Mechanisms of Corticosteroid Resistance in Asthmatic Patients

Abstract

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.

Depression in Asthma: Prevalence and Clinical Implications

“…53 This breed of rat also exhibits airway hyper-responsiveness after exposure to allergens. 54 In human studies, a subset of asthma patients 55,56 as well as a subset of persons with depression exhibit evidence of glucocorticoid resistance. 57,58 Additional controlled studies are needed, examining the prevalence of depression in asthma patients and persons with comparable disability from other general medical conditions, to determine if asthma patients are at increased risk of depression compared with other general medical conditions.…”

The therapeutic outcome of intravenous steroid therapy for active Graves' orbitopathy is influenced by the time of response but not polymorphisms of the glucocorticoid receptor

“…Clinical Study G Vannucchi and others Steroid therapy in Graves' orbitopathy 170:1frequently observed; this situation has been reported in as many as 50% of patients who present with severe and difficult-to-treat asthma (17,18). In this study, we have not been able to find GR variants that were significantly associated with either the therapeutic response or the occurrence of adverse events.…”

Difficult asthma

“…This suggests that these patients are relatively resistant to the anti-inflammatory effects of GCS and may be part of a continuum, as described above. The mechanisms of relative GCS resistance are not yet known, as these patients are difficult to investigate with invasive techniques (62). Studies with biopsies, bronchoalveolar lavage and induced sputum have shown that inflammation persists, despite high doses of GCS and there is an increase in neutrophils in the airways of these patients (63,64).…”