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1.  Cysteinyl leukotriene receptor antagonist regulates allergic airway inflammation in an organ- and cytokine-specific manner 
Background
Cysteinyl leukotrienes (cys-LTs) are very important factors in the pathophysiology of bronchial asthma. Cys-LT receptor antagonists (LTRAs) decrease allergic airway inflammation. The aim of the present study was to determine the differential effects of LTRAs and corticosteroids on allergic airway inflammation and allergen-specific cytokine production from lymphoid tissues using a murine model of asthma.
Material/Methods
Four groups of female BALB/c mice [control (Cont); Dermatophagoides farinae allergen-sensitized (AS); pranlukast (Prl), an LTRA-treated AS; and dexamethasone (Dex)-treated AS] were examined. Lung pathology and cytokine production by prepared mononuclear cells isolated from mediastinal lymph nodes (MLNs) and spleen were compared among these groups.
Results
AS mice exhibited allergic airway inflammation and significant increases in allergen-specific Th1 and Th2 cytokines in MLNs and spleen. Prl-treated mice showed significant attenuation of allergic airway inflammation concomitant with reduction of Th2 cytokines and IFN-γ in MLNs but not in spleen. In contrast, Dex significantly decreased Th1 and Th2 cytokines in MLNs and also decreased them (except IL-13 and IL-2) in spleen.
Conclusions
The inflammatory effects of cys-LTs could differ in lymphoid organs. LTRAs potentially regulate allergic airway inflammation in an organ- and cytokine-specific manner, while systemic corticosteroid shows nonspecific effects.
doi:10.12659/MSM.889865
PMCID: PMC3937047  PMID: 24561545
Leukotriene Antagonists; Lymphoid Tissue; Pranlukast; Asthma
2.  Leukotriene-receptor antagonists. Role in asthma management. 
Canadian Family Physician  2000;46:872-879.
OBJECTIVE: To examine the role of leukotriene-receptor antagonists (LTRAs) in management of asthma. QUALITY OF EVIDENCE: Most data were derived from randomized, double-blind, controlled trials. MAIN MESSAGE: Leukotrienes appear to have an important role in the pathophysiology of asthma, including airway inflammation. Leukotriene-receptor antagonists are effective in improving asthma control end points, such as allergen, ASA, and exercise challenge, in clinical models of asthma. In chronic asthma, LTRA administration reduces asthma symptoms and rescue beta 2-agonist use, changes that are paralleled by improvements in lung function. Both zafirlukast and montelukast decrease circulating levels of eosinophils and could have other useful anti-inflammatory properties. Administration of LTRAs allows doses of inhaled corticosteroids to be reduced. Currently available LTRAs are free of serious side effects and are available as oral formulations. CONCLUSIONS: Leukotriene-receptor antagonists belong to a new class of asthma medication. While inhaled corticosteroids remain first-line therapy for managing chronic asthma, LTRAs should be considered for patients with ASA-sensitive asthma; as adjunct therapy when low to moderate doses of inhaled steroid alone provide incomplete control; or as adjunct therapy to allow reduction in doses of inhaled corticosteroids.
PMCID: PMC2144811  PMID: 10790819
3.  Concentration dependent non-CysLT1 receptor mediated inhibitory activity of leukotriene receptor antagonists 
Background:
The use of leukotriene antagonists (LTRAs) for asthma therapy has been associated with a significant degree of inter-patient variability in response to treatment. Some of that variability may be attributable to non-cysteinyl leukotriene type 1 receptor (CysLT1) mediated inhibitory mechanisms that have been demonstrated for this group of drugs.
Objective:
We have used a model of CysLT1 signaling in human monocytes to characterize CysLT1-dependent and CysLT1-independent anti-inflammatory activity of two chemically different, clinically relevant, LTRAs (montelukast and zafirlukast).
Results:
Using receptor desensitization experiments in monocytes and CysLT1 transfected HEK293 cells, and IL-10 and CysLT1 siRNA induced downregulation of CysLT1 expression, we showed that reported CysLT1 agonists, LTD4 and uridine diphosphate (UDP), signal through calcium mobilization, acting on separate receptors and that both pathways were inhibited by montelukast and zafirlukast. However, 3 logs higher concentrations of LTRAs were required for inhibition of UDP induced signaling. In monocytes, UDP, but not LTD4, induced IL-8 production that was significantly inhibited by both drugs at micromolar concentrations. Both LTRAs, at low micromolar concentrations, also inhibited calcium ionophore induced leukotriene (LTB4 and LTC4) production, indicating 5-lipoxygenase inhibitory activities.
