Glucocorticoid (GC) metabolism by the 11- hydroxysteroid dehydrogenase (HSD) system is an important pre-receptor regulator of GC action. The HSD enzymes catalyze the interconversion of the endogenous, biologically active GC cortisol and its inactive, 11- dehydro metabolite, cortisone. The role of the HSD enzymes in the metabolism of synthetic GCs, such as dexamethasone (Dex), is more complex. The human lung is a classic GCsensitive organ; however, the roles of the HSD enzymes (HSD1 and HSD2) in the human lung are poorly understood. In the present study, we examined the expression of the HSD enzymes in human adult and fetal lung tissues and in the human lung epithelial cell line, NCIH441. We observed that human adult and fetal lung tissues, as well as H441 cells, express HSD2 protein and that it is up-regulated by Dex (10^-7 M). In contrast, HSD1 protein was undetectable. We also show that the Dex-mediated regulation of SP-A is attenuated by inhibition of HSD2 activity. Furthermore, we demonstrate that unlike the inactive, 11-dehydro metabolite of cortisol (i.e., cortisone), the 11-dehydro metabolite of Dex, 11-dehydro Dex, competes for binding to the glucocorticoid receptor (GR) in human lung epithelial cells and retains GR agonist activity. Together, these data suggest that differences exist in the biological activities of the metabolites of cortisol and dexamethasone.