Effect of Maternal Administration of Betamethasone on Peripheral Arterial Development in Fetal Rabbit Lungs

Abstract

Objectives: Glucocorticoids promote lung maturation and reduce the incidence of respiratory distress syndrome in premature newborns. We hypothesized that betamethasone (BM), which is known to induce thinning of the alveolar walls, would also thin the arterial media and adventitia of intra-parenchymatic vessels in developing rabbit lungs. Study Design: 112 fetuses from 21 time-mated, pregnant, giant white rabbits received maternal injections of BM at either 0.05 or 0.1 mg/kg/day on days 25–26 of gestational age. Controls received either saline (10 does, 56 fetuses) or no injection (10 does, 59 fetuses). Fetuses were harvested from day 27 onwards until term (day 31). 44 additional fetuses (8 does) were harvested between days 23 and 26. Endpoints were wet lung-to-body weight ratio, vascular morphometric indices and immunohistochemistry staining for α-smooth muscle actin, Flk-1, vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). ANOVA (Tukey’s test) and independent t test (p < 0.05) were used for comparison between BM and saline groups. Results: Maternal BM injected on days 25–26 to pregnant rabbits induced a significant decrease in fetal body and lung weight and the lung-to-body weight ratio in the preterm pups shortly after injection. BM led to a dose-dependent thinning of the arterial media and adventitia (pulmonary arteries with an external diameter (ED) of <100 µm), to an increase in the percentage of non-muscularized peripheral vessels (ED <60 µm), in eNOS and VEGF immunoreactivity of the endothelial and smooth muscle cells in the pulmonary vessels and to an increase in Flk-1-positive pulmonary epithelial cell density. Conclusions: Maternal administration of BM caused thinning of the arterial wall of pulmonary vessels (ED <100 µm) and a decrease in muscularization in peripheral vessels (ED <60 µm). This coincided with increased expression of Flk-1 in the endothelium and smooth muscle cells of the pulmonary arteries. All the effects studied were dose-dependent.

Antenatal betamethasone attenuates intrauterine infection-aggravated hyperoxia-induced lung injury in neonatal rats

“…Both chorioamnionitis and antenatal steroids improve postnatal lung function. Some studies have shown that maturational changes can occur at the expense of normal alveolar development (14); others report that antenatal betamethasone did not affect alveolarization (23) and that it even decreased both pulmonary hypertension (24) and ventilation-induced lung injury (25). Although antenatal corticosteroid administration worsened chorioamnionitis-related lung development impairment in rabbits, suggesting an additive effect on fetal lung alveolar simplification (8), betamethasone treatment after intra-amniotic LPS injection enhanced fetal lung maturation in lambs (26).…”

Congenital Diaphragmatic Hernia: Comparison of Animal Models and Relevance to the Human Situation

“…Examples of investigated interventions are administration of corticosteroids, in utero repair of the diaphragmatic defect and fetal tracheal occlusion or a combination of the two [11,12] . In utero repair has been attempted with either primary closure of the defect by using a patch (immediate reduction) or secondary closure by using the slow 'silo' reduction technique in which the opening gradually reduces as the fetus grows [13][14][15] .…”

Forkhead box m1 mRNA expression of lung of preterm and term rabbits

“…In addition, reciprocal chromosome painting using human chromosomes showed complete homology in more than three chromosomes (7). Based on these observations, a rabbit seems to be a more appropriate model compared with other classical animal models for studying human lung development and various gene expressions during intrauterine and early neonatal life (11)(12)(13)(14).…”