Conclusion:
We report here that montelukast and zafirlukast, acting in a concentration dependent manner, can inhibit non-CysLT1 mediated, proinflammatory reactions, suggesting activities potentially relevant for inter-patient variability in response to treatment. Higher doses of currently known LTRAs or new compounds derived from this class of drugs may represent a new strategy for finding more efficient therapy for bronchial asthma.
doi:10.4049/jimmunol.0900071
PMCID: PMC2826199  PMID: 20083671
bronchial asthma; leukotrienes; leukotriene antagonists; monocytes; UDP
4.  Dectin-2 Recognition of House Dust Mite Triggers Cysteinyl Leukotriene Generation by Dendritic Cells1 
House dust mites are a significant source of airborne allergen worldwide, but there is little understanding of how they so potently generate allergic inflammation. We found that extracts from the house dust mites Dermatophagoides farinae (Df) and Dermatophagoides pteronyssinus and from the mold Aspergillus fumigatus stimulated a rapid and robust production of cysteinyl leukotrienes (cys-LTs), proinflammatory lipid mediators, from mouse bone marrow-derived dendritic cells (BMDCs). Con A affinity chromatography of the Df extract revealed that the relevant ligand is a glycan(s), suggesting stimulation via a dendritic cell (DC) lectin receptor. Cys-LT production in BMDCs from wild-type mice was inhibited by spleen tyrosine kinase (Syk) inhibitors and was abolished in BMDCs from FcRγ−/− mice, implicating either Dectin-2 or DC immunoactivating receptor. Transfection of each receptor in bone marrow-derived mast cells revealed that only Dectin-2 mediates cys-LT production by Df, Dermatophagoides pteronyssinus, and Aspergillus fumigatus. Lentiviral knockdown of Dectin-2 in BMDCs attenuated Df extract-elicited cys-LT generation, thereby identifying Dectin-2 as the receptor. Lung CD11c+ cells, but not peritoneal or alveolar macrophages, also generated cys-LTs in response to Df. These findings place Dectin-2 among the C-type lectin receptors that activate arachidonic acid metabolism and identify the Dectin-2/FcRγ/Syk/cys-LT axis as a novel mechanism by which three potent indoor allergens may activate innate immune cells to promote allergic inflammation.
PMCID: PMC3682801  PMID: 19124755
5.  Montelukast during Primary Infection Prevents Airway Hyperresponsiveness and Inflammation after Reinfection with Respiratory Syncytial Virus 
Rationale: Respiratory syncytial virus (RSV) bronchiolitis in infants may be followed by the development of asthma-like symptoms. Age at first infection dictates consequences upon reinfection. Reinfection of mice initially exposed as neonates to RSV enhanced development of airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus hyperproduction. RSV lower respiratory tract disease is associated with activation of the leukotriene pathway.
Objectives: To determine the effects of montelukast (MK), a cysteinyl leukotriene (cysLT) receptor antagonist, in primary and secondary RSV-infected newborn and adult mice.
Methods: BALB/c mice were infected with RSV at 1 week (neonate) or 6 to 8 weeks (adult) of age and reinfected 5 weeks later. MK was administered 1 day before the initial infection and through Day 6 after infection. Seven days after primary or secondary infection, airway function was assessed by lung resistance to increasing doses of inhaled methacholine; lung inflammation, goblet cell metaplasia, and cytokine levels in bronchoalveolar lavage fluid were monitored.
Measurements and Main Results: RSV infection induced cysLT release in bronchoalveolar lavage fluid. MK decreased RSV-induced AHR, airway inflammation, and increased IFN-γ production in primary infected adult and neonatal mice. MK, administered during initial infection of neonates but not during secondary infection, prevented subsequent enhancement of AHR, airway eosinophilia, and mucus hyperproduction upon reinfection.
Conclusions: MK attenuated the initial responses to primary RSV infection in both age groups and altered the consequences of RSV reinfection in mice initially infected as neonates. These data support an important role for cysLT in RSV-induced AHR and inflammation.
doi:10.1164/rccm.200912-1811OC
PMCID: PMC2937239  PMID: 20442434
airway; inflammation; RSV; cysteinyl leukotrienes
6.  Montelukast: its role in the treatment of childhood asthma 
The cysteinyl leukotrienes, LTC4, LTD4, and LTE4, play an integral role in the pathophysiology of asthma. Acting via the type 1 leukotriene (CysLT1) receptor, these proinflammatory mediators have numerous effects in the lungs, including decreased activity of respiratory cilia, increased mucus secretion, increased venopermeability, and promotion of eosinophil migration into airway mucosa. Blocking studies show that Cys-LTs are pivotal mediators in the pathophysiology of asthma. Cys-LTs are key components in the early and late allergic airway response and also contribute to bronchial obstruction after exercise and hyperventilation of cold, dry air in asthmatics. Effects of the cysteinyl leukotrienes are blocked by leukotriene receptor antagonists; these agents inhibit bronchoconstriction in normal subjects provoked with inhaled cysteinyl leukotrienes, as well as in patients with asthma undergoing allergen, exercise, cold air, or aspirin challenge. Montelukast is a potent and selective blocker of the CysLT1 receptor. For treatment of chronic asthma, montelukast is administered once daily to adults as a 10-mg film-coated tablet, to children aged 6–14 years as a 5-mg chewable tablet, and to children aged 2–5 years as a 4-mg chewable tablet form. Given their efficacy, antiinflammatory activity, oral administration, and safety, leukotriene modifiers will play an important role in the treatment of asthmatic children.
