9 Hormonal and developmental regulation of pulmonary surfactant synthesis in fetal lung

Pulmonary surfactant, a unique developmentally regulated, phospholipid-rich lipoprotein, is synthesized by the type II cells of the pulmonary alveolus, where it is stored in organelles termed lamellar bodies. The principal surface-active component of surfactant, dipalmitoylphosphatidylcholine, a disaturated form of phosphatidylcholine, acts in concert with the surfactant-associated proteins to reduce alveolar surface tension. Relatively large amounts of phosphatidylglycerol also are present in lung surfactants of a number of species, including man. The role of phosphatidylglycerol in surfactant function has not been elucidated; however, its presence in increased amounts in pulmonary surfactant is correlated with enhanced fetal lung maturity. Surfactant glycerophospholipid synthesis in fetal lung tissue is regulated by a number of hormones and factors, including glucocorticoids, prolactin, insulin, oestrogens, androgens, thyroid hormones, and catecholamines acting through cyclic AMP. In studies with human fetal lung in organ culture, we have observed that glucocorticoids, in combination with prolactin and/or insulin, increase the rate of lamellar body phosphatidylcholine synthesis and alter lamellar body glycerophospholipid composition to one reflective of surfactant secreted by the human fetal lung at term. Four surfactant-associated proteins, SP-A, SP-B, SP-C and SP-D, have recently been characterized. Recognition of their potential importance in the reduction of alveolar surface tension and in endocytosis and re-utilization of secreted surfactant by type II cells has stimulated rapid advancement of knowledge concerning the structures of the surfactant proteins and their genes, as well as their developmental and hormonal regulation in fetal lung tissue. The genes encoding SP-A, SP-B and SP-C are expressed in a cell-specific manner and are independently regulated in fetal lung tissue during development. SP-A gene expression occurs exclusively in the type II cell and is initiated after 75% of gestation is complete. In the human fetus, expression of the SP-B and SP-C genes is detectable much earlier in development than SP-A, before the time of appearance of differentiated type II cells. It is apparent from studies using human and rabbit fetal lung in culture that cyclic AMP and glucocorticoids serve important roles in the regulation of SP-A gene expression. While the effects of cyclic AMP are exerted primarily at the level of gene transcription in human fetal lung tissue, glucocorticoids have stimulatory effects on SP-A gene transcription and inhibitory effects on SP-A mRNA stability. In addition, cyclic AMP and glucocorticoids act synergistically to increase SP-A gene transcription in human fetal lung in vitro. Glucocorticoids appear to be of primary importance in the regulation of the genes encoding SP-B and SP-C. It will be of great interest to define the factors involved in the timing and cell-specific regulation of expression of the surfactant protein genes in developing fetal lung tissue, as well as the mechanisms whereby hormones modulate this process. It is anticipated that an increased understanding of the factors that regulate the developmental and cell-specific expression of the surfactant protein genes in fetal lung tissue will provide invaluable information that can be used in the design of regimens to accelerate lung maturation and surfactant synthesis in prematurely born infants.