Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate.
BACKGROUND
Inhaled corticosteroids are highly effective in asthma, reducing inflammatory markers and bronchial hyperresponsiveness. Cysteinyl-leukotrienes are major mediators of airway obstruction and display proinflammatory effects. Although the synthesis of leukotrienes is not affected by corticosteroid treatment, the influence of corticosteroids on the leukotriene pathway remains unresolved.


OBJECTIVE
We investigated whether or not bronchial responsiveness to leukotriene (LT) D(4) is reduced by fluticasone propionate in subjects with asthma.


METHODS
In 13 subjects with mild asthma, inhalation challenges with methacholine and LTD(4) were performed on consecutive days before and after 2 weeks of treatment with inhaled fluticasone 500 mug, twice daily, in a double-blind, randomized, placebo-controlled study with crossover design and 3 weeks of washout between periods. Exhaled nitric oxide was measured as a marker of corticosteroid responsiveness, and baseline urinary LTE(4) concentrations as an index of cysteinyl-leukotriene biosynthesis.


RESULTS
Fluticasone produced a significant decrease in methacholine responsiveness, corresponding to 2.6-fold shift in the PD(20) FEV(1), and a significant reduction in the levels of exhaled nitric oxide. By contrast, bronchial responsiveness to LTD(4) in the same subjects was unaffected by fluticasone, as were urinary LTE(4) concentrations.


CONCLUSIONS
These new data indicate that neither the biosynthesis nor the actions of leukotrienes appear to be sensitive to inhaled corticosteroids.


CONCLUSIONS
The study provides mechanistic support for the additive therapeutic efficacy of antileukotrienes and inhaled corticosteroids in asthma.
Gyllfors
Pär
P
Division of Respiratory Medicine, Department of Medicine, Karolinska University Hospital Solna, Sweden.
Dahlén
Sven-Erik
SE
Kumlin
Maria
M
Larsson
Kjell
K
Dahlén
Barbro
B
D000280:Administration, Inhalation; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D001980:Bronchi / Q000187:drug effects* / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D000068298:Fluticasone; D006801:Humans; D017998:Leukotriene D4 / Q000494:pharmacology*; D017999:Leukotriene E4 / Q000652:urine; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology
D000730:Androstadienes; D016210:Methacholine Chloride; D017998:Leukotriene D4; D017999:Leukotriene E4; D000068298:Fluticasone