Mechanisms of corticosteroid resistance in asthmatic patients

Corticosteroid-resistant (CR) asthma is associated with disease chronicity, a more frequent family history of asthma and impaired in vitro and in vivo responsiveness of peripheral blood mononuclear cells to the suppressive effects of glucocorticoids. CR asthma is associated with normal suppression of the hypothalamic-pituitary-adrenal axis and of biochemical indices of bone turnover by dexamethasone, indicating that the phenomenon of glucocorticoid resistance is specific to inflammatory leukocytes and that these patients are equally at risk of developing 'cushingoid' side effects. We have been unable to detect altered bioavailability of administered glucocorticoid, impaired ligand binding or nuclear translocation of the activated glucocorticoid receptor (GR) complex or structural abnormalities of the GR cDNA in our population of CR asthmatics. We have recently demonstrated that CR asthma is associated with decreased GR and increased AP-1 (Fos; Jun) DNA binding in peripheral blood mononuclear cells as compared to corticosteroid-sensitive asthma. These results highlight the central role of the AP-1/GR interactions in glucocorticoid action in CR asthma.