Asthma is characterised by airway inflammation, hyper-responsiveness and airway remodelling. Features of airway remodelling include hypertrophy/hyperplasia of airway smooth muscle cells (ASMC), which possess an important synthetic capacity in addition to their contractile function. Patients with severe asthma respond poor to even high-dose corticosteroids and consume enormous healthcare resources. Corticosteroid insensitivity in peripheral blood mononuclear cells and alveolar macrophages of severe asthma has been reported. It is still unclear whether ASMC display a similar phenotype. I hypothesised that corticosteroid insensitivity exists in ASMC of severe asthma, and the underlying mechanisms were investigated. ASMC were obtained from endobronchial biopsy and were experimented with at passage 4-5.
TNF-α induced CCL11, CXCL8 and CXCL10 expression in ASMC. IFN-γ suppressed TNFα-induced CCL11 and CXCL8, through attenuation of NF-κB (p65) recruitment to the gene promoters, but potentiated induced CXCL10. CX3CL1 was induced synergistically only by combined both cytokines. Baseline and TNFα-induced CCL11 expression in non-severe asthma were greater than the healthy and severe asthma, while IFNγ-induced CXCL10 was increased in severe asthma. Whereas TNFα-induced p65 expression was increased in severe asthma, there was no difference in nuclear translocation or recruitment to the gene promoters between groups. The effect of dexamethasone was reduced in terms of suppressing induced CCL11 and CXCL8 expression in severe asthma, while the potentiating effect on CX3CL1 was not different between groups. Of the mitogen-activated protein kinases (MAPK), p38 activation was heightened in severe asthma, and p38 inhibition restored the corticosteroid sensitivity. Expression of glucocorticoid receptor (GR) was decreased in asthma, while nuclear translocation of GR was impaired only in severe asthma.
In conclusion, there is differential expression of inflammatory chemokines in ASMC of asthma. Corticosteroid insensitivity exists in ASMC of severe asthma in terms of suppressing induced chemokines, partially attributed to heightened p38 MAPK activity and impaired nuclear translocation of GR.