Glucocorticoid Resistance in Chronic Asthma: Glucocorticoid Pharmacokinetics, Glucocorticoid Receptor Characteristics, and Inhibition of Peripheral Blood T Cell Proliferation by GlucocorticoidsIn Vitro

Abstract

A total of 37 chronic, severe, nonsmoking asthmatic patients with documented reversible airways obstruction were classified as glucocorticoid-sensitive or -resistant on the basis of changes in FEV1, FVC, and peak expiratory flow (PEF) after oral prednisolone. The resistant patients showed no significant improvements in airflow limitation. Phytohemagglutinin (PHA)-induced proliferation of peripheral blood T lymphocytes from the sensitive but not the resistant asthmatic patients was significantly (p less than 0.01) inhibited by dexamethasone (10(-7) mol/L), reflecting a shift of the dose-response curve. When all the asthmatic patients were analyzed together, there was a significant correlation between the degree of sensitivity of T cells to dexamethasone and the clinical responsiveness to prednisolone (p less than 0.01). No differences were observed between six of the sensitive and resistant patients in the clearance of plasma prednisolone derived from orally administered prednisone. Peripheral blood mononuclear cell glucocorticoid receptors were also characterized in five sensitive and seven resistant patients. The numbers and binding affinities of these receptors could not account for the observed difference in the susceptibility of these cells to functional inhibition by dexamethasone in vitro. These results suggest that clinical glucocorticoid resistance in chronic asthma does not reflect abnormal glucocorticoid clearance but may be due at least partly to a relative insensitivity of T lymphocytes to glucocorticoids. This lack of sensitivity is unexplained but is not attributable to abnormalities of cellular glucocorticoid receptors.

Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation

“…Consistent with previous observations [4], the refractoriness of PBMC from the current patients to dexamethasone inhibition underlines their relative glucocorticoid-insensitivity. It is unlikely that the chronic use of systemic glucocorticoids in these patients is responsible for this observation because after 8 weeks of treatment with MTX, during which the dose of glucocorticoids remained unaltered, the unresponsiveness of PBMC to dexamethasone was completely abrogated.…”

“…A proportion of these patients is found to be relatively resistant to the anti-inflammatory effects of glucocorticoids as judged by the reduced suppressive effects of dexamethasone on the proliferative response of peripheral blood mononuclear cells (PBMC) to the mitogen phytohaemagglutinin (PHA) [4] and increased peripheral blood T-cell activation [5]. Recently the authors have extended these observations to the bronchial mucosa by demonstrating the existence of increased mucosal T-cell activation in severe glucocorticoid-dependent asthmatics as compared to mild asthma and healthy control subjects [6].…”

How Do Corticosteroids Work in Asthma?

“…In patients with steroid-resistant and steroid-dependent asthma, the inhibitory effect of corticosteroids on cytokine release is reduced in peripheral blood mononuclear cells (60,61). In one group of patients, nuclear localization of glucocorticoid receptors in response to a high concentration of corticosteroids was impaired, and this may be due to such abnormalities as the increased activation of p38 MAP kinase described earlier.…”

The pharmacogenetics of asthma: a candidate gene approach

“…50 Studies carried out in our laboratory and others have demonstrated that patients with GCresistant asthma have decreased cellular immune responses to GC. 51,52 These abnormalities involving their T cells, monocytes, and eosinophils make GC treatment less effective in suppressing the activation of cells from GC-resistant asthmatics than from GC-sensitive asthmatics.…”