PMCID: PMC2376066  PMID: 18473012
montelukast; asthma; children; efficacy
7.  GPR17 Regulates Immune Pulmonary Inflammation Induced By House Dust Mite 
Antagonists of the type 1 cysteinyl leukotriene receptor (CysLT1R) are efficacious for bronchoconstriction in humans with bronchial asthma; however, the clinical response to these drugs is heterogeneous. In particular, how CysLT1R expression and function are constitutively regulated in vivo is not known. Here we show that a 7-transmembrane receptor GPR17 negatively regulates the CysLT1R-mediated inflammatory cell accumulation in the bronchoalveolar lavage fluid and lung, the levels of IgE and specific IgG1 in serum, and Th2/Th17 cytokine expression in the lung after intranasal sensitization and challenge with house dust mite (Df) in mice. Sensitization of naïve wild-type recipients with Df-pulsed bone marrow-derived dendritic cells (BMDCs) of each genotype or sensitization of each genotype with Df-pulsed wild-type BMDCs and Df challenge revealed markedly increased pulmonary inflammatory and serum IgE responses for GPR17-deficient mice as compared to wild-type mice and reduced responses in the genotypes lacking CysLT1R. These findings reveal a constitutive negative regulation of CysLT1R functions by GPR17 in both the antigen presentation and downstream phases of allergic pulmonary inflammation.
doi:10.4049/jimmunol.1001131
PMCID: PMC4014011  PMID: 20574000
Knockout Mice; Lipid Mediators; Allergy; Inflammation; Lung
8.  Effects of Leukotriene Receptor Antagonists on Peripheral Eosinophil Counts and Serum IgE Levels in Children with Food Allergy 
Drugs in R&d  2012;10(3):147-154.
Background: Although the efficacy of leukotriene receptor antagonists (LTRAs) for bronchial asthma is already established, their effect on food allergy remains unclear.
Objective: To investigate the efficacy of LTRAs in children with food allergy. Methods: This retrospective study examined 65 children with food allergy who were aged between 3 and 36 months (mean 14±9.6 months) from 2005 to 2008. Thirty-two children were treated as a dietary control group by avoiding any antigenic foods to which they had previously experienced adverse reactions. The remaining 33 children, designated the LTRA group, were treated with pranlukast (7mg/kg bodyweight/day) in addition to maintaining dietary control. Clinical symptoms and laboratory data before and after 1 year of treatment were compared between the groups.
Results: Allergic symptoms improved in both the dietary controlled and LTRA groups, and there was no significant difference observed in the clinical parameters examined between the groups after the 1-year trial. Peripheral eosin-ophil count, serum IgE, interleukin (IL)-4, IL-5, IL-6, and eosinophil cationic protein (ECP) levels in children with food allergy were above standardized values in both groups. Although both the dietary controlled and LTRA groups showed a decreased eosinophil count (−273 ± 232 vs -595 ± 295/μL; p < 0.05 and p < 0.001, respectively), only children treated with LTRA showed a significant decrease in serum IgE (-73.5 ± 115 IU/mL; p < 0.01); conversely, the control group exhibited a significant increase in serum IgE (+159 ± 138 IU/mL; p < 0.01). Furthermore, the LTRA group also showed a significant decrease in serum IL-4 (54.5 ± 31.0 to 27.3 ± 10.1 pg/mL), IL-5 (6.7 ± 5.2 to 5.0 ± 0.4 pg/mL), and ECP (45.4 ± 15.0 to 15.0 ± 9.8 μg/L) levels (p < 0.05 for each).
Conclusion: Early intervention with LTRAs may be effective in regulating eosinophil count and serum IgE, IL-4, IL-5, and ECP levels. These data support the potential effectiveness of LTRAs in young children with food allergy to prevent further allergic development.
doi:10.2165/11586150-000000000-00000
PMCID: PMC3586155  PMID: 20945945
9.  Combination Therapy with a Long-Acting β-Agonist and a Leukotriene Antagonist in Moderate Asthma 
Rationale: Long-acting β-agonists (LABAs) and inhaled corticosteroids administered together appear to be complementary in terms of effects on asthma control. The elements of asthma control achieved by LABAs (improved lung function) and leukotriene receptor antagonists (LTRAs; protection against exacerbations) may be complementary as well.
Objective: We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma.
Methods and Measurements: In a randomized, placebo-controlled, crossover study of 192 subjects with moderate asthma, we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma. The primary efficacy outcome was time to treatment failure.
Main Results: Three months after the randomization of the last subject, the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial. The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures (p = 0.0008), lung function (26 L/min difference in a.m. peak expiratory flow rate, p = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity.
Conclusions: Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA.
doi:10.1164/rccm.200601-112OC
PMCID: PMC1899264  PMID: 16973987
combination therapy; leukotriene; beta-agonists; inhaled corticosteroids
10.  Introduction of leukotriene receptor antagonists in Manitoba 
Patient characteristics and prescribing patterns during the introduction of leukotriene receptor antagonists (LTRA) in Manitoba are described using the provincial health database. Residents of Manitoba with asthma, chronic obstructive pulmonary disease, bronchitis or claims for respiratory medications were identified. Six thousand forty-one of 160,626 (3.8%) patients received LTRA; the likelihood of receiving LTRA increased if a patient was younger than 15 years, lived in a rural locale, had asthma, had frequent physician visits or used inhaled corticosteroids. Subsequent prescriptions (68%) were associated with the number of physician visits and inhaled corticosteroid use, which were thought to be indexes of severity. Patients, especially children, who received more than five prescriptions showed evidence of increased asthma control, but there was little evidence of benefit in less selected patient groups due, at least in part, to poor compliance with all respiratory drugs.
