The Role and Contribution of Leukotrienes in Asthma

doi:10.1016/S1081-1206(10)63106-7

Annals of Allergy, Asthma & Immunology

Volume 81, Issue 1, July 1998, Pages 17-26, 29

https://doi.org/10.1016/S1081-1206(10)63106-7 Get rights and content

Learning objectives

Reading this article will reinforce the reader's knowledge of the biochemistry and pharmacology of leukotrienes (LTs), including the enzymes and cells involved in their synthesis, the receptors that mediate their biologic effects, and the evidence that cysteinyl leukotrienes (CysLT) may play an important role in asthma. The 5-lipoxygenase inhibitors, 5-lipoxygenase-activating protein antagonists, and Cys LT receptor antagonists are three classes of LTs modulators now in clinical use. The effects of these agents in clinical models of asthma induced by allergens, exercise, and aspirin and in multicenter asthma trials are reviewed.

Data sources

Key papers published in peer-reviewed journals.

Study selection

Key papers published in peer-reviewed journals.

Conclusions

The pharmacology of these new medications and experience in clinical trials suggest that they may play a therapeutic role in the treatment of asthma.

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Cited by (32)

Airway eicosanoids in acute severe respiratory syncytial virus bronchiolitis
2004, Journal of Pediatrics
We prospectively studied the levels of eicosanoids in intubated patients with severe bronchiolitis and compared them to electively intubated non-infected infants. LeukotrieneE₄ (LTE₄), leukotrieneB₄ (LTB₄), and prostaglandinE₂ (PGE₂) levels were significantly increased (P <.01) from endotracheal (ET) aspirates of infants with bronchiolitis compared with controls, as were urinary LTE₄ levels (P <.001). We conclude that eicosanoids are increased in the tracheal aspirates and urine of children with bronchiolitis.
Efficacy and safety of low-dose fluticasone propionate compared with zafirlukast in patients with persistent asthma
2002, American Journal of Medicine
Citation Excerpt :
Although the mechanism of action of inhaled corticosteroids is unknown, they do have several anti-inflammatory effects in the airways, including the inhibition of inflammatory cells and cytokines, as well as the prevention of arachidonic acid formation, which in turn inhibits the synthesis of prostaglandins (cyclooxygenase pathway) and leukotrienes (5-lipoxygenase pathway) (29–33). In contrast, the primary mechanism of action of the leukotriene modifiers (e.g., zafirlukast and zileuton) is to prevent the action of leukotrienes on cells (34). Thus, the greater improvements in efficacy observed with fluticasone compared with zafirlukast may be because of the broad range of anti-inflammatory activity of inhaled corticosteroids compared with the single-pathway mechanism of leukotriene modifiers.
To compare the efficacy and safety of fluticasone propionate and zafirlukast in patients with relatively stable persistent asthma who were previously treated with inhaled corticosteroids and short-acting β₂-agonists.
A total of 440 patients (≥12 years of age) previously treated with inhaled corticosteroids (beclomethasone dipropionate or triamcinolone acetonide) and short-acting β₂-agonists were included in this randomized double-blind study. After an 8-day run-in period, patients were treated with fluticasone (88 μg) or zafirlukast (20 mg) twice daily for 6 weeks. Outcome measures included pulmonary function (forced expiratory volume in 1 second [FEV₁], peak expiratory flow [peak flow]), albuterol use, asthma symptoms, withdrawals due to lack of efficacy, and asthma exacerbations.
Patients treated with fluticasone (n = 224) experienced greater mean increases in FEV₁ (0.24 L vs. 0.08 L, P <0.001), morning peak flow (30 L/min vs. 6 L/min, P <0.001), and evening peak flow (23 L/min vs. 5 L/min, P <0.001) during the study than did those treated with zafirlukast (n = 216). Fluticasone-treated patients had significantly greater increases in the mean percentages of symptom-free days (22% vs. 8%, P <0.001), rescue-free days (23% vs. 10%, P = 0.002), nights with uninterrupted sleep (<1% vs. –5%, P = 0.006), and fewer asthma exacerbations (1% vs. 6%, P = 0.005). Fewer fluticasone-treated patients were withdrawn due to lack of efficacy (2% vs. 13%, P <0.001).
Inhaled fluticasone was more effective than zafirlukast in maintaining or improving asthma control in patients with relatively stable asthma who were switched from low-dose inhaled corticosteroids.
Reduction of eosinophilic inflammation in the airways of patients with asthma using montelukast
2002, Chest
Leukotrienes (LTs) are involved in airway eosinophilic inflammation in patients with asthma. We examined the effects of a cysteinyl LT 1-receptor antagonist, montelukast, on sputum eosinophil levels, and the correlation between sputum eosinophils and bronchodilatation in patients with asthma.
Double-blind, randomized, crossover study.
University hospital and private hospital.
Twenty-nine patients with mild-to-moderate asthma.
Montelukast, 10 mg, and placebo tablet, once daily, each for 4 weeks.
Sputum eosinophils analyzed using hypertonic saline solution-induced sputum and airway hyperresponsiveness to histamine were evaluated before and after treatment. In addition, morning and evening peak expiratory flow (PEF), asthma symptoms, and peripheral blood eosinophil levels were assessed.
The percentage of eosinophils in sputum decreased from 24.6 ± 12.3% at baseline to 15.1 ± 11.8% after montelukast treatment, for a change of − 9.5 ± 12.7% (n = 20). During placebo administration, the percentage of eosinophils fell from 21.3 ± 12.1% to 21.0 ± 11.5%, resulting in a decrease of − 0.3 ± 10.8% (n = 20). There was a statistically significant difference in the change in sputum eosinophil levels between these two periods (p < 0.005). The number of peripheral blood eosinophils also significantly decreased after montelukast treatment (314.1 ± 237.6/mL) compared with placebo (413.1 ± 232.1/mL; p < 0.005, n = 21). Although morning and evening PEF values were significantly improved from baseline after montelukast treatment (p < 0.01, n = 20), asthma symptoms and airway responsiveness to histamine were not significantly altered. Furthermore, there was no significant correlation between the decrease in sputum eosinophils and the increase in PEF.
