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11Beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) catalyzes the conversion of cortisol to biologically inactive cortisone and is thought to confer specificity on mineralocorticoid receptors (MR). Cortisol is a prerequisite for surfactant synthesis and fetal lung maturation. Recently, expression of 11betaHSD2 was demonstrated in human fetal lung, but its localization and possible biological roles remain unknown. Therefore, in this study, we examined immunohistochemical localization of 11betaHSD2, MR, and glucocorticoid receptor (GR) in nonpathological human lungs from fetus to adult (8 weeks gestation to 55 yr of age; n = 40) retrieved from pathology files. Both 11betaHSD2 and MR immunoreactivities were detected in airway epithelia, from bronchiole to trachea and in fetal and neonatal ciliated collecting duct cells of tracheal and bronchial glands, but were undetectable in alveoli. On the other hand, GR was detected in all cell types. These results indicate that 11betaHSD2 colocalizes with MR in human airway epithelia and suggest that 11betaHSD2 play an important role in pulmonary mineralocorticoid activity such as sodium and fluid transport.

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The enzyme 11␤-hydroxysteroid dehydrogenase type II (11␤HSD2) has been shown to confer specificity on mineralocorticoid receptors (MR) by inactivating glucocorticoids. In the present study we examined the colocalization of 11␤HSD2 and MR in various exocrine and secretory glands by immunostaining of serial mirror tissue sections with subsequent computerized image analysis. Both 11␤HSD2 and MR proteins were expressed in the same cells in the distal convoluted tubules, Henle's loop, and collecting tubules of the kidney and the absorptive epithelia of duodenum, jejunum, ileum, colon, and excretory ducts of anal and esophageal glands. Significantly, 11␤HSD2 and MR immunoreactivity also colocalized in the respiratory tract, in collecting ducts of the tracheal and bronchial glands, ciliated bronchial epithelial cells, and type II alveolar epithelial cells, suggesting important and unexpected roles for mineralocorticoids in the lung. In the skin, 11␤HSD2 and MR were present only in excretory ducts of eccrine sweat glands, but not in sebaceous or apocrine glands. In eccrine glands, MR immunoreactivity was present in the basal cells of excretory ducts, while 11␤HSD2 immunoreactivity was localized in the luminal cells. Neither 11␤HSD2 nor MR proteins were expressed in the lacrimal gland, prostate, bile ducts, gall bladder, urinary bladder, urethra, or ureter. These results indicate that 11␤HSD2 protein colocalizes with MR protein in the great majority of sodium-transporting epithelia involved in serous secretion and supports the proposal that 11␤HSD2 is a pivotal determinant of mineralocorticoid receptor occupancy in man. Furthermore, our demonstration of colocalization in discrete areas of the lung suggests that mineralocorticoid agonists or antagonists, and/or inhibitors of 11␤HSD2, may have unexpected applications in respiratory disease. (J Clin Endocrinol Metab 82: 3859 -3863, 1997) T HE ENZYME 11␤-hydroxysteroid dehydrogenase type II (11␤HSD2) is thought to confer specificity on the nonselective mineralocorticoid receptor (MR) (1) by converting glucocorticoids to their receptor inactive metabolites, thereby allowing the much lower circulating level of aldosterone to bind to mineralocorticoid receptors (2, 3). When 11␤HSD2 is compromised, patients manifest severe hypertension, marked sodium retention, and hypokalemia (4, 5). Recent studies prove that selective aldosterone action requires the colocalization of MR and the enzyme 11␤HSD2 in target cells (6 -9).In man, immunolocalization of MR has been reported in classic mineralocorticoid target tissues including kidney, pancreas, salivary and sweat glands, and gastrointestinal tracts (10 -14), and that of 11␤HSD2 in kidney, gastrointestinal tracts, sweat, and salivary glands (15)(16)(17)(18)(19). To better understand mineralocorticoid action, it is important to determine whether MR and 11␤HSD2 proteins are expressed in the same cells or not. However, detailed intraglandular localization of 11␤HSD2 and MR, in particular colocalization, has not been established ...

11Beta-Hydroxysteroid dehydrogenase type II (11betaHSD2) confers specificity on the mineralocorticoid receptor (MR) by converting biologically active glucocorticoids to inactive 11-keto metabolites. The biological significance of 11betaHSD2 activity during fetal development is currently being explored, but the temporal and spatial distributions of the enzyme and receptor have not been examined. We therefore examined their distributions during various stages of human fetal development using immunohistochemistry. Both 11betaHSD2 and MR immunoreactivity were detected in the distal convoluted and collecting tubules of the kidney from early in gestation. Fetal skin, intermediate layer of the epidermis, peridermal cells, and hair follicles were positive for both 11betaHSD2 and MR. Weak 11betaHSD2 and MR immunoreactivity was detected in the superficial ciliated epithelium of the esophagus, the deep layer of gastric epithelial cells, and the superficial epithelium of the small intestine. Columnar epithelium in the terminal bronchiolar budding component of fetal lung and tracheal and bronchial ciliated epithelium were also positive for MR and 11betaHSD2 from early gestation. Colonic epithelium and pancreatic exocrine duct cells, which demonstrated marked immunoreactivity of both MR and 11betaHSD2 in the adult, did not express MR and 11betaHSD2 until very late in gestation. These results imply that mineralocorticoid action in the upper fetal gastrointestinal tract, kidney, skin, and lung is facilitated by 11betaHSD2 and is involved in water and electrolyte transport between fetus and amniotic fluid as well as fetal urine production.