Modeling Glucocorticoid-Mediated Fetal Lung Maturation: II. Temporal Patterns of Gene Expression in Fetal Rat Lung

Abstract

Our previous report described the temporal steroid patterns during pharmacokinetic (PK) studies with dexamethasone (DEX) where doses of six 1 micromol/kg injections were given during gestational ages 18 to 20 days in rats. DEX PK was used in conjunction with the endogenous corticosterone profile to understand the regulation of fetal lung pharmacodynamics (PD). Expression of the glucocorticoid receptor (GR) and surfactant proteins A and B mRNA were chosen as lung maturational markers. GR seemed to be insensitive to the circulating glucocorticoids, indicating that unlike the adult situation, GR was not under negative feedback control of its ligand. Surfactant protein B exhibited approximately 400-fold induction in control fetal lung during the last days of gestation, and the inductive effect was even greater in the treatment group. Surfactant protein A displayed approximately 100-fold induction in control fetal lung during late gestation. However, the treatment group exhibited biphasic stimulatory and inhibitory effects for surfactant protein A. The inhibitory effect indicated that the chosen dosing scheme for DEX was not an optimal regimen. These data were used to determine by simulation the DEX regimen that would reproduce the temporal pattern of lung maturation observed in control animals. PK/PD modeling indicated that maintaining steroid exposure at approximately twice the equilibrium dissociation constant for the steroid/receptor interaction should produce optimal stimulation of both surfactant proteins. The simulations illustrate that administering smaller quantities of steroids over extended periods that produce sustained steroid exposure might be the optimal approach for designing dose-sparing antenatal corticosteroid therapy.