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1.  Cysteinyl leukotriene receptor antagonist regulates allergic airway inflammation in an organ- and cytokine-specific manner 
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.
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.
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.
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.
PMCID: PMC3937047  PMID: 24561545
Leukotriene Antagonists; Lymphoid Tissue; Pranlukast; Asthma
2.  Concentration dependent non-CysLT1 receptor mediated inhibitory activity of leukotriene receptor antagonists 
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.
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).
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.
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.
PMCID: PMC2826199  PMID: 20083671
bronchial asthma; leukotrienes; leukotriene antagonists; monocytes; UDP
3.  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.
PMCID: PMC3586155  PMID: 20945945
4.  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.
PMCID: PMC3586155  PMID: 20945945
5.  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.
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
6.  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
7.  Update on Recent Advances in the Management of Aspirin Exacerbated Respiratory Disease 
Yonsei Medical Journal  2009;50(6):744-750.
Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1*301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach.
PMCID: PMC2796398  PMID: 20046412
Aspirin; asthma; genetic polymorphism; leukotriene; eosinophil
8.  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.
PMCID: PMC2937239  PMID: 20442434
airway; inflammation; RSV; cysteinyl leukotrienes
9.  Protection of leukotriene receptor antagonist against aspirin-induced bronchospasm in asthmatics 
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.
We investigated the efficacy of a 12-week treatment with a LTRA in protecting against aspirin-induced asthma in AIA patients.
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.
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.
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.
PMCID: PMC2831603  PMID: 20224678
Asthma; leukotriene antagonists; aspirin; eosinophils
10.  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.
PMCID: PMC1899264  PMID: 16973987
combination therapy; leukotriene; beta-agonists; inhaled corticosteroids
11.  Step-up Therapy for Children with Uncontrolled Asthma While Receiving Inhaled Corticosteroids 
The New England journal of medicine  2010;362(11):975-985.
For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.
We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 µg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 µg of fluticasone twice daily (ICS step-up), 100 µg of fluticasone plus 50 µg of a long-acting beta-agonist twice daily (LABA step-up), or 100 µg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.
A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P = 0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P = 0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P = 0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P = 0.005).
Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child’s asthma therapy. ( number, NCT00395304.)
PMCID: PMC2989902  PMID: 20197425
12.  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.
PMCID: PMC4014011  PMID: 20574000
Knockout Mice; Lipid Mediators; Allergy; Inflammation; Lung
13.  Add-on therapy options in asthma not adequately controlled by inhaled corticosteroids: a comprehensive review 
Respiratory Research  2004;5(1):17.
Many patients with persistent asthma can be controlled with inhaled corticosteroids (ICS). However, a considerable proportion of patients remain symptomatic, despite the use of ICS. We present systematically evidence that supports the different treatment options. A literature search was made of Medline/PubMed to identify randomised and blinded trials. To demonstrate the benefit that can be obtained by increasing the dose of ICS, dose-response studies with at least three different ICS doses were identified. To demonstrate whether more benefit can be obtained by adding long-acting β2-agonist (LABA), leukotriene antagonist (LTRA) or theophylline than by increasing the dose of ICS, studies comparing these options were identified. Thirdly, studies comparing the different "add-on" options were identified. The addition of a LABA is more effective than increasing the dose of ICS in improving asthma control. By increasing the dose of ICS, clinical improvement is likely to be of small magnitude. Addition of a LTRA or theophylline to the treatment regimen appears to be equivalent to doubling the dose of ICS. Addition of a LABA seems to be superior to an LTRA in improving lung function. However, addition of LABA and LTRA may be equal with respect to asthma exacerbations. However, more and longer studies are needed to better clarify the role of LTRAs and theophylline as add-on therapies.
PMCID: PMC528858  PMID: 15509300
Asthma; inhaled corticosteroids; long-acting β2-agonists; theophylline; leukotriene antagonists
14.  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.
PMCID: PMC2818547  PMID: 19941848
Leukotriene A4; Leukotriene B4; Fos; Dorsal vagal complex; Enteric nervous system
15.  Synthesis of tenascin and laminin beta2 chain in human bronchial epithelial cells is enhanced by cysteinyl leukotrienes via CysLT1 receptor 
Respiratory Research  2008;9(1):44.
