THE COMBINED EFFECTS OF INSULIN AND CORTISOL ON SURFACTANT PROTEIN MESSENGER-RNA LEVELS

Infants of diabetic mothers are frequently hyperinsulinemic and have a n increased incidence of neonatal respiratory distress syndrome, a dis ease caused by a deficiency in the production of pulmonary surfactant by alveolar type II cells. It has been hypothesized that insulin inhib its fetal lung type II cell differentiation. We have shown previously that insulin inhibits the accumulation of surfactant protein (SP)-A an d SP-B mRNA and has no effect on SP-C mRNA levels in human fetal lung tissue maintained in vitro. We hypothesized that treatment with glucoc orticoids, which are used clinically to accelerate human fetal lung ma turation, would overcome the inhibitory effects of insulin on human fe tal lung development. In the present study, human fetal lung explants were maintained in the presence or absence of cortisol added alone, or in insulin plus cortisol added together. Cortisol significantly decre ased SP-A mRNA levels by approximately 50% at the 100 nM concentration and significantly increased levels by approximately 20% at the 1 nM c oncentration. Cortisol increased SP-B and SP-C mRNA levels in a dose-d ependent fashion (5- and 45-fold at 100 nM cortisol, respectively). Th e combination of 1 nM cortisol and insulin resulted in inhibition of m RNA levels for SP-A, SP-B, and SP-C at the high insulin concentrations (approximately 50% inhibition for SP-A and SP-B and approximately 25% inhibition of SP-C mRNA levels, in the presence of 40 pmol/L X 10(-3) insulin). Surprisingly, 100 nM cortisol plus inhibitory concentration s of insulin increased SP-A mRNA levels (2-fold at 40 pmol/L X 10(-3)) . SP-B and SP-C mRNA levels in the presence of 100 nM cortisol plus in sulin were generally unchanged when compared with levels in explants c ultured in cortisol alone. Thus, cortisol modulates the inhibitory eff ects of insulin on SP mRNA levels in a dose-dependent manner.