Background: It has been shown that treatment with a long acting β 2 agonist in addition to a glucocorticoid is beneficial in the treatment of asthma. In asthma inflammatory cells, particularly eosinophils, migrate into the pulmonary tissue and airway lumen by means of adhesion molecules expressed on resident tissue cells-that is, fibroblasts-and become activated by cytokines and adhesive interactions. A study was undertaken to determine whether an interaction exists between the long acting β 2 agonist formoterol and the glucocorticoid budesonide on inhibition of adhesion molecule expression, as well as chemo/cytokine production by human lung fibroblasts. Methods: Lung fibroblasts were preincubated with therapeutically relevant drug concentrations of 10 -8 M to 10 -10 M. Cells were stimulated with interleukin (IL)-1β (1 or 10 U/ml) for 8 hours and supernatants were collected for measurement of GM-CSF and IL-8 concentrations. The cells were fixed and subjected to a cell surface ELISA technique to measure the expression of ICAM-1 and VCAM-1. Results: Formoterol exerted an additive effect on the inhibition of IL-1β stimulated ICAM-1 and VCAM-1 upregulation and GM-CSF production by budesonide in concentrations of 10 -9 M and above (p<0.05). IL-8 production was not influenced by formoterol. Conclusion: Formoterol exerts an additive effect on the anti-inflammatory properties of budesonide. In vitro data support the finding that the combination of budesonide and formoterol in asthma treatment strengthens the beneficial effect of either drug alone.

The expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and more specifically vascular adhesion molecule-1 (VCAM-1) on lung fibroblasts may be important for migration of inflammatory cells through the submucosa to the airway lumen in the asthmatic inflammatory response. This study aimed to assess which cytokines are regulating ICAM-1 and VCAM-1 expression on human lung fibroblasts. For this purpose, confluent fibroblast cultures (derived from lung tissue from a nonasthmatic donor) were stimulated for 4 h with interleukin(IL)-1b, tumour necrosis factor (TNF)a, interferon (IFN)c, IL-4, IL-5 or transforming growth factor (TGF)b.IL-1b (optimal concentration (OC) 1 U . mL -1 ) and TNFa (OC 100 U . mL -1 ) both increased ICAM-1 and VCAM-1 expression. IFNc (OC 2 U . mL -1 ) increased only ICAM-1 expression and IL-4 (OC 5 ng . mL -1 ) increased only VCAM-1 expression, whereas IL-5 (20 ng . mL -1 ) and TGFb (10 ng . mL -1 ) did not influence ICAM-1 or VCAM-1 expression. ICAM-1 expression reached a plateau at 8±12 h after cytokine stimulation and remained constant for at least 24 h. VCAM-1 showed a transient increased expression within 24 h after IL-1b and TNFa stimulation. In contrast, VCAM-1 expression did not decrease after maximal expression at 4 h upon IL-4 stimulation.It is concluded that the Helper-1T-cell, type cytokine interferon c and the Helper-2 T-cell type cytokine interleukin-4 differentially regulate intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression on human lung fibroblasts. The proinflammatory cytokines interleukin-1b and tumour necrosis factor a increase both intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, without differential regulation of the expression of these adhesion molecules. Eur Respir J 1999; 14: 759±766.

The glucocorticoid budesonide and the long-acting b 2 -adrenoceptor agonist formoterol are used in asthma therapy for their anti-inflammatory and bronchodilating effects, respectively. Since expression of adhesion molecules on resident cells in the lung plays an important role in asthmatic inflammatory responses, the effects of these drugs on the cytokine-induced intercellular adhesion molecule-1 (ICAM)-1 and vascular cell adhesion molecule-1 (VCAM)-1 expression of human lung fibroblasts were investigated.Budesonide and formoterol were added in the absence or presence of interleukin (IL)-1b, tumour necrosis factor-a (TNF-a), interferon gamma (IFN-c) or IL-4 to human lung fibroblasts; ICAM-1 and VCAM-1 expression were measured after 8 h using a cell surface enzyme linked immunosorbent assay (ELISA).It was found that both budesonide and formoterol significantly inhibited (p<0.05) the increased expression of ICAM-1 and VCAM-1 after stimulation with IL-1b (maximal inhibition (median (25±75% percentiles) 50 (48±52) and 61% (42±69), respectively, with budesonide and 55 (50±73) and 86% (64±94), respectively, with formoterol (10 -7 M)), TNF-a (maximal inhibition 49 (46±57) and 57% (44±68), respectively, with budesonide and 44 (40±75) and 62% (52±83) respectively, with formoterol), IFN-c (maximal inhibition 64% (41±67) with budesonide and 39% (29±49) with formoterol for ICAM-1) and IL-4 (maximal inhibition 82% (69±92) with budesonide and 43% (33±67) with formoterol for VCAM-1) in a dose-dependent manner.The results show that budesonide, as well as formoterol, in probably clinically relevant concentrations inhibits cytokine-induced adhesion molecule expression on human lung fibroblasts from a concentration of 10 -9 M. This inhibitory effect on resident cells may have implications for the infiltration of inflammatory cells into pulmonary tissue during therapy with these drugs in asthma. Eur Respir J 2000; 15: 68±74.

No abstract