PMCID: PMC2539010  PMID: 16550267
Asthma; Inhaled corticosteroids; Leukotriene receptor antagonists; Population-based
11.  Retrospective cohort study of leukotriene receptor antagonist therapy for preventing upper respiratory infection-induced acute asthma exacerbations 
Allergy & Rhinology  2013;4(3):e127-e131.
Upper respiratory tract infections (URIs) represent the most frequent cause of acute asthma exacerbations. It has yet to be determined whether leukotriene receptor antagonist (LTRA) treatment prevents URI-induced acute asthma exacerbations in adults. The objective of the present study was to evaluate the preventive effects of LTRA treatment on URI-induced acute asthma exacerbations. The incidences of URI alone, acute asthma exacerbation without URI, and URI-induced acute asthma exacerbation were determined retrospectively by analyzing diary and medical records of 321 adult asthmatic patients (mean age, 56.3 ± 17.2 years; male/female ratio, 117:204) over 1 year. Results were compared between patients who had been taking an LTRA (n = 137) and those who had never taken any LTRA (n = 184) during the study periods. Significantly fewer URIs alone and acute asthma exacerbations without URI occurred in patients with than in those without prophylactic daily use of LTRA. LTRA treatment significantly reduced the durations of URIs alone and of total acute asthma exacerbations, as well as the incidence of mild exacerbations of asthma. In contrast, in patients with URI-induced acute asthma exacerbations, LTRA treatment failed to significantly reduce the interval between URI onset and acute asthma exacerbation, as well as the duration and severity of both URIs and acute asthma exacerbations. Use of an LTRA for adult asthmatic patients appears to reduce the incidences of URIs alone and acute asthma exacerbations without URI, but it failed to prevent URI-induced acute asthma exacerbations once a URI occurred.
doi:10.2500/ar.2013.4.0062
PMCID: PMC3911801  PMID: 24498517
Acute asthma exacerbation; bronchial asthma; inhaled corticosteroids; inhaled long-acting beta2-agonist; leukotriene receptor antagonist; montelukast; pranlukast; retrospective cohort study; short-acting beta2-agonist; upper respiratory tract infection
12.  Pranlukast prevents cysteinyl leukotriene-induced emesis in the least shrew (Cryptotis parva) 
European journal of pharmacology  2009;628(1-3):195.
Many chemotherapeutic agents activate multiple signaling systems, including potentially emetogenic arachidonic acid metabolites. Of these messengers, the emetic role of the leukotriene family has been neglected. The aims of this study were to test the emetic potential of key leukotrienes (LTA4, LTB4, LTF4, and the cysteinyl leukotrienes LTC4, LTD4 and LTE4), and to investigate whether the leukotriene CysLT1 receptor antagonist pranlukast or mixed leukotriene CysLT1/2 receptor antagonist Bay u9773 can prevent the LTC4 induced emesis. Least shrews were injected with varying doses of one of the six tested leukotrienes and vomiting parameters measured for 30 minutes. LTC4 and LTD4 were most efficacious, and significantly increased both the frequency and percentage of animals vomiting at doses from 0.1 and 0.05 mg/kg, respectively. The other tested leukotrienes were either weakly emetic or ineffective at doses up to 4 mg/kg. The relative emetogenic activities of the cysteinyl leukotrienes (LTC4=LTD4>LTE4) suggest leukotriene CysLT2 receptors have a key role in emesis. However, pranlukast dose-dependently, and at 10 mg/kg completely, blocked LTC4-induced vomiting, implicating a leukotriene CysLT1 receptor-mediated emetic effect. Bay u9773 dose-dependently reduced the percentage of animals vomiting, but did not significantly reduce vomiting frequency. Fos immunoreactivity, measured subsequent to LTC4-induced vomiting to define its putative anatomical substrates, was significantly increased in the enteric nervous system and medullary dorsal vagal complex following LTC4 (P < 0.05) versus vehicle injections. This study is the first to show that some leukotrienes induce emesis, possibly involving both central and peripheral leukotriene CysLT1 and/or leukotriene CysLT2 receptors.
doi:10.1016/j.ejphar.2009.11.030
PMCID: PMC2818547  PMID: 19941848
Leukotriene A4; Leukotriene B4; Fos; Dorsal vagal complex; Enteric nervous system
13.  Protection of leukotriene receptor antagonist against aspirin-induced bronchospasm in asthmatics 
Purpose
Leukotriene receptor antagonists (LTRAs) are used to treat aspirin-intolerant asthma (AIA); however, the protective effects of long-term LTRA administration against aspirin-induced bronchospasm have not been evaluated.
Objectives
We investigated the efficacy of a 12-week treatment with a LTRA in protecting against aspirin-induced asthma in AIA patients.
Methods
Fifty-two adult patients with AIA underwent an aspirin challenge test just before administration of montelukast (10 mg/day) and just after 12 weeks of treatment. The protective effect was assessed as the disappearance of aspirin-induced bronchospasm after 12 weeks of treatment. The results were compared according to the patients' clinical and physiological parameters.
