Effects of glucocorticoids on lymphocyte activation in patients with steroid-sensitive and steroid-resistant asthma,☆☆,,★★

https://doi.org/10.1016/S0091-6749(96)80194-1Get rights and content

Abstract

BACKGROUND: Glucocorticoids are important medications used to control the airway inflammation associated with asthma. Synthetic glucocorticoids vary in their binding affinity for the glucocorticoid receptor (GCR). METHODS: We compared hydrocortisone, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, and budesonide with regard to their capacity to inhibit phytohemagglutinin-induced peripheral blood mononuclear cell proliferation from six patients with steroid-sensitive asthma and seven patients with steroid-resistant asthma. Peripheral blood mononuclear cell GCR binding affinities for dexamethasone and budesonide were also determined for both patient groups by using a radioligand binding assay and Scatchard analysis. RESULTS: Dose-dependent inhibition was demonstrated for all glucocorticoids in both patient groups, with the steroid-resistant group requiring approximately 2 log-fold more glucocorticoids for an equivalent degree of inhibition. The mean concentrations necessary to cause 50% inhibition of lymphocyte proliferation (IC 50s) for the steroid-sensitive group ranged from 2 × 10-10 mol/L for budesonide to 7 × 10-8 mol/L for hydrocortisone, whereas the mean IC 50s for the steroid-resistant group ranged from approximately 2 × 10-8 mol/L for budesonide to greater than 10-6 mol/L for hydrocortisone. In addition, a significant correlation was noted between the degree of inhibition of lymphocyte proliferation (IC 50) and the binding affinity of dexamethasone to the GCR. Patients with steroid-resistant asthma have been shown to have a reduced GCR binding affinity. The GCR binding affinity for budesonide was significantly higher in both groups (i.e., lower dissociation constant) than that obtained for dexamethasone. CONCLUSION: These data suggest that glucocorticoids such as budesonide, by virtue of their high GCR binding affinities and greater ability to suppress lymphocyte proliferation, may therefore be beneficial in the management of difficult-to-control asthma. (J Allergy Clin Immunol 1996;98:1073-9.)

Section snippets

Subjects

Thirteen patients with a diagnosis of asthma, according to American Thoracic Society criteria, were selected for evaluation. Informed consent was obtained from all patients before entry into the study. Seven patients were classified as having SR asthma on the basis of their prebronchodilator morning FEV 1 of less than 70% of predicted value and failure to improve their morning prebronchodilator FEV 1 by more than 15% after a course of oral prednisone in doses equal to or exceeding 40 mg/day for

Clinical characteristics and the effect of glucocorticoids on lymphocyte proliferation

The mean ages of the study groups were similar, whereas the majority of other characteristics were significantly different. As expected, patients with SR asthma had poorer pulmonary function and were receiving higher doses of inhaled steroids; and six of the seven were receiving maintenance oral steroid therapy (Table I). Patients with SS asthma were significantly more sensitive to the suppressive effects of all glucocorticoids studied compared with those with SR asthma. Fig. 1 compares the

Discussion

The vast majority of patients with asthma respond favorably to glucocorticoid therapy with relief of symptoms, improvement in baseline pulmonary function, and reductions in nonspecific bronchial hyperresponsiveness. Unfortunately, a small subset of patients with severe asthma that fails to adequately respond to high-dose inhaled and long-term oral glucocorticoid therapy exists. These “steroid resistant” asthmatic patients are often the most difficult group of patients with asthma to treat.

References (14)

  • J Alvarez et al.

    Steroid-resistant asthma: immunologic and pharmacologic features

    J Allergy Clin Immunol

    (1992)
  • BJ. Lipworth

    Clinical pharmacology of corticosteroids in bronchial asthma

    Pharmacol Ther

    (1993)
  • CJ Corrigan et al.

    Glucocorticoid resistance in chronic asthma: glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro

    Am Rev Respir Dis

    (1991)
  • CJ Corrigan et al.

    CD4 T-lymphocyte activation in acute severe asthma

    Am Rev Respir Dis

    (1990)
  • ER Sher et al.

    Steroid-resistant asthma: cellular mechanisms contributing to inadequate response to glucocorticoid therapy

    J Clin Invest

    (1994)
  • JC Kam et al.

    Combination of IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids

    J Immunol

    (1993)
  • DYM Leung et al.

    Dysregulation of interleukin 4, interleukin 5, and interferon γ gene expression in steroid-resistant asthma

    J Exp Med

    (1995)
There are more references available in the full text version of this article.

Cited by (0)

From the Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Divisions of Allergy-Clinical Immunology and Clinical Pharmacology (the Ira J. and Jacqueline Neimark Laboratory of Clinical Pharmacology in Pediatrics) and the Departments of Pediatrics and Pharmacology, University of Colorado Health Sciences Center, Denver.

☆☆

Supported in part by a grant from Astra USA and United States Public Health Service grants HL-36577, and RR-00051. Dr. Szefler is the Helen Wohlberg and Herman Lambert Chair in Pharmacokinetics.

Reprint requests: Stanley J. Szefler, MD, Department of Pediatrics, The National Jewish Center for Immunology and Respiratory Medicine, 1400 Jackson St., Denver, CO 80206.

★★

0091-6749/96 $5.00 + 0 1/1/75058

View full text