Glucocorticoid Resistance in Chronic Asthma: Glucocorticoid Pharmacokinetics, Glucocorticoid Receptor Characteristics, and Inhibition of Peripheral Blood T Cell Proliferation by GlucocorticoidsIn Vitro
- 1 November 1991
- journal article
- research article
- Published by American Thoracic Society in American Review of Respiratory Disease
- Vol. 144 (5) , 1016-1025
- https://doi.org/10.1164/ajrccm/144.5.1016
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.Keywords
This publication has 16 references indexed in Scilit:
- Identification and characterization of a monocyte-derived neutrophil-activating factor in corticosteroid-resistant bronchial asthma.Journal of Clinical Investigation, 1989
- Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthmaJournal of Allergy and Clinical Immunology, 1987
- Hydrocortisone-mediated inhibition of monocyte antigen presentation: Dissociation of inhibitory effect and expression of DR antigensCellular Immunology, 1984
- Effect of Corticosteroids in Asthma Is Not Due to Suppression of Leukotriene ReleaseNew England Journal of Medicine, 1983
- The effects of corticosteroids on the antigen presenting properties of human monocytes and endothelial cellsClinical Immunology and Immunopathology, 1982
- Prednisolone pharmacokinetics in asthmatic patientsRespiratory Medicine, 1980
- Interaction of glucocorticoids with macrophages. Identification of glucocorticoid receptors in monocytes and macrophages.The Journal of Experimental Medicine, 1978
- Glucocorticoid receptors and glucocorticoid sensitivity of mitogen stimulated and unstimulated human lymphocytesNature, 1977
- The Effect of In Vivo Hydrocortisone on Subpopulations of Human LymphocytesJournal of Clinical Investigation, 1974
- Corticosteroids in liver disease: Studies on the biological conversion of prednisone to prednisolone and plasma protein bindingGut, 1972