We investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma.
ASMCs cultured from bronchial biopsy specimens of nonasthmatic control subjects (n?= 12) and patients with nonsevere (n?= 10) or severe (n?= 10) asthma were compared for the effect of dexamethasone on suppression of TNF-¦Á- and IFN-¦Ã-induced CCL11 (eotaxin), CXCL8 (IL-8), and CX3CL1 (fractalkine) expression. The mechanisms of corticosteroid insensitivity are also determined.
CCL11 release was higher in ASMCs of patients with nonsevere but not severe asthma and nonasthmatic control subjects; CXCL8 and CX3CL1 release were similar in all groups. In patients with severe asthma, dexamethasone caused less suppression of CCL11 and CXCL8 release induced by TNF-¦Á. Dexamethasone potentiated TNF-¦Á- and IFN-¦Ã-induced CX3CL1 release equally in all 3 groups. TNF-¦Á-induced phosphorylated p38 mitogen-activated protein kinase levels were increased in ASMCs from patients with severe asthma compared with those from patients with nonsevere asthma and nonasthmatic subjects, whereas TNF-¦Á-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. A?p38 inhibitor increased the inhibitory effect of dexamethasone.
ASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen-activated protein kinase levels.