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Fluticasone and salmeterol downregulate in vitro, fibroblast proliferation and ICAM-1 or H-CAM expression

¹ Pulmonary Division, G. Gaslini Institute, Genoa, and ² GlaxoWellcome S.p.A., Verona, Italy

CORRESPONDENCE: G.A. Rossi, Dept. of Pulmonary Diseases, G. Gaslini Institute, Largo G. Gaslini 5, 16147, Genoa, Italy. Fax: 39 0103776590

Keywords: airway remodelling, ß₂-agonists, bronchial asthma, corticosteroids

Received: July 27, 2000
Accepted March 6, 2001

ß₂-adrenoreceptor agonists have pharmacological properties that may suggest an inhibitory effect on various aspects of the inflammatory and repair processes that characterize asthma.

Since fibroblasts express ß₂-adrenoreceptors, the effects of different concentrations (0.1–100 nM) of fluticasone propionate (FP), salmeterol (S) and their combination (FP+S) on lung fibroblast proliferation and adhesion molecule expression were evaluated.

Stimulation of human foetal lung fibroblasts with a fibrogenic cytokine, basic fibroblast growth factor (bFGF), resulted in a [methyl-³H] thymidine ([³H]TdR) uptake, four-fold higher than that of control cultures (p=0.0001) and was significantly inhibited by S, at all the concentrations tested (0.1–100 nM; p<0.05). No changes in bFGF-induced cell proliferation were observed in the presence of FP (0.1–100 nM; p>0.05, all comparisons). In addition, the association FP+S did not improve the inhibitory activity of S alone (p>0.05, each comparison). An upregulation of intercellular adhesion molecule-1 (ICAM-1) expression was induced by tumour necrosis factor- (TNF-) (p=0.0004), but not by interleukin-4 (IL-4) (p>0.05), while none of the two cytokines were able to increase hyaluronic-cellular adhesion molecule (H-CAM) expression by lung fibroblasts (p>0.05). A significant downregulation of ICAM-1 or H-CAM expression was demonstrated in the presence of FP or S, at all concentrations tested (0.1–100 nM; p<0.01, each comparison). Interestingly, S (10 nM and 100 nM) was able to enhance the inhibitory activity of FP on ICAM-1 expression (p<0.01), but not on H-CAM expression (p>0.1).

These results show that in human foetal lung fibroblasts, fluticasone propionate and salmeterol are effective in modulating in vitro, different lung fibroblast biological functions that are likely to be involved in airway remodelling.