Cooperative inhibitory effects of budesonide and formoterol on eosinophil superoxide production stimulated by bronchial epithelial cell conditioned medium.
BACKGROUND
Improved asthma control by combinations of inhaled glucocorticosteroids (GCs) and long-acting beta(2)-agonists (LABAs) includes a reduced frequency and severity of exacerbations. In view of the association of exacerbations with increased airway inflammation, the question has arisen as to whether LABAs are able to complement the known anti-inflammatory activity of GCs. To address this, we studied the effects of a LABA, formoterol (FORM), and a GC, budesonide (BUD), alone and in combination, on bronchial epithelial cell-mediated eosinophil superoxide production in vitro.


METHODS
We employed 2 experimental approaches. First, superoxide production by human eosinophils incubated with conditioned medium (CM) from human bronchial epithelial cells cultured for 24 h with vehicle, BUD, FORM or BUD + FORM was measured (Epi/Eos assay). Second, eosinophils were stimulated with vehicle-CM to which the drugs were added (Eos assay). Superoxide production was determined as the superoxide dismutase-inhibitable reduction of ferricytochrome C.


RESULTS
CM increased eosinophil superoxide generation (p < 0.01) and epithelial-derived granulocyte macrophage colony-stimulating factor was the mediator responsible. In both assays, FORM dose-dependently inhibited eosinophil superoxide similarly and in the same concentration range as BUD. The BUD + FORM combination was more effective than BUD alone, and it completely inhibited CM-induced superoxide production in the Epi/Eos assay, suggesting complementary effects of both drugs on bronchial epithelial cells and eosinophils.


CONCLUSIONS
The cooperative, inhibitory effects of BUD and FORM on eosinophils and bronchial epithelial cells, in terms of their effects on eosinophil superoxide production, may represent a possible mechanism for the enhanced anti-inflammatory efficacy of BUD and FORM combination therapy of asthma.
Persdotter
Sofia
S
AstraZeneca R&D Lund, Lund, Sweden.
Lindahl
Maria
M
Malm-Erjefalt
Monika
M
von Wachenfeldt
Karin
K
Korn
Solange H
SH
Stevens
Tim
T
Miller-Larsson
Anna
A
D001249:Asthma / Q000188:drug therapy; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D013481:Superoxides / Q000378:metabolism*
D001993:Bronchodilator Agents; D017077:Culture Media, Conditioned; D004983:Ethanolamines; D013481:Superoxides; D019819:Budesonide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000068759:Formoterol Fumarate