We examined the effects of interferon-gamma (IFN-gamma) on development of the surfactant system in alveolar epithelial cells of fetal lung. Explants of second-trimester human fetal lung were cultured for 1 to 6 days in serum-free medium containing recombinant human IFN-gamma (0.03 to 30 ng/ml) and/or dexamethasone (10 or 100 nM). Treatment for 3 days with IFN-gamma alone, dexamethasone alone, and IFN plus dexamethasone increased the content of surfactant protein A (SP-A, 28 to 36 kD) by approximately 3-, 2.5-, and 10-fold, respectively. The biphasic response pattern of SP-A to dexamethasone (stimulation initially and inhibition with continued culture) was not altered by the presence of IFN-gamma. IFN-gamma also stimulated accumulation of SP-A mRNA (2.7-fold at 24 h) but did not affect the levels of mRNAs for surfactant protein B (18 kD) and surfactant protein C (5 kD). To assess the effect of IFN-gamma on synthesis of surfactant lipids, we determined the content of phosphatidylcholine, the rate of labeled choline incorporation into phosphatidylcholine, saturation of newly synthesized phosphatidylcholine, and the activity of fatty acid synthetase, a glucocorticoid-inducible enzyme. Treatment of explants for 5 days with IFN-gamma had no effect on these parameters. Studies by light and electron microscopy revealed little difference between control and IFN-treated explants with regard to cell viability and epithelial cell differentiation. We conclude that IFN-gamma has a selective stimulatory effect on SP-A among surfactant components.(ABSTRACT TRUNCATED AT 250 WORDS)