Cysteinyl leukotrienes (CysLTs) are key mediators of asthma, but their role in the genesis of airway remodeling is insufficiently understood. Recent evidence suggests that increased expression of tenascin (Tn) and laminin (Ln) β2 chain is indicative of the remodeling activity in asthma, but represents also an example of deposition of extracellular matrix, which affects the airway wall compliance. We tested the hypothesis that CysLTs affect production of Tn and Ln β2 chain by human bronchial epithelial cells and elucidated, which of the CysLT receptors, CysLT1 or CysLT2, mediate this effect.
Cultured BEAS-2B human bronchial epithelial cells were stimulated with leukotriene D4 (LTD4) and E4 (LTE4) and evaluated by immunocytochemistry, Western blotting, flow cytometry, and RT-PCR. CysLT receptors were differentially blocked with use of montelukast or BAY u9773.
LTD4 and LTE4 significantly augmented the expression of Tn, whereas LTD4, distinctly from LTE4, was able to increase also the Ln β2 chain. Although the expression of CysLT2 prevailed over that of CysLT1, the up-regulation of Tn and Ln β2 chain by CysLTs was completely blocked by the CysLT1-selective antagonist montelukast with no difference between montelukast and the dual antagonist BAY u9773 for the inhibitory capacity.
These findings suggest that the CysLT-induced up-regulation of Tn and Ln β2 chain, an important epithelium-linked aspect of airway remodeling, is mediated predominantly by the CysLT1 receptor. The results provide a novel aspect to support the use of CysLT1 receptor antagonists in the anti-remodeling treatment of asthma.
PMCID: PMC2412865  PMID: 18503712
16.  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
17.  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.
PMCID: PMC3478400  PMID: 23002438
Knockout mouse; Lipid mediator; G protein-coupled receptor; Asthma; Lung
18.  Transforming growth factor β1-induced astrocyte migration is mediated in part by activating 5-lipoxygenase and cysteinyl leukotriene receptor 1 
Transforming growth factor-β1 (TGF-β1) is an important regulator of cell migration and plays a role in the scarring response in injured brain. It is also reported that 5-lipoxygenase (5-LOX) and its products, cysteinyl leukotrienes (CysLTs, namely LTC4, LTD4 and LTE4), as well as cysteinyl leukotriene receptor 1 (CysLT1R) are closely associated with astrocyte proliferation and glial scar formation after brain injury. However, how these molecules act on astrocyte migration, an initial step of the scarring response, is unknown. To clarify this, we determined the roles of 5-LOX and CysLT1R in TGF-β1-induced astrocyte migration.
In primary cultures of rat astrocytes, the effects of TGF-β1 and CysLT receptor agonists on migration and proliferation were assayed, and the expression of 5-LOX, CysLT receptors and TGF-β1 was detected. 5-LOX activation was analyzed by measuring its products (CysLTs) and applying its inhibitor. The role of CysLT1R was investigated by applying CysLT receptor antagonists and CysLT1R knockdown by small interfering RNA (siRNA). TGF-β1 release was assayed as well.
TGF-β1-induced astrocyte migration was potentiated by LTD4, but attenuated by the 5-LOX inhibitor zileuton and the CysLT1R antagonist montelukast. The non-selective agonist LTD4 at 0.1 to 10 nM also induced a mild migration; however, the selective agonist N-methyl-LTC4 and the selective antagonist Bay cysLT2 for CysLT2R had no effects. Moreover, CysLT1R siRNA inhibited TGF-β1- and LTD4-induced astrocyte migration by down-regulating the expression of this receptor. However, TGF-β1 and LTD4 at various concentrations did not affect astrocyte proliferation 24 h after exposure. On the other hand, TGF-β1 increased 5-LOX expression and the production of CysLTs, and up-regulated CysLT1R (not CysLT2R), while LTD4 and N-methyl-LTC4 did not affect TGF-β1 expression and release.
TGF-β1-induced astrocyte migration is, at least in part, mediated by enhanced endogenous CysLTs through activating CysLT1R. These findings indicate that the interaction between the cytokine TGF-β1 and the pro-inflammatory mediators CysLTs in the regulation of astrocyte function is relevant to glial scar formation.
PMCID: PMC3419068  PMID: 22734808
Transforming growth factor-β1; Cysteinyl leukotriene; Cysteinyl leukotriene receptor; 5-lipoxygenase; Astrocyte; migration; Glial scar
19.  Cysteinyl leukotrienes acting via granule membