Antenatal Dexamethasone Administration Impairs Normal Postnatal Lung Growth in Rats

Abstract

Our purpose was to determine the influences of antenatal dexamethasone administration on neonatal lung development in rats. Dexamethasone (0.4 mg/kg maternal body weight per day) was administered i.p. on the 21st d (group 1) or on the 20th and 21st d (group 2) of gestation in Sprague Dawley rats with timed pregnancies. After natural deliveries, the lungs of the pups 1-60 d of age were removed and processed for morphometric analysis. In 60-d-old pups, groups 1 and 2 both showed a lower numerical density of alveoli and a larger mean alveolar radius than control pups. Antenatal administration of dexamethasone to rats impairs the normal postnatal lung growth. Some aspects of the use of antenatal glucocorticoid therapy in humans may require reconsideration. Antenatal glucocorticoid therapy, including the administration of DXM and betamethasone, is widely used in the perinatal care of premature infants (1-3) The effects of antenatal glucocorticoid therapy include a reduction in the severity of respiratory distress syndrome, reductions in the incidences of several other complications associated with prematurity (hypotension, intracranial hemorrhage, etc.), and a reduction in mortality. In animal experiments, glucocorticoid administration appears to accelerate not only the establishment of the surfactant system, but also the activities of antioxidant enzymes (4) and, via surfactant-independent mechanisms, an increase in alveolar wall compliance (5).The growth of the lung during the human perinatal period consists of several phases (6): 1) the establishment of a surfactant system, 2) an increase in the number of alveoli through division of the existing alveoli (alveolarization), and 3) alveolar wall thinning and capillary fusion (microvascular maturation). The latter two phases are accompanied by structural changes. Alveolarization occurs mainly between the 35th wk of gestation and approximately the third postnatal year. Microvascular maturation begins after birth and is completed by 5 y of age. Alveolarization is said to occur only in the presence of immature thick septa (6).These three phases of lung growth have been observed in most mammals (6), but the times at which the phases occur differ among species. For example, the pulmonary ultrastructure of newborn rats corresponds to that of humans at about the 28th wk of gestation. In other words, rats are born before the process of alveolarization has begun. Alveolarization in the rat lung takes place predominantly within the first 2 wk of life, with microvascular maturation occurring during the third wk (7).Postnatal administration of DXM (1 g/d, i.e. 3.3-12.5 g·kg Ϫ1 ·d Ϫ1 , from d 2 to 15) is known to impair subsequent alveolarization in rats (8,9) During the first 2 wk, DXM accelerates microvascular maturation and suppresses alveolarization. One week after drug withdrawal, the trend toward precocious maturation is reversed. The alveolar wall returns to a more immature state, and a delayed burst of alveolarization begins. At d 60, the lungs appear emphysematous, with l...

Retinoic Acid Combined with Vitamin A Synergizes to Increase Retinyl Ester Storage in the Lungs of Newborn and Dexamethasone-Treated Neonatal Rats

“…Table 1 shows growth during and following treatment with Dex, and lung histology parameters measured on P14, seven days after the last treatments with Dex and VARA. During treatment, Dex reduced growth by approximately 30%, as expected from several previous reports [38,[46][47][48] . The slowing of growth by Dex was significant within the first day of treatment (p !…”

Effects of Maternal Undernutrition During Late Gestation on the Lung Surfactant System and Morphometry in Rats

“…These morphometric changes were consistent with the observations of Maritz et al (37), who found that in lambs fetal growth restriction induced by umbilico-placental embolization causes smaller airspace volume density at 8 wk after birth. Our data showed that maternal undernutrition during late gestation resulted in morphometric changes similar to those observed after the antenatal administration of dexamethasone as reported by Okajima et al 334 (38). These results further support that maternal undernutrition during late gestation increases the fetal exposure to maternal glucocorticoids (13).…”

Glucocorticoid exposure and tissue gene expression of 11β HSD-1, 11β HSD-2, and glucocorticoid receptor in a porcine model of differential fetal growth

“…In small fetuses at day 100, increased GC sensitivity in the lung and liver could increase the vulnerability of these organs to excess cortisol. Excess cortisol can downregulate growth critical hepatic genes, such as the insulin-like growth factors and cause lung dysfunction (Li et al 1993, Nyirenda et al 1998, Okajima et al 2001.…”