Search

The data indicate that the proliferation of airway smooth-muscle cells in patients with asthma may result from an absence of C/EBPalpha. Lines of bronchial smooth-muscle cells were established from cells from 20 subjects with asthma. The antiproliferative and the cytokine-inhibitory effects of glucocorticoids are mediated by different signaling pathways are demonstrated.

Summary: Background: Increased airway smooth muscle bulk is a pathological feature of asthma. Asthma is well controlled by the combined inhalation of glucocorticoids and β [sub 2]-adrenoceptor agonists. The basic molecular mechanism of the interaction of the two drugs on proliferation of airway smooth muscle cells is yet to be identified. Our aim was to elucidate how glucocorticoids and β [sub 2] agonists affect the growth of human bronchial airway smooth muscle cells. Methods: We assessed the effect of formoterol and budesonide on the activation and function of transcription factors by immunohistochemistry, western blotting, DNA mobility shift assay, and a luciferase reporter gene assay. The effect of the drugs and the involvement of specific transcription factors on cell proliferation was ascertained by direct cell count and confirmed by thymidine incorporation. Findings: Both classes of drugs (10[-8] mol/L) activated C/EBP-α and the glucocorticoid receptor with different kinetic profiles, and inhibited proliferation. The combination of lower doses of drugs (10[-12] to 10[-9] mol/L) resulted in a synchronised activation of the transcription factors and an enhanced antiproliferative effect. The action of the drugs alone or in combination on transcription-factor activity and proliferation was suppressed by either depletion of C/EBP-α or in the presence of a glucocorticoid-receptor blocker. Interpretation: Our findings could provide one explanation for the interaction of β [sub 2 ]agonists and glucocorticoids at a molecular level, and indicate that the concentration of inhaled glucocorticoids can be reduced when combined with β [sub 2] agonists, minimising the side-effects of the drugs. [ABSTRACT FROM AUTHOR]