Glucocorticoids both stimulate and inhibit production of pulmonary surfactant protein A in fetal human lung.
Pulmonary surfactant is a mixture of phospholipids and proteins which stabilizes lung alveoli and prevents respiratory failure. The surfactant-associated protein of Mr = 28,000-36,000 (SP-A) influences the structure, function (film formation), and metabolism of surfactant. We have characterized glucocorticoid regulation of SP-A and SP-A mRNA in explants of fetal human lung. The time course of response to dexamethasone was biphasic, with early stimulation and later inhibition of SP-A accumulation. Maximal induction of SP-A occurred with 3-10 nM dexamethasone and approximately 300 nM cortisol for 72 hr, and stimulation diminished at higher concentrations. SP-A mRNA accumulation was maximally stimulated at 24-48 hr of exposure to dexamethasone (10 nM) and was generally inhibited by 4-6 days. Stimulation was also observed with cortisone and corticosterone but not with sex steroids, suggesting a receptor-mediated process. When explants were exposed to cortisol for only 24 hr, SP-A content was transiently increased above the level in continuously treated tissue and subsequently was similar to control. The content of SP-A and its mRNA was also increased by dibromo-cAMP, terbutaline, and forskolin, and effects were approximately additive with those of dexamethasone. However, elevated in tracellular cAMP did not alter the biphasic time course or dose-response patterns of dexamethasone. We propose that glucocorticoids have both stimulatory and inhibitory effects on SP-A gene expression. This biphasic regulation is not consistent with generalized toxic effects, product-feedback inhibition, or receptor down-regulation, and it appears to be specific for SP-A among the various surfactant components.
Liley
H G
HG
Department of Pediatrics, University of California, San Francisco 94143.
White
R T
RT
Benson
B J
BJ
Ballard
P L
PL
D000328:Adult; D003907:Dexamethasone / Q000494:pharmacology*; D005333:Fetus; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D009924:Organ Culture Techniques; D011500:Protein Synthesis Inhibitors; D011510:Proteolipids / Q000096:biosynthesis* / Q000235:genetics; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics
D011500:Protein Synthesis Inhibitors; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D003907:Dexamethasone; D006854:Hydrocortisone