Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate

doi:10.1016/j.jaci.2006.03.040

Journal of Allergy and Clinical Immunology

Volume 118, Issue 1, July 2006, Pages 78-83

https://doi.org/10.1016/j.jaci.2006.03.040 Get rights and content

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) D₄ is reduced by fluticasone propionate in subjects with asthma.

Methods

In 13 subjects with mild asthma, inhalation challenges with methacholine and LTD₄ were performed on consecutive days before and after 2 weeks of treatment with inhaled fluticasone 500 μg, 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 LTE₄ 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 PD₂₀ FEV₁, and a significant reduction in the levels of exhaled nitric oxide. By contrast, bronchial responsiveness to LTD₄ in the same subjects was unaffected by fluticasone, as were urinary LTE₄ concentrations.

Conclusion

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

Clinical implications

The study provides mechanistic support for the additive therapeutic efficacy of antileukotrienes and inhaled corticosteroids in asthma.

Section snippets

Subjects

Fourteen nonsmoking subjects with stable mild atopic asthma treated only with a short-acting β₂-agonist as needed ≤ twice a week, an FEV₁ greater than 70% of predicted, and established bronchial hyperresponsiveness to methacholine (PD₂₀ FEV₁ ≤ 5579 nmol) were recruited. Exclusion criteria were significant allergen exposure, a respiratory tract infection within 6 weeks before and during the study, and use of glucocorticosteroids within 3 months. One subject failed to produce a methacholine PD₂₀

Results

The 2-week treatment with fluticasone propionate 500 μg bid did not change baseline lung function (Table II). Thus, prechallenge FEV₁ values did not differ among the 8 bronchoprovocation days.

The levels of F_ENO were, however, significantly depressed after treatment with fluticasone propionate, indicating that the subjects were compliant with the study medication. The reduction (ie, before minus after treatment) in F_ENO was 22.0 (range, −1.7 to 154) ppb from a median baseline of 40.4 after

Discussion

This is, to our knowledge, the first study that investigates whether bronchial responsiveness to a cysteinyl-leukotriene is decreased by treatment with an inhaled glucocorticosteroid in subjects with asthma. We found that 2 weeks of treatment with the potent glucocorticosteroid fluticasone 1000 μg/d caused a decrease in F_ENO and a decrease in bronchial responsiveness to methacholine. In contrast, the study could not confirm our hypothesis that ICS treatment would diminish bronchial

