Retinoic acid (RA) is an important signal for growth and differentiation. Studies of RA action on lung development have resulted in conflicting data. Some investigators have reported enhanced maturation, whereas others found inhibitory effects. Inhibition was generally associated with the use of high concentrations and prolonged periods of treatment. RA effects which occur early (within hours) and with low doses tend to be due to direct action on target genes. Accordingly, we exposed explants of fetal rat and mouse lung to nmolar concentrations for brief periods. Culture of 17 or 19 day fetal rat lung in all-trans RA for 4 h resulted in a significant, dose dependent increase in SP-A, B, and C mRNA. There was, however, a marked difference in the dose-response curves. The maximal (2.5 ×) increase in SP-A mRNA occurred with 10-10 M, whereas treatment with 10-5 M resulted in decreased SP-A mRNA. In contrast, maximal stimulation of SP-C (6 ×) was noted at 10-5 M and that of SP-B (2 ×) at 10-7 to 10-5 M. Stimulation was detectable after 2 h in culture and peaked at 7 h. Similar dose-response characteristics were noted when the explants were exposed to 9-cis RA and in explants of 15 day fetal mouse lung. Consistent with published reports, treatment of explants with high concentrations(10-6 M) of all-trans RA for 7 days resulted in abnormal branching morphogenesis with distended proximal airways. A GenBank search revealed a RA response element consensus sequence in the murine SP-A gene, but no such sequence was found in the SP-B or SP-C genes. We hypothesize that RA-receptor complexes act directly on the SP-A gene via this response element. Supported by HL 46488 (SCOR).