Abstract
During asthma exacerbations, increased airway inflammation may impair the effects of β2-adrenoceptor (β2AR) agonists. It is unclear whether this impairment is prevented by inhaled glucocorticoids (GCs). We have investigated the relaxation of carbachol-contracted mouse tracheal segments to the β2AR agonists formoterol, terbutaline, and salmeterol. The segments were pre-exposed for 4 days to the proinflammatory cytokines tumor necrosis factor α (100 ng/ml) and interleukin-1β (10 ng/ml) with or without the GC, budesonide (1 μM). Formoterol and terbutaline induced greater maximal relaxation (Rmax) than salmeterol. The cytokines decreased Rmax of all β2AR agonists, whereas budesonide had no effect. However, after concomitant treatment with cytokines and budesonide, the Rmax values of formoterol and terbutaline were not impaired, whereas budesonide did not prevent the decrease in the Rmax of salmeterol. A similar pattern was observed for cAMP production by the agonists. In tracheal smooth muscle, β2AR mRNA was not affected by the cytokines but increased with budesonide. However, the cytokines markedly increased cyclooxygenase (COX)-2 mRNA expression, which may lead to heterologous desensitization of β2AR. It is noteworthy that the cytokine-induced increase of COX-2 was blocked by concomitant budesonide suggesting that heterologous desensitization of β2AR by the cytokines may be prevented by budesonide treatment. Budesonide prevented cytokine-induced impairment of the tracheal relaxation and β2AR/cAMP signaling for formoterol but not for salmeterol. This suggests that differences exist between formoterol and salmeterol in β2AR coupling/activation and/or signal transduction upstream of cAMP. These results imply that maximal bronchodilator effects of formoterol, but not of salmeterol, are maintained by budesonide treatment during periods with increased inflammation, such as asthma exacerbations.
Footnotes
- Received May 14, 2009.
- Accepted January 7, 2010.
This work was supported by the Swedish Medical Research Council [Grant 2007-9071]; the Swedish Heart-Lung Foundation [Grant 20080575]; Vinnova (Chronic Inflammation-Diagnostic and Therapy); the Stockholm County Council Research Funds (ALF); Karolinska Institutet; and AstraZeneca.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.156224.
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ABBREVIATIONS:
- GC
- glucocorticoid
- β2AR
- β2-adrenoceptor
- TNFα
- tumor necrosis factor α
- IL-1β
- interleukin-1β
- COX
- cyclooxygenase
- PCR
- polymerase chain reaction
- Ct
- cycle threshold
- EIA
- enzyme immunonoassay
- Gs
- stimulatory G-protein
- Gi
- inhibitory G-protein
- ANOVA
- analysis of variance
- CGP 20712A
- [2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluormethyl-2-imidazolyl)-phenoxy]-2-propanolmethanesulfonate
- ICI 118551
- (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol
- BUD
- budesonide.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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