11beta-hydroxysteroid
dehydrogenases (11beta-HSD) are responsible for the conversion of bioactive
glucocorticoids to and from inactive metabolites.
11beta-HSD2 is generally considered a high-affinity inactivator of natural
glucocorticoids, although its activity with synthetic compounds in vivo is unknown. Inhaled
corticosteroids (ICS) remain the primary
antiinflammatory agents for treating
asthma, but little is known about their metabolism in the lung. The aims of this study were to determine whether the
11beta-HSD2 enzyme can be localized to human airway tissue and whether differential expression of this
enzyme relates to
asthma severity and ICS needs. We studied airway biopsy specimens from 22 asthmatic subjects, in two groups: (1) a group not treated with ICS (n = 7); and (2) a group treated with ICS (range: 200 to 1,500 microg/d; n = 15). A control population consisted of nine nonasthmatic subjects. Immunostaining was done with an immunopurified antibody to human
11beta-HSD2. Immunoreactivity was generally localized to the endothelium of vessels in the lamina propria and to airway epithelium both in asthmatic patients and nonasthmatic controls. There was a statistically significant inverse relationship between the ICS dose required for effective treatment and the extent of epithelial
11beta-HSD2 staining (r = -0.44; p = 0.04). This is consistent with
11beta-HSD2 acting as an
oxidoreductase that regenerates rather than inactivates ICS. This study suggests that
glucocorticoid sensitivity in the lung is not determined by ICS breakdown, but may be related to
11beta-HSD2 sustaining the activation of synthetic
glucocorticoids.