Hormonal Control of the Surfactant System in Fetal Lung

Abstract

The synthesis of surfactant glycerophospholipids and proteins is under multifactorial control and is regulated by a number of hormones and factors, including glucocorticoids, prolactin, insulin, growth factors, estrogens, androgens, thyroid hormones and catecholamines acting through beta-adrenergic receptors, and cAMP. In studies with human fetal lung in organ culture, glucocorticoids, in combination with prolactin and/or insulin, were found to increase the rate of lamellar body PC synthesis and increase the molar ratio of surfactant PG to PI to a value similar to that of surfactant secreted by the human fetal lung at term. Recognition of the potential importance of the surfactant proteins SP-A, SP-B, and SP-C in the reduction of alveolar surface tension and in endocytosis and reutilization of secreted surfactant by type II cells has stimulated rapid advancement of knowledge concerning the structures of these proteins and their genes, as well as their developmental and hormonal regulation in fetal lung tissue. The genes encoding the surfactant proteins are expressed in a lung-specific manner and appear to be regulated independently during fetal development. SP-A gene expression is initiated in fetal lung tissue after 75-85% of gestation is completed in all mammalian species studied to date. In the human fetus, however, expression of the SP-B and SP-C genes is detectable prior to mid-gestation. In situ hybridization studies of human lung tissue indicate that the SP-A gene is expressed only in type II cells, whereas SP-B gene expression is detectable in bronchioalveolar epithelial cells as well. Cyclic AMP and glucocorticoids have pronounced effects on the regulation of SP-A gene expression in human and rabbit fetal lung in culture. In human fetal lung in vitro, the effects of cAMP are primarily at the level of gene transcription. By contrast, glucocorticoids have stimulatory effects on SP-A gene transcription and inhibitory effects on SP-A mRNA stability. Furthermore, the combined effects of cAMP and glucocorticoids on SP-A gene transcription in human fetal lung in vitro are synergistic. Glucocorticoids appear to be of primary importance in the regulation of the genes encoding SP-B and SP-C. Elucidation of the molecular mechanisms involved in the regulation of expression of the surfactant protein genes in developing fetal lung will be of fundamental importance to our understanding of the developmental and tissue-specific regulation of eukaryotic gene expression.