Results
The decline in FEV1 following aspirin challenge was significantly reduced from 28.6±1.9% to 10.2±1.7% (P=0.0001) after 12 weeks of montelukast treatment. However, 14 subjects (30%) still showed a positive response (>15% decline in FEV1) to aspirin challenge. Grouping the subjects into good and poor responders according to post-treatment responses revealed that the pretreatment aspirin-induced FEV1 decline was significantly greater in the poor responders and that the triggering dose of aspirin and the induction time for a positive response were lower and shorter, respectively, in the poor responders. Histories of aspirin hypersensitivity and sinusitis were more prevalent among the poor responders than among the good responders.
Conclusions
Twelve weeks of treatment with montelukast protected against aspirin-induced bronchospasm in 70% of the AIA cases. A poor response was associated with more severe aspirin-induced bronchospasms before treatment and a history of aspirin hypersensitivity or sinusitis.
Clinical implications
A severe response to aspirin challenge may be a predictor of poor responsiveness to leukotriene antagonist treatment.
doi:10.4168/aair.2010.2.1.48
PMCID: PMC2831603  PMID: 20224678
Asthma; leukotriene antagonists; aspirin; eosinophils
14.  Reversal of Allergen-induced Airway Remodeling by CysLT1 Receptor Blockade 
Rationale: Airway inflammation in asthma is accompanied by structural changes, including goblet cell metaplasia, smooth muscle cell layer thickening, and subepithelial fibrosis. This allergen-induced airway remodeling can be replicated in a mouse asthma model.
Objectives: The study goal was to determine whether established airway remodeling in a mouse asthma model is reversible by administration of the cysteinyl leukotriene (CysLT)1 receptor antagonist montelukast, the corticosteroid dexamethasone, or the combination montelukast + dexamethasone.
Methods: BALB/c mice, sensitized by intraperitoneal ovalbumin (OVA) as allergen, received intranasal OVA periodically Days 14–73 and montelukast or dexamethasone or placebo from Days 73–163.
Measurements and Main Results: Allergen-induced trafficking of eosinophils into the bronchoalveolar lavage fluid and lung interstitium and airway goblet cell metaplasia, smooth muscle cell layer thickening, and subepithelial fibrosis present on Day 73 persisted at Day 163, 3 mo after the last allergen challenge. Airway hyperreactivity to methacholine observed on Day 73 in OVA-treated mice was absent on Day 163. In OVA-treated mice, airway eosinophil infiltration and goblet cell metaplasia were reduced by either montelukast or dexamethasone alone. Montelukast, but not dexamethasone, reversed the established increase in airway smooth muscle mass and subepithelial collagen deposition. By immunocytochemistry, CysLT1 receptor expression was significantly increased in airway smooth muscle cells in allergen-treated mice compared with saline-treated controls and was reduced by montelukast, but not dexamethasone, administration.
Conclusions: These data indicate that established airway smooth muscle cell layer thickening and subepithelial fibrosis, key allergen-induced airway structural changes not modulated by corticosteroids, are reversible by CysLT1 receptor blockade therapy.
doi:10.1164/rccm.200501-088OC
PMCID: PMC2662952  PMID: 16387808
eosinophils; fibrosis; mucus; smooth muscle
15.  Cysteinyl Leukotriene 2 Receptor on Dendritic Cells Negatively Regulates Ligand-Dependent Allergic Pulmonary Inflammation 
Cysteinyl leukotrienes (cys-LTs) can mediate Th2 immunity to the house dust mite, Dermatophagoides farinae (Df), via the type 1 receptor CysLT1R on dendritic cells (DCs). However, the role of the homologous type 2 receptor CysLT2R in Th2 immunity is unknown. Df sensitization and challenge of CysLT2R-deficient mice showed a marked augmentation of eosinophilic pulmonary inflammation, serum IgE, and Th2 cytokines. Wild-type (WT) mice sensitized by adoptive transfer of Df-pulsed CysLT2R-deficient bone marrow-derived DCs (BMDCs) also had a marked increase in Df-elicited eosinophilic lung inflammation and Th2 cytokines in restimulated hilar nodes. This response was absent in mice sensitized with Df-pulsed BMDCs lacking leukotriene C4 synthase (LTC4S), CysLT1R, or both CysLT2R/LTC4S, suggesting that CysLT2R negatively regulates LTC4S- and CysLT1R-dependent DC-mediated sensitization. CysLT2R-deficient BMDCs had increased CysLT1R-dependent LTD4-induced ERK phosphorylation, whereas N-methyl LTC4 activation of CysLT2R on WT BMDCs reduced such signaling. Activation of endogenously expressed CysLT1R and CysLT2R occurred over an equimolar range of LTD4 and N-methyl LTC4, respectively. Although the baseline expression of cell surface CysLT1R was not increased on CysLT2R-deficient BMDCs, it was upregulated at 24 h by a pulse of Df, as compared to WT or CysLT2R/LTC4S-deficient BMDCs. Importantly, treatment with N-methyl LTC4 reduced Df-induced CysLT1R expression on WT BMDCs. Thus, CysLT2R negatively regulates the development of cys-LT-dependent Th2 pulmonary inflammation by inhibiting both CysLT1R signaling and Df-induced LTC4S-dependent cell surface expression of CysLT1R on DCs. Furthermore, these studies highlight how the biologic activity of cys-LTs can be tightly regulated by competition between these endogenously expressed receptors.