These results suggest that montelukast has anti-inflammatory effects on the airway in patients with asthma, and that its bronchodilatory effect is not solely dependent on a decrease in airway eosinophilia.
Understanding the pathogenesis of allergic asthma using mouse models
2001, Annals of Allergy, Asthma and Immunology
This paper reviews the current views of the pathogenesis of airway eosinophilic inflammation and airway hyperresponsiveness (AHR) in allergic asthma based on mouse models of the disease. The reader will also encounter new treatment strategies that have arisen as this knowledge is applied in practice.
MEDLINE searches were conducted with key words asthma, mouse model, and murine. Additional articles were identified from references in articles and book chapters.
Original research papers and review articles from peer-reviewed journals were chosen.
Although the mouse model does not replicate human asthma exactly, the lessons learned about the pathogenesis of allergic airway inflammation and AHR are generally applicable in humans. Type 2 T helper lymphocytes (Th2) orchestrate the inflammation and are crucial for the development of AHR. Cells and molecules involved in T cell activation (dendritic cells, T cell receptor, major histocompatibility complex molecule, and costimulatory molecules) are also vital. Besides these, no other cell or molecule could be shown to be indispensable for the establishment of the model under all experimental conditions. There are at least three pathways that lead to AHR. One is dependent on immunoglobulin E and mast cells, one on eosinophils and interleukin-5 (IL-5), and one on IL-13. Eosinophils are probably the most important effector cells of AHR. Radical methods to treat asthma have been tested in the animal model, including modifying the polarity of lymphocyte response and antagonizing IL-5.
AHR, the hallmark of asthma, is attributable to airway inflammation ultimately mediated by helper T cells via three pathways, at least. The mouse model is also a valuable testing ground for new therapies of asthma.
Lack of effect of the 5-lipoxygenase inhibitor zileuton in blocking oral aspirin challenges in aspirin-sensitive asthmatics
2000, Annals of Allergy, Asthma and Immunology
Leukotrienes (LTs) have been implicated as major mediators of aspirin-(ASA)-induced respiratory reactions. It was therefore logical to assume that an inhibitor of 5-lipoxygenase (5-LO), such as zileuton, given before and during oral challenges with ASA, might prevent ASA-induced respiratory reactions. Indeed, in prior studies, pretreatment of ASA-sensitive respiratory disease patients with leukotriene modifiers eliminated or attenuated respiratory reactions upon re-challenge with the previously established provoking dose of ASA. However, doses higher than the provoking doses were not administered during these reported studies.
We wished to determine whether zileuton pretreatment could prevent ASA-induced respiratory reactions in our six volunteers with aspirin-sensitive respiratory disease when ASA challenge doses were started below the usual provoking dose of 60 mg and then increased until a respiratory reaction occurred.
Aspirin sensitivity was established previously in all six patients during a prior ASA oral challenge. In this study, pretreatment with zileuton 600 mg qid was initiated 7 days prior to, and continued during oral ASA challenges. Patients underwent single-blind oral ASA challenges with escalating doses of ASA, every 3 hours, according to our standard protocol.
All six patients reacted to doses of ASA between 45 and 325 mg. Four patients experienced bronchospasm (FEV₁ declined 19% to 53%) while receiving zileuton. All six had naso-ocular reactions. Concentrations of urine LTE₄ also increased significantly (mean 334 pg/mg Cr at baseline, increasing to 1024 pg/mg Cr at respiratory reactions).
During ASA challenges, zileuton, in standard doses of 600 mg qid was associated with increased synthesis of LTs in five of six patients and nasoocular reactions in all six patients, as well as bronchospasm in four patients.
Montelulkast adult (10-mg film-coated tablet) and pediatric (5-mg chewable tablet) dose selections
2000, Journal of Allergy and Clinical Immunology
Montelukast is a selective leukotriene receptor antagonist that has been shown to be effective in the treatment of chronic asthma. It is approved in more than 70 countries for patients 6 years of age and older. For adults (≥15 years of age), a 10-mg film-coated tablet (FCT) is available, and for children (aged 6 to 14 years), a 5-mg chewable tablet (CT) is available. The adult montelukast dose (10-mg FCT) was selected on the basis of classic dose-ranging studies as the lowest dose that produces maximal improvement in both measures of airway function and patient-reported outcomes in chronic asthma and in the attenuation of exercise-induced bronchoconstriction. The strategy used for the pediatric dose selection for montelukast was based on the determination of a CT dose that would provide an overall systemic exposure to montelukast in children similar to that in adults who receive a 10-mg FCT dose. Because montelukast was to be given chronically for the treatment of asthma, the area under the plasma concentration-time curve was considered to be the pharmacokinetic measurement that best represented systemic exposure to the drug. A 5-mg CT yielded a comparable single-dose area under the plasma concentration-time curve profile to that of the adult 10-mg FCT dose and, therefore, was selected as the pediatric dose for children aged 6 to 14 years with asthma. Subsequently, 2 studies of efficacy and tolerability validated the choice of the 5-mg CT dose. (J Allergy Clin Immunol 2000;106:S171-8.)

