Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma

Background: We have recently demonstrated an increased number of glucocorti coid receptor-beta (GR beta)-positive cells in steroid-insensitive subjects with severe asthma, Insensitivity to steroids may be a major contributing factor in fatal asthma; however, no such direct evidence has been report pr eviously. Objective: Our aims were to investigate the expression of GR beta immunorea ctivity, an endogenous inhibitor of steroid action previously associated wi th steroid insensitivity, within the airways of patients who died of slow-o nset fatal asthma and to compare its expression in patients with emphysema and in nonasthmatic subjects who died of unrelated causes. Sections from ai rways, both large and small, were obtained from 7 patients who died of asth ma, 6 who died from emphysema, and 8 who died from nonpulmonary diseases. S ections from lungs of 6 patients with mild asthma whose lungs were resected for carcinoma were also included as controls. Methods: Tissue samples were processed for immunocytochemistry with a polyc lonal antibody to GR beta with use of the avidin-biotin technique and with monoclonal CD3, major basic protein, CD68, and elastase antibodies with the alkaline phosphatase-anti-alkaline phosphatase technique. Sequential immun ocytochemistry was performed to phenotype the GR beta immunoreactive cells. Tissue sections from both large (>2 mm) and small (<2 mm) airways were exa mined. Results: There was a significantly greater number of GR beta immunoreactive cells in fatal asthma compared with emphysema and controls (P < .001 and P < .05, respectively). There was no difference in the expression of GR beta in emphysema compared with controls. GR beta immunoreactivity was also sig nificantly higher in fatal asthma compared with mild asthma, The expression of GR beta in the small airways of patients with severe asthma did not dif fer significantly from that in the large airways. The majority of GR beta-p ositive cells were T cells and to a lesser extent eosinophils, macrophages, and neutrophils. Conclusion: The results of this study support the association of GR beta ex pression with fatal asthma and suggest that alternative anti-inflammatory a gents need to be considered in the acute setting for patients who are not r esponding to steroid therapy.