doi:10.4049/jimmunol.1201865
PMCID: PMC3478400  PMID: 23002438
Knockout mouse; Lipid mediator; G protein-coupled receptor; Asthma; Lung
16.  The linkage between Churg-Strauss syndrome and leukotriene receptor antagonists: fact or fiction? 
Epidemiologic evidence has shown that the worldwide prevalence of asthma is increasing. The leukotriene receptor antagonists (LTRAs) represent a new class of therapy for asthma. They have been developed in the last decade and play a pivotal steroid-sparing role in treating the inflammatory component of asthma. Consequently, reports of Churg-Strauss syndrome (CSS), a rare form of systemic vasculitis, have been recognized as a potential side effect in individuals with moderate to severe asthma on LTRA therapy. The serious nature of this disorder is worthy of prompt recognition by clinicians and aggressive therapy to avoid the subsequent longstanding effects of vasculitis. To validate the postulated linkage between the LTRAs and CSS, this review comprehensively evaluates reported cases in the literature and supports a pathophysiological relationship between the LTRAs and the development of CSS.
PMCID: PMC1661620  PMID: 18360552
asthma; Churg-Strauss syndrome; leukotrienes; leukotriene receptor antagonists; montelukast; zafirlukast
17.  A Novel 5-Lipoxygenase-Activating Protein Inhibitor, AM679, Reduces Inflammation in the Respiratory Syncytial Virus-Infected Mouse Eye▿  
Clinical and Vaccine Immunology : CVI  2009;16(11):1654-1659.
Respiratory syncytial virus (RSV) is an important cause of viral respiratory disease in children, and RSV bronchiolitis has been associated with the development of asthma in childhood. RSV spreads from the eye and nose to the human respiratory tract. Correlative studies of humans and direct infection studies of BALB/c mice have established the eye as a significant pathway of entry of RSV to the lung. At the same time, RSV infection of the eye produces symptoms resembling allergic conjunctivitis. Cysteinyl leukotrienes (CysLTs) are known promoters of allergy and inflammation, and the first step in their biogenesis from arachidonic acid is catalyzed by 5-lipoxygenase (5-LO) in concert with the 5-LO-activating protein (FLAP). We have recently developed a novel compound, AM679, which is a topically applied and potent inhibitor of FLAP. Here we show with the BALB/c mouse eye RSV infection model that AM679 markedly reduced the RSV-driven ocular pathology as well as the synthesis of CysLTs in the eye. In addition, AM679 decreased the production of the Th2 cell cytokine interleukin-4 but did not increase the viral load in the eye or the lung. These results suggest that FLAP inhibitors may be therapeutic for RSV-driven eye disease and possibly other inflammatory eye indications.
doi:10.1128/CVI.00220-09
PMCID: PMC2772391  PMID: 19759251
18.  Cysteinyl Leukotriene Receptor-1 Antagonists as Modulators of Innate Immune Cell Function 
Journal of Immunology Research  2014;2014:608930.
Cysteinyl leukotrienes (cysLTs) are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and monocytes/macrophages. Notwithstanding potent bronchoconstrictor activity, cysLTs are also proinflammatory consequent to their autocrine and paracrine interactions with G-protein-coupled receptors expressed not only on the aforementioned cell types, but also on Th2 lymphocytes, as well as structural cells, and to a lesser extent neutrophils and CD8+ cells. Recognition of the involvement of cysLTs in the immunopathogenesis of various types of acute and chronic inflammatory disorders, especially bronchial asthma, prompted the development of selective cysLT receptor-1 (cysLTR1) antagonists, specifically montelukast, pranlukast, and zafirlukast. More recently these agents have also been reported to possess secondary anti-inflammatory activities, distinct from cysLTR1 antagonism, which appear to be particularly effective in targeting neutrophils and monocytes/macrophages. Underlying mechanisms include interference with cyclic nucleotide phosphodiesterases, 5′-lipoxygenase, and the proinflammatory transcription factor, nuclear factor kappa B. These and other secondary anti-inflammatory mechanisms of the commonly used cysLTR1 antagonists are the major focus of the current review, which also includes a comparison of the anti-inflammatory effects of montelukast, pranlukast, and zafirlukast on human neutrophils in vitro, as well as an overview of both the current clinical applications of these agents and potential future applications based on preclinical and early clinical studies.
doi:10.1155/2014/608930
PMCID: PMC4058211  PMID: 24971371
19.  A randomized, double-blind, placebo-controlled trial of oral montelukast in acute asthma exacerbation 
Background
Leukotriene receptor antagonists (LTRAs) are well established in the management of outpatient asthma. However, there is very little information as to their role in acute asthma exacerbations. We hypothesized that LTRAs may accelerate lung function recovery when given in an acute exacerbation.
Methods
A randomized, double blind, placebo-controlled trial was conducted at the Aga Khan University Hospital to assess the efficacy of oral montelukast on patients of 16 years of age and above who were hospitalized with acute asthma exacerbation. The patients were given either montelukast or placebo along with standard therapy throughout the hospital stay for acute asthma. Improvements in lung function and duration of hospital stay were monitored.