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REVIEW ARTICLEThe Role and Contribution of Leukotrienes in Asthma

Learning objectives

Data sources

Study selection

Conclusions

J Biol Chem

Biochem Biophys Res Comm

J Biol Chem

J Biol Chem

J Biol Chem

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Clin Ther

J Allergy Clin Immunol

J Allergy Clin Immunol

Leukotriene C, a slow reacting substance (SRS) from mouse mastocytoma cells

Proc Nat Acad Sci USA

Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis

Nature

Leukotrienes and lipoxis: structures, biosynthesis and biological effects

Science

Molecular cloning and expression of human leukotriene C4 synthase

Adv Prost Throm Leuko Res

Prostanoid and leukotriene receptors: a progress report from the IUPHAR working parties on classification and nomenclature

Adv Prost Throm Leuko Res

Leukotriene C4 production by murine mast cells: evidence of a role for extracellular leukotriene A4

Proc Natl Acad Sci USA

Generation of leukotrienes by purified human lung mast cells

J Clin Invest

Co-culture of human lung-derived mast cells with mouse 3T3 fibroblasts: morphology and IgE-mediated release of histamine, prostaglandin D2, and leukotrienes

J Immunol

Leukotriene generation by eosinophils

J Exp Med

Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4

Proc Natl Acad Sci USA

Release of leukotrienes by human monocytes on stimulation of their phagocytic receptor for particulate activators

J Immunol

Propagation and characterization of human blood basophils

Int Arch Allergy Appl Immunol

Detection of leukotrienes B4, C4 and their isomers in arterial mixed venous blood and bronchoalveolar lavage fluid from ARDS patients

Intensive Care Med

Comparative actions of inhaled leukotriene C4, leukotriene D4 and histamine in normal human subjects

Thorax

The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock

J Physiol

Slow-reacting substances, leukotriene C4 and D4, increase the release of mucus from human airways in vitro

Am Rev Respir Dis

Eosinophilic inflammation in asthma

N Engl J Med

The role of eosinophils in the patho-physiology of asthma

Ann NY Acad Sci

Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro

J Leuko Biol

REVIEW ARTICLE
The Role and Contribution of Leukotrienes in Asthma

Molecular cloning and expression of human leukotriene C₄ synthase

Leukotriene C₄ production by murine mast cells: evidence of a role for extracellular leukotriene A₄

Co-culture of human lung-derived mast cells with mouse 3T3 fibroblasts: morphology and IgE-mediated release of histamine, prostaglandin D₂, and leukotrienes

Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C₄

Detection of leukotrienes B₄, C₄ and their isomers in arterial mixed venous blood and bronchoalveolar lavage fluid from ARDS patients

Comparative actions of inhaled leukotriene C₄, leukotriene D₄ and histamine in normal human subjects

Slow-reacting substances, leukotriene C₄ and D₄, increase the release of mucus from human airways in vitro

Comparison of leukotriene B₄ and D₄ effects on human eosinophil and neutrophil motility in vitro