Metyrapone Delays Surfactant and Antioxidant Enzyme Maturation in Developing Rat Lung

Abstract

ABSTRACT. The surfactant system and the antioxidant enzyme system of the fetal lung have chronologically similar developmental patterns and both can be accelerated by the administration of exogenous glucocorticoids. To test whether the antioxidant enzyme system, like the surfactant system, is regulated, at least in part, by endogenous glucocorticoids, we injected pregnant rats for 3 days prior to delivery with me&rapone, an adrenal 11-/3 hydroxylase inhibitor which crosses the ~lacenta and blocks endogenous glucocorticoid synthesis, o; saline. Metyrapone ofispring had significantly decreased lung tissue disaturated phosphatidylcholine and disaturatedphosphatidylcholine/total phospholipids ( p < 0.05) compared to controls at days 21 and 22 of gestation. Activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase were similarly significantly reduced ( p < 0.01) in the lungs of metyrapone offspring at both gestational days studied. One day premature metyrapone pups demonstrated poorer survival than control pups from 25 min after delivery (44% survival versus 83%, p < 0.05) to 90 min (6% survival versus 78%, p < 0.01). These findings of delayed maturation of the surfactant and antioxidant enzyme systems following adrenal glucocorticoid blockade suggest that both systems are regulated, at least in part, by an endogenous glucocorticoid mechanism. (Pediatr Res 20: 672-675, 1986) Abbreviations DSPC, disaturated phosphatidylcholine TPL, total phospholipids AOE, antioxidant enzymes SOD, superoxide dismutase CAT, catalase GP, glutathione peroxidaseThe developmental patterns of the surfactant system and the antioxidant enzyme system of the fetal lung are chronologically similar, with both systems demonstrating marked increases during the final 10-15% of gestation in the several species studied (1-3). Both systems are important in the neonatal adaptation to independent respiration in the relatively oxygen-rich ex utero Received December 16, 1985; accepted March 11, 1986. Address all correspondence to Ilene R. environment. While the surfactant system provides reduction in alveolar surface tension and prevents alveolar collapse at end expiration, the antioxidant enzyme system of the lung prevents cell injury from reactive species of oxygen which are produced under normoxic and hyperoxic conditions (4-6). Multiple lines of evidence indicate that surfactant development is regulated, in part, by endogenous glucocorticoids: elevation of plasma glucocorticoid levels prior to the increase in surfactant (7), the presence of and increase in glucocorticoid receptors in fetal lung prior to elevation in surfactant (8-lo), and delays in surfactant maturation following interference with glucocorticoid production either biochemically (i.e. with metyrapone) or surgically (i.e. by fetal decapitation or hypophysectomy) (1 1-15).It has recently been demonstrated that the maturation of the pulmonary AOE, namely superoxide dismutase, catalase, and glutathione peroxidase, as well as surfactant (as measured ...

Prenatal Hormone Treatment with Thyrotropin Releasing Hormone and with Thyrotropin Releasing Hormone Plus Dexamethasone Delays Antioxidant Enzyme Maturation but Does Not Inhibit a Protective Antioxidant Enzyme Response to Hyperoxia in Newborn Rat Lung

“…The development of these two critical lung biochemical systems has been shown to be not only chronologically related, but also related by some similar hormonal control mechanisms; i.e. prenatal DEX therapy has been found to accelerate both fetal lung surfactant system and AOE system maturation, whereas prenatal metyrapone (an inhibitor of endogenous glucocorticoid synthesis) treatment causes significantly delayed development of both lung systems (23). In terms of thyroid hormones, however, unlike their role in promoting surfactant system maturation (24-29), prenatal T, treatment has been found to significantly depress the normal maturation of the fetal lung AOE system (8).…”

Effects of oligohydramnios on lung growth and maturation in the fetal rat

“…Possibilities include species differences, the method of inducing pulmonary hypoplasia (oligohydramnios vs. spinal cord section), the magnitude of change in distension, and the relative maturity of the lungs (10,36). Previous investigators have shown that pulmonary surfactant in fetal rats is increased by both endogenous (45) and exogenous glucocorticoids (38). Therefore, the finding in the current study of similar plasma concentrations of corticosterone, the active glucocorticoid in rats, is consistent with the similar lung concentrations of the various indicators of surfactant in controls and in oligohydramnios fetuses.…”

Intraamniotic Endotoxin Increases Lung Antioxidant Enzyme Activity in Preterm Lambs

“…In a time course similar to the maturation of the surfactant system, fetal lung AOE activity, specifically SOD, CAT, and GP, increases during the final 15-20% of intrauterine life (9, 10). In terms of hormonal influences on AOE and surfactant maturation, both systems are accelerated by antenatal glucocorticoids (11,12), whereas thyroid hormones appear to stimulate surfactant maturation while delaying late gestational AOE activity increases (13).…”