Results
100 patients were randomized; their mean age was 52 years (SD +/− 18.50). The majority were females (79%) and non-smokers (89%). The mean hospital stay was 3.70 ± 1.93 days with 80% of patients discharged in 3 days. There was no significant difference in clinical symptoms, PEF over the course of hospital stay (p = 0.20 at day 2 and p = 0.47 at day 3) and discharge (p = 0.15), FEV1 at discharge (p = 0.29) or length of hospital stay (p = 0.90) between the two groups. No serious adverse effects were noted during the course of the study.
Conclusion
Our study suggests that there is no benefit of addition of oral montelukast over conventional treatment in the management of acute asthma attack.
Trial registration
Trial registration number: 375-Med/ERC-04
doi:10.1186/1471-2466-13-20
PMCID: PMC3616955  PMID: 23537391
Asthma attack; Leukotriene receptor antagonist; Montelukast; PEF; FEV1
20.  Montelukast versus inhaled corticosteroids in the management of pediatric mild persistent asthma 
International guidelines recommend the use of inhaled corticosteroids (ICSs) as the preferred therapy, with leukotriene receptor antagonists (LTRAs) as an alternative, for the management of persistent asthma in children. Montelukast (MLK) is the first LTRA approved by the Food and Drug Administration for the use in young asthmatic children.
Therefore, we performed an analysis of studies that compared the efficacy of MLK versus ICSs. We considered eligible for the inclusion randomized, controlled trials on pediatric populations with Jadad score > 3, with at least 4 weeks of treatment with MLK compared with ICS.
Although it is important to recognize that ICSs use is currently the recommended first-line treatment for asthmatic children, MLK can have consistent benefits in controlling asthmatic symptoms and may be an alternative in children unable to use ICSs or suffering from poor growth. On the contrary, low pulmonary function and/or high allergic inflammatory markers require the corticosteroid use.
doi:10.1186/2049-6958-7-13
PMCID: PMC3436659  PMID: 22958412
Childhood asthma; Inhaled corticosteroids; Leukotriene receptor antagonist; Montelukast
21.  Effects of Montelukast on free radical production in whole blood and isolated human polymorphonuclear neutrophils (PMNs) in asthmatic children 
Montelukast is a highly selective leukotriene-receptor antagonist (LTRA). It is widely used in the treatment of bronchial asthma, primarily as an adjunct to corticosteroids. Reactive oxygen species (ROSs) play an important role in the pathogenesis of asthma and oxidative stress contributing to the initiation and worsening of inflammatory respiratory disorders, such as asthma. Antioxidant drugs may have a role in minimizing or preventing damage in asthmatic children. The aim of this study was to assess the antioxidant effect of montelukast on the production of free radicals in the whole blood and polymorphonuclear neutrophils (PMNs) in asthmatic children. A group of 48 (38 males and 10 females), apparently healthy asthmatic children were recruited with ages ranging between 6 and 14 years. In asthmatic children, base line (premedication) and post medication free radicals activity in the whole blood and polymorphonuclear neutrophils (PMNs) was determined by measuring chemiluminescence (CL) response through chemiluminescence luminometer. Free radical productions were significantly decreased in the whole blood, when stimulated with Phorbol Myristate Acetate (p < 0.04) and Opsonised Zymosan (p < 0.05). The free radicals were also significantly decreased in isolated polymorphonuclear neutrophils (PMNs) when stimulated with Opsonised Zymosan (p < 0.05) after the post medication treatment of montelukast in asthmatic children. Montelukast decreased the reactive oxygen species production, both in the whole blood as well as isolated PMNs in asthmatic children.
doi:10.1016/j.jsps.2011.06.002
PMCID: PMC3745193  PMID: 23960762
Montelukast; Antioxidant; Free radicals production; Bronchial asthma
22.  Lung Type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production 
Background
Cysteinyl leukotrienes contribute to asthma pathogenesis, in part through CysLT1 receptor (CysLT1R). Recently discovered lineage-negative type 2 innate lymphoid cells (ILC2) potently produce IL-5 and IL-13.
Objectives
We hypothesized that lung ILC2 may be activated by leukotrienes through CysLT1R.
Methods
ILC2 (Thy 1.2+ lineage-negative lymphocytes) and CysLT1R were detected in the lungs of WT, STAT6−/−, and RAG2−/− mice by flow cytometry. Levels of Th2 cytokines were measured in purified lung ILC2 stimulated with leukotriene D4 (LTD4) in the presence or absence of the CysLT1R antagonist montelukast. Calcium influx was measured by Fluo-4 intensity. Intranasal LTD4 and LTE4 were administered to naive mice and levels of ILC2 IL-5 production determined. Finally, LTD4 was co-administered with Alternaria repetitively to RAG2−/− mice (have ILC2) and IL-7R−/− mice (lack ILC2) and total ILC2 numbers, proliferation (Ki-67+) and BAL eosinophils measured.
