New insights into steroid resistant asthma.

The term "steroid resistant (SR) asthma" refers to a group of asthmatics who have persistent airway obstruction and immune activation despite treatment with high doses of systemic glucocorticoids. There are at least two forms of SR asthma, i.e. primary and acquired types. Type I SR asthma is acquired and is associated with abnormally reduced glucocorticoid receptor (GCR) ligand and DNA binding affinity. Type II SR asthma appears to be due to a constitutive defect and is associated with low numbers of GCRs. An important distinction between these two types of SR asthma is that the GCR defect in Type I, but not Type II, SR asthma is reversible in culture and is sustained by incubation with combination IL-2 and IL-4. Recent studies suggest that the abnormal GCR binding in Type I SR asthma may be due to cytokine-driven alternative splicing of the GCR pre-mRNA to a novel isoform called GCRbeta which does not bind glucocorticoids but antagonizes the transactivating activity of the classic GCR. These GCR changes along with recent evidence for increased transcription factor activation in SR asthma which may inhibit GCR/DNA interactions as well as the selective recruitment of neutrophils into the airways of certain patients with severe asthma contribute to the heterogeneity of mechanisms underlying steroid resistance.