Effects of Neonatal High-Dose Short-Term Glucocorticoid Treatment on the Lung: A Morphologic and Morphometric Study in the Rat

Abstract

Glucocorticoids are often applied in neonatology and perinatology to fight the problems of respiratory distress and chronic lung disease. There are, however, many controversies regarding the adverse side effects and long-term clinical benefits of this therapeutic approach. In rats, glucocorticoids are known to seriously impair the formation of alveoli when applied during the first two postnatal weeks even at very low dosage. The current study investigates short-term and long-term glucocorticoid effects on the rat lung by means of morphologic and morphometric observations at light and electron microscopic levels. Application of a high-dosage protocol for only few days resulted in a marked acceleration of lung development with a precocious microvascular maturation resulting in single capillary network septa in the first 4 postnatal days. By postnatal d 10, the lung morphologic phenotype showed a step back in the maturational state, with an increased number of septa with double capillary layer, followed by an exceptional second round of the alveolarization process. As a result of this process, there was an almost complete recovery in the parenchymal lung structure by postnatal d 36, and by d 60, there were virtually no qualitative or quantitative differences between experimental and control rats. These findings indicate that both dosage and duration of glucocorticoid therapy in the early postnatal period are very critical with respect to lung development and maturation and that a careful therapeutic strategy can minimize late sequelae of treatment. GC therapy is widely used in the prenatal and postnatal periods either as a prophylactic or curative measure. Use of prenatal GCs is often motivated by the observed positive effects on lung maturation and surfactant production in preterm babies (1, 2), who otherwise stand a high chance of developing respiratory distress syndrome (3) and subsequent chronic lung disease, also known as bronchopulmonary dysplasia (4, 5). The positive effects of postnatal GCs on pulmonary inflammatory processes (6, 7) and the prophylactic effects against hyperoxic lung injury (8) seem to improve the survival chances of preterm neonates. In perinatal medicine, a variety of therapeutic schemes have been adopted, but controversies regarding the long-term benefits and the negative side effects of GC in neonatology abound (9 -11). Indeed, besides the apparent benefits of GC therapy, adverse effects on lung maturation have been reported in animal experiments (12, 13). Furthermore, reserves have been expressed over the general outcome of treated newborns (14,15). In the recent past, there have been numerous studies on the positive and negative effects of postnatal GC therapy, but as noted by Barrington (16), there are no published long-term pulmonary data.Previously we have indicated that long-term administration of minute doses of GC results in a permanent impairment of lung alveolarization in postnatal rats (17,18). Alveolarization is achieved by subdivision of the preexisting saccular air spaces ...

Efficient estimation of the total number of acini in adult rat lung

“…The results also showed that for a specific age (postnatal day 60) the body weight and the lung volume are not correlating (R 2 : 27 9 10 À6 ). However, because a correlation between body weight and lung volume exists throughout lung development (for our rat strain (Tschanz et al 2003)), a similar correlation may or may not exist for the mean acinar volume.…”

Effects of betamethasone on peripheral arterial development in term fetal rabbit

“…Steroids can affect pulmonary vascular development, through the regulation of vasoactive mediators, 20 remodeling of vascular walls, 15,27 and maturation of capillary loops. 3 Also architectural changes to the air-blood barrier can be induced. As the alveolar walls become thinner, the double layered capillaries fuse.…”

“…As the alveolar walls become thinner, the double layered capillaries fuse. Tschanz et al 3 studied rat pups that were exposed in utero to dexamethasone, born at term and which eventually were evaluated in the first 4 days after birth, an acceleration of microvascular maturation, resulting in formation of single capillary network septa. Haworth reported that, within 30 min after birth, the endothelial cells, which in the fetal state are cuboidal and bulge into the lumen, flatten.…”

“…Antenatal GC decrease the risk of respiratory distress syndrome, and persistent pulmonary hypertension of the newborn (PPHN), hence reduces morbidity and mortality of preterm neonates. GC cause thinning of the inter-airspace septa, a reduction of the number of sprouting secondary septa and, at the ultrastructural level, formation of a single capillary network, 3 suggesting an accelerated lung maturation and alveolization. GC cause a decrease in the lung interstitium with a consequent decrease in alveolar wall thickness.…”

Glucocorticoid receptor disruption delays structural maturation in the lungs of newborn mice

“…10 Finally, GCs enhance the structural maturation of lung capillaries. 11 Although the importance of GC for all of the above processes has been 1 Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. established, the exact mechanisms of GC mediated enhancement of lung maturation remains to be elucidated.…”