11-beta hydroxysteroid dehydrogenase type 2 in the human lung and the regulation of SP-A by dexamethasone metabolites

Normal development of the human lung is acutely influenced by hormones known as glucocorticoids (GCs). The 11-beta hydroxysteroid dehydrogenase enzymes (HSD1 and HSD2) regulate GC action at the pre-receptor level by catalyzing the interconversion of the biologically active GC, cortisol, and its inactive metabolite, cortisone. While the expression and function of the HSD genes have been elucidated in several human tissues, their role in the human lung is less clear.; I observed that human adult and fetal lung tissues possess similar amounts of HSD2 mRNA and protein. However, HSD2 protein and enzyme activity levels were significantly higher in differentiated fetal lung tissues maintained in culture than in undifferentiated tissues. Interestingly, HSD1 protein was not detectable in any of the human lung tissues tested. In humans, fetal lung development is delayed in males as compared to females. Although there were no sex-specific differences in the levels of HSD2 protein in the human fetal lung, HSD2 levels were influenced by sex steroids in male, but not female, fetal lung explants.; Glucocorticoids are routinely used to treat inflammatory lung diseases and accelerate fetal lung maturation. Inhibition of HSD2 activity in human lung epithelial cells treated with the synthetic GC, dexamethasone (Dex), had little effect on the GC-mediated regulation of the pulmonary surfactant protein A (SP-A) gene. I later determined that unlike the 11-keto form of cortisol, cortisone, the 11-keto form of Dex retains GC agonist activity. Thus, significant differences exist in the biological activities of endogenous versus synthetic GCs.; In studies using the HSD2-specific inhibitor, Thiram (tetramethylthiuram disulfide), I observed that Thiram blocks GC signaling by reducing ligand binding to the GC receptor (GR), in addition to inhibiting HSD2 enzyme activity in human lung epithelial cells.; Collectively, these studies describe the patterns of HSD2 gene expression and enzyme activity in human lung tissues. Additionally, I determined that the 1 significance of GC metabolism by HSD2 activity likely depends on the chemical nature of the GC administered. I also determined that decreased GC signaling, secondary to reduced ligand binding to the GR, is a novel cellular effect of exposure to the HSD2-specific inhibitor, Thiram.