Glucocorticoid regulation of the major surfactant associated protein (SP-A) and its messenger ribonucleic acid and of morphological development of human fetal lung in vitro

Abstract

In the present study we investigated the effects of dexamethasone (DEX) on the accumulation of the major pulmonary surfactant-associated protein (SP-A), a glycoprotein of about 35,000 mol wt, and on the levels of mRNA encoding this protein in human fetal lung in organ culture. In addition, the effects of DEX on the structural development of the fetal lung tissue was investigated using morphometric techniques. We observed that DEX had a biphasic effect on the accumulation of SP-A and its mRNA; at concentrations of 10(-10) and 10(-9) M, a stimulatory effect was observed, while at concentrations of 10(-8) M or greater, the glucocorticoid was markedly inhibitory. The inhibitory effect of DEX (10(-7) M) was evident at all time points of incubation and was apparent within 24 h of its addition to the medium at any time during the culture period. In addition, DEX (10(-7) M) antagonized the stimulatory effects of (Bu)2cAMP on the accumulation of SP-A and its mRNA. DEX also had pronounced effects on the morphological development of human fetal lung tissue. At a concentration of 10(-7) M or greater, DEX caused a marked reduction of alveolar lumen size compared to that of fetal lung explants maintained in control medium. A biphasic effect of DEX on the volume density of type II cells in fetal lung explants was observed; at a concentration of 10(-10) M, DEX significantly increased the volume density of type II cells, whereas at a concentration of 10(-7) M or more, the glucocorticoid significantly reduced the volume density of type II cells compared to that of control explants. These findings suggest that synthetic glucocorticoids at concentrations of 10(-10) and 10(-9) M are stimulatory whereas elevated levels are inhibitory of SP-A synthesis and morphological development of the human fetal lung.