGF no desenvolvimento pulmonar e na produção de surfactante tem sido correlacionada, o VEGF parece induzir a conversão de glicogênio em surfactante nos pneumócitos II 6 , no entanto, poucos estudos abordam os receptores de VEGF.…”

The effect of maternal betamethasone and fetal tracheal occlusion on pulmonary vascular morphometry in fetal rabbits with surgically induced diaphragmatic hernia: a placebo controlled morphologic study

“…We, as well as others, already looked at the vascular effects of prenatal steroids in preterm rabbits, showing a dose-dependent reduction in arterial medial thickness and number of small muscularized (ED≤ 60 µm) peripheral pulmonary vessels (Roubliova et al, 2007). In lungs of rabbits with DH, GC reverse structural changes, such as medial thickening of pulmonary vessels (Tannuri et al, 1998a,b;Rodrigues et al, 2002). Herein, we aimed to investigate the pulmonary effects of GC in rabbits with CDH, which also underwent TO and were delivered at term.…”