title: Effects of budesonide and formoterol on eosinophil activation induced by human lung fibroblasts.
abstract: Budesonide and formoterol are extensively used in current asthma therapy. Budesonide is known as potent antiinflammatory agent and formoterol also appears to have some antiinflammatory properties. We investigated inhibitory effects of these drugs on eosinophil activation in vitro as induced by fibroblast-conditioned medium (FCM). We measured the modulation of expression of clonal designator (CD)11b and L-selectin with flow cytometry after 4 h or 16 h of culture of eosinophils when budesonide or formoterol was applied either directly to the eosinophils while they were stimulated with FCM (direct method) or when each drug was applied to lung fibroblasts from which conditioned medium was then administered to eosinophils (indirect method). In the direct method, budesonide (10(-)(8) M) inhibited the modulation of CD11b (44 [25th to 75th percentiles: 26 to 66]% of control) and L-selectin (30 [-13 to 48]% of control) only after 16 h, and not after 4 h. Formoterol did not directly inhibit the modulation of eosinophil CD11b and L-selectin expression. In the indirect method, both budesonide and formoterol inhibited lung fibroblast activation, resulting in diminished eosinophil activation after 4 h. Budesonide or formoterol at 10(-)(8) M inhibited upregulation of CD11b to 26 [15 to 40]% and 38 [23 to 46]%, respectively, and inhibited L-selectin shedding to 14 [-3 to 50]% and 27 [2 to 62]%, respectively, of control values. These results show that budesonide inhibits eosinophil activation primarily through effects on lung fibroblasts, presumably by inhibiting production of granulocyte-macrophage colony-stimulating factor. After longer incubation periods, budesonide also directly inhibits eosinophil activation. In contrast, formoterol can inhibit eosinophil activation only via inhibitory effects on lung fibroblasts. We did not observe an additional effect of formoterol, beyond the effects induced by budesonide under any circumstance studied. Lung fibroblasts, in addition to eosinophils, may serve as important target cells for antiinflammatory treatment in asthma.
authors.affiliation: Departments of Allergology and Pulmonology, University Hospital Groningen, Groningen, The Netherlands.
authors.forename: F M
authors.initials: FM
authors.lastname: Spoelstra
authors.forename: H F
authors.initials: HF
authors.lastname: Kauffman
authors.forename: H
authors.initials: H
authors.lastname: Hovenga
authors.forename: J A
authors.initials: JA
authors.lastname: Noordhoek
authors.forename: J G
authors.initials: JG
authors.lastname: de Monchy
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000276:immunology*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology*; D017077:Culture Media, Conditioned; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects*; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D000068759:Formoterol Fumarate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D008168:Lung / Q000187:drug effects*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male
chemical_list: D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D017077:Culture Media, Conditioned; D004983:Ethanolamines; D016177:Macrophage-1 Antigen; D019041:L-Selectin; D019819:Budesonide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018819:Dipeptidyl Peptidase 4; D000068759:Formoterol Fumarate