Am. J. Respir. Crit. Care Med., Volume 159, Number 5, May 1999, 1600-1604

Increased Glucocorticoid Receptor  in Airway Cells of Glucocorticoid-insensitive Asthma

QUTAYBA A. HAMID, SALLY E. WENZEL, PIA J. HAUK, ANNE TSICOPOULOS, BENOIT WALLAERT, JEAN-JACQUES LAFITTE, GEORGE P. CHROUSOS, STANLEY J. SZEFLER, and DONALD Y. M. LEUNG

Divisions of Allergy-Immunology, Pulmonary Medicine, and Clinical Pharmacology, National Jewish Medical and Research Center; Departments of Pediatrics and Medicine, University of Colorado Health Sciences Center, Denver, Colorado; Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland; Meakins-Christie Laboratories and Department of Pathology, McGill University, Montreal, Quebec, Canada; and Immuno-Allergique Respiratoire, Institute Pasteur, Lille, France

Glucocorticoid (GC)-insensitive asthma is a challenging clinical problem that can be associated with life-threatening disease progression. The molecular basis of GC insensitivity is unknown. Alternative splicing of the GC receptor (GCR) pre-mRNA generates a second GCR, termed GCR, which does not bind GC but antagonizes the transactivating activity of the classic GCR. Thus increased expression of GCR could account for glucocorticoid insensitivity. Bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC) were examined for GCR immunoreactivity using a GCR-specific antibody by immunohistochemical staining. Cell localization of GCR expression was performed using a double immunostaining technique. Patients with GC-insensitive asthma expressed a significantly higher number of GCR-immunoreactive cells in their BAL and peripheral blood than GC-sensitive asthmatics or normal control subjects. Furthermore, GCR expression in GC-insensitive asthma was particularly high in airway T cells, which are thought to play a major role in the pathogenesis of asthma. We also examined the expression of GCR in specimens from the airways of patients with chronic bronchitis. In chronic bronchitis, few cells were GCR-positive and their numbers did not differ significantly from normal control subjects. We conclude that GC-insensitive asthma is associated with increased expression of GCR in airway T cells.

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