Clinical relevance of airway 11beta-hydroxysteroid dehydrogenase type II enzyme in asthma.
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.
Orsida
Bernadette E
BE
Department of Respiratory Medicine, The Alfred Hospital and Monash University Medical School, Melbourne, Australia.
Krozowski
Zygmunt S
ZS
Walters
E Haydn
EH
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000280:Administration, Inhalation; D000287:Administration, Topical; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D001507:Beclomethasone / Q000008:administration & dosage; D001980:Bronchi / Q000098:blood supply / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000201:enzymology; D005260:Female; D005541:Forced Expiratory Volume; D005938:Glucocorticoids; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020545:Respiratory Mucosa / Q000201:enzymology
D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D001507:Beclomethasone