Results
CysLT1R was expressed on lung ILC2 from WT, RAG2−/−, and STAT6−/−naïve and Alternaria-challenged mice. In vitro, LTD4 induced ILC2 to rapidly generate high levels of IL-5 and IL-13 within six hours of stimulation. Interestingly, LTD4, but not IL-33, induced high levels of IL-4 by ILC2. LTD4 administered in-vivo rapidly induced ILC2 IL-5 production that was significantly reduced by montelukast pre-treatment. Finally, LTD4 potentiated Alternaria-induced eosinophilia as well as ILC2 accumulation and proliferation.
Conclusions
We present novel data that CysLT1R is expressed on ILC2 and LTD4 potently induces CysLT1R-dependent ILC2 production of IL-4, IL-5, and IL-13. Additionally, LTD4 potentiates Alternaria-induced eosinophilia and ILC2 proliferation and accumulation.
doi:10.1016/j.jaci.2013.03.048
PMCID: PMC3704056  PMID: 23688412
Asthma; Type 2 Innate Lymphoid Cells; Cysteinyl Leukotrienes; CysLT1R
23.  Interleukin-4 in the Generation of the AERD Phenotype: Implications for Molecular Mechanisms Driving Therapeutic Benefit of Aspirin Desensitization 
Journal of Allergy  2012;2012:182090.
Aspirin-exacerbated respiratory disease (AERD) is explained in part by over-expression of 5-lipoxygenase, leukotriene C4 synthase (LTC4S) and the cysteinyl leukotriene (CysLT) receptors (CysLT1 and 2), resulting in constitutive over-production of CysLTs and the hyperresponsiveness to CysLTs that occurs with aspirin ingestion. Increased levels of IL-4 have been found in the sinus mucosa and nasal polyps of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the upregulation of LTC4S by mast cells and the upregulation of CysLT1 and 2 receptors on many immune cell types. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD reflecting diminished expression of cyclooxygenase (COX)-2. IL-4 can inhibit basal and stimulated expression of COX-2 and microsomal PGE synthase 1 leading to decreased capacity for PGE2 secretion. Thus, IL-4 plays an important pathogenic role in generating the phenotype of AERD. This review will examine the evidence supporting this hypothesis and describe a model of how aspirin desensitization provides therapeutic benefit for AERD patients.
doi:10.1155/2012/182090
PMCID: PMC3259477  PMID: 22262978
24.  Cysteinyl leukotriene signaling through perinuclear CysLT1 receptors on vascular smooth muscle cells transduces nuclear calcium signaling and alterations of gene expression 
Leukotrienes are pro-inflammatory mediators that are locally produced in coronary atherosclerotic plaques. The response induced by cysteinyl leukotrienes (CysLT) in human coronary arteries may be altered under pathological conditions, such as atherosclerosis. The aim of the present study was to elucidate cysteinyl leukotriene signaling in vascular smooth muscle cells (SMCs) and the effects of inflammation on this process. Immunohistochemical analysis of human carotid endarterectomy samples revealed that the CysLT1 leukotriene receptor was expressed in areas that also stained positive for α-smooth muscle actin. In human coronary artery smooth muscle cells, lipopolysaccharide significantly upregulated the CysLT1 receptor and significantly enhanced the changes in intracellular calcium induced by leukotriene C4 (LTC4). In these cells, the CysLT1 receptor exhibited a perinuclear expression, and LTC4 stimulation predominantly enhanced nuclear calcium increase, which was significantly inhibited by the CysLT1 receptor antagonist MK-571. Microarray analysis revealed, among a number of significantly upregulated genes after 24 h stimulation of human coronary artery smooth muscle cells with LTC4, a 5-fold increase in mRNA levels for plasminogen activator inhibitor (PAI)-2. The LTC4-induced increase in PAI-2 expression was confirmed by real-time quantitative PCR and ELISA and was inhibited by the CysLT1 receptor antagonist MK-571 and by calcium chelators. In summary, pro-inflammatory stimulation of vascular SMCs upregulated a perinuclear CysLT1 receptor expression coupled to nuclear calcium signaling and changes in gene expression, such as upregulation of PAI-2. Taken together, these findings suggest a role of nuclear CysLT1 receptor signaling in vascular SMCs inducing gene expression patterns associated with atherosclerosis.
Electronic supplementary material
The online version of this article (doi:10.1007/s00109-012-0904-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00109-012-0904-1
PMCID: PMC3438394  PMID: 22527886
Atherosclerosis; Eicosanoids; Inflammation; Lipoxygenase; PAI-2
25.  Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis 
Cysteinyl leukotrienes (CysLTs) are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages. This article reviews the data for the role of CysLTs as multi-functional mediators in allergic rhinitis (AR). We review the evidence that: (1) CysLTs are released from inflammatory cells that participate in AR, (2) receptors for CysLTs are located in nasal tissue, (3) CysLTs are increased in patients with AR and are released following allergen exposure, (4) administration of CysLTs reproduces the symptoms of AR, (5) CysLTs play roles in the maturation, as well as tissue recruitment, of inflammatory cells, and (6) a complex inter-regulation between CysLTs and a variety of other inflammatory mediators exists.
doi:10.1111/j.1365-2222.2006.02498.x
PMCID: PMC1569601  PMID: 16776669
allergic rhinitis; cysteinyl leukotrienes; CysLT1 receptor; eosinophils; inflammation; leukotriene C4 synthase; 5-lipoxygenase

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