Mechanisms of Glucocorticoid‐Resistant Asthma^a

A bstract : The term “steroid‐ or glucocorticoid‐resistant (GR) asthma” has been used to describe a group of asthmatics who demonstrate persistent airway obstruction and inflammation despite treatment with high doses of systemic glucocorticoids (GCs). There are at least two forms of GR asthma. The first group of patients has an acquired form of GC resistance. Analysis of their bronchoalveolar lavage (BAL) cells indicates an extremely high level of IL‐2 and IL‐4 gene expression as compared to BAL cells from GC‐sensitive asthmatics. The incubation of T cells from normal individuals with the combination of IL‐2 and IL‐4 induces GC receptor binding defects, and concomitant GC receptor β expression, in their cells. Similar abnormalities in GC receptor binding defects can be detected in freshly isolated cells from type 1 GR asthmatics, but this defect is reversible when their cells are cultured in the absence of IL‐2 and IL‐4. The second group involves patients with primary GC resistance who do not develop side effects on high‐dose GCs and have very low numbers of GC receptors in their mononuclear cells. This defect is irreversible in culture and affects their T cells as well as non‐T cells. The current studies provide new insights into mechanisms by which inflammation induces GC resistance and how defects in the GC receptor may contribute to chronic inflammation, creating the vicious cycle leading to chronic inflammatory diseases.