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Cysteinyl leukotrienes (CysLTs) are released, and their levels are significantly elevated during viral airway infection in infants. Montelukast is a potent cysteinyl leukotriene (cysteinyl-LT) receptor antagonist, which exerts some anti-inflammatory effects.3–6 Cysteinyl-leukotrienes represent a rational target for the treatment of acute bronchiolitis as they are potent pro-inflammatory mediators known to cause bronchial obstruction, mucosal oedema, eosinophil recruitment, and increased bronchial hyper-responsiveness.
Acute bronchiolitis comprises a major cause for morbidity in infants with viral infection which induces an immune inflammatory response that may produce long lasting harmful effects. Currently, there is no effective therapy for bronchiolitis.
Our aim was to investigate the efficacy of five-day montelukast therapy in acute bronchiolitis management.
The study included 50 infants with acute bronchiolitis. The infants with first episode of acute bronchiolitis were randomly assigned to receive daily montelukast dose of 4 mg over five days after admission or no treatment. Plasma eotaxin, IL-4, IL-8 and IFN-gamma levels were evaluated before and after treatment by ELISA method. In the present study, the primary outcome measure was change in clinical severity score, whilst secondary outcome measures were changes in plasma eotaxin, IL-4, IL-8, IFN-gamma levels.
No significant differences was found in clinical severity score with five-day montelukast treatment (p > 0.05, Mann–Whitney U test). There were no significant differences in plasma eotaxin, IL-4, IL-8, IFN-gamma levels between the groups (p > 0.05 Mann–Whitney U test). There was significant decrease in plasma IFN-gamma levels following five-day montelukast treatment (p = 0.027, Wilcoxon). There were no significant differences in plasma IL-4, IL-8, IFN-gamma levels between the groups after five-day montelukast treatment (p > 0.05, Wilcoxon). There was significant increase in eotaxin levels after five-day montelukast treatment (p = 0.009, Wilcoxon).
Our study showed that montelukast affected plasma IFN-gamma and eotaxin levels after five days of treatment. Further studies are needed to demonstrate effects of montelukast on chemokine levels in bronchiolitis.
Genome-wide association study identifies ALLC polymorphisms correlated with FEV<inf>1</inf> change by corticosteroid
2014, Clinica Chimica Acta
Asthma can be suppressed by inhaled corticosteroids (ICS). However, response to ICS shows marked inter-individual variability. This study is aimed to identify the genetic variants associated with the change in the percentage of forced expiratory volume in 1 second (%ΔFEV1) following ICS treatment.
A genome-wide association study was performed in a Korean asthmatic cohort. To further investigate these genetic associations, 11 additional single-nucleotide polymorphisms (SNPs) on the allantoicase (ALLC) gene were selected from the HapMap database and genotyped in the same asthmatic patients in the follow-up study.
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Although the associated signals could not overcome the genome-wide multiple correction due to small sample size (n = 189), our results suggest that associated SNPs of ALLC might be genetic predictors of response to ICS, at least with respect to ΔFEV1 in Korean asthmatics.
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A very recent paper also reported the bronchodilatory capacity of inhaled montelukast [95]; its clinical potential in asthma therapy awaits further studies. Additional interest in the therapeutic potential of LT blockade derives from the facts that 1) neither LT synthesis [3–5] nor receptor expression [5,6] is inhibitable by corticosteroids, and 2) anti-LT agents have demonstrated a remarkable capacity to prevent [96] or even reverse [97] the airway remodeling observed in a mouse model of chronic allergic asthma. In contrast, corticosteroids notably lack this action in the mouse model and ICS fail to prevent progressive loss of lung function in children with chronic asthma [98].
Asthma is a common chronic inflammatory disease of the airways characterized by airway obstruction and hyperresponsiveness. Leukotrienes (LTs) are lipid mediators that contribute to many aspects of asthma pathogenesis. As the LT pathway is relatively steroid-resistant, its blockade by alternative strategies is a desirable component of asthma management. Cysteinyl LT (cysLT) receptor 1 antagonists (LTRAs) have been utilized worldwide for more than 10 years, and while their efficacy in asthma is well accepted, their limitations are also evident.
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CysLTs play pathogenetic roles in many aspects of asthma, and blockade of cysLT receptor 1 by currently available LTRAs is certainly beneficial in disease management. On the other hand, the limitations of LTRAs are also apparent. Recent studies have revealed new receptors for cysLTs other than classical cysLT receptors 1 and 2, as well as the potential importance of LTB₄ in asthma.
Recent findings provide clues to new approaches for targeting the LT pathway that may overcome the current limitations of LTRAs and achieve superior control of asthma. This article is part of a Special Issue entitled: Biochemistry of Asthma.
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Bronchial hyperresponsiveness to 5-adenosine mono-phosphate (AMP) is a marker of airway inflammation. Inhaled corticosteroids and antileukotrienes are used as anti-inflammatory drugs for the treatment of asthma. To find out if these two drugs exert their protection in an additive fashion, we compared the effects of acute treatment with inhaled beclomethasone (BDP) and montelukast (ML), alone or in combination, on methacholine and AMP induced bronchoconstriction.
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BDP pretreatment significantly increased the AMP PC₂₀ value (68.34 ± 15.9 mg/mL) as compared to placebo (22.87 ± 5.7 mg/mL). Combined treatment, BDP plus ML, afforded a further significant increase of AMP PC₂₀ (154.57 ± 55.0 mg/mL) as compared to each single treatment. The significant protection exerted by combined treatment as compared to each single active treatment was also demonstrated by the change of AMP PC₂₀ doubling dose as compared to placebo and each single active treatment.
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Anti-inflammatory drug therapy in asthma
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Citation Excerpt :
Leukotrienes are very potent mediators through interaction with the Cystinyl leukotriene receptor 1. Neither the synthesis nor the leukotriene induced actions are responsive to steroid treatment.36 LTRA are the first new anti-inflammatory drugs since the introduction of ICS and the first to target a specific type of mediator.
Asthma is a disease with chronic inflammation of the airways and and-inflammatory treatment is a logical treatment. Inhaled corticosteroids [ICS] remain the cornerstone of anti-inflammatory therapy in recent international guidelines. Asthma cannot be cured by any medication: if the drug is discontinued, the disease manifestations return. This has been proven at all ages. In preschool children the diagnosis of asthma is difficult to establish. In this heterogeneous group ICS or leukotriene receptor antagonists [LTRA] are just as effective as placebo; in the future it will hopefully be possible to describe characteristics of responders. LTRA are an alternative in mild asthma, especially when mono-triggered viral related wheeze is present. Theophylline is effective and also has bronchodilatory properties, which need to be balanced against the relatively frequent side effects. The working mechanisms of anti-inflammatory asthma medications including ICS, LTRA, cromones, macrolides and theophylline are described.

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Supported by Karolinska Institutet, the Centre for Allergy Research and the Stockholm County Council, and the following Swedish foundations: Heart Lung Foundation, Association Against Asthma and Allergy, Consul Bergh's Foundation, Medical Research Council (projects 14X-9071 and 74X-15067), and the Foundation for Health Care Sciences and Allergy Research (Vårdal).

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

View full text

Mechanisms of asthma and allergic inflammationBronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate

Background

Objective

Methods

Results

Conclusion

Clinical implications

Section snippets

Subjects

Results

Discussion

Eur J Pharmacol

Respir Med

Lancet

Antiinflammatory action of glucocorticoids: new mechanisms for old drugs

N Engl J Med

Indirect airway challenges

Eur Respir J

Treatment of asthma with drugs modifying the leukotriene pathway

N Engl J Med

Measurement of leukotrienes in humans

Am J Respir Crit Care Med

Inhibition of eicosanoid biosynthesis by glucocorticoids in humans

Proc Natl Acad Sci U S A

In vivo and in vitro effects of glucocorticoids on arachidonic acid metabolism and monocyte function in humans

Eur Respir J

Differential effects of fluticasone proprionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion

Am Rev Respir Dis

Effect of oral prednisone on airway inflammatory mediators in atopic asthma

Am J Respir Crit Care Med

Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial

Am J Respir Crit Care Med

The effect of inhaled budesonide on the maximal degree of airway narrowing to leukotriene D4 and methacholine in normal subjects in vivo

Am Rev Respir Dis

Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics

Am J Respir Crit Care Med

The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma

Clin Exp Allergy

Effects of montelukast and budesonide on airway responses and airway inflammation in asthma

Am J Respir Crit Care Med

Mechanisms of asthma and allergic inflammation
Bronchial responsiveness to leukotriene D₄ is resistant to inhaled fluticasone propionate

Differential effects of fluticasone proprionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E₄ excretion

The effect of inhaled budesonide on the maximal degree of airway narrowing to leukotriene D₄ and methacholine in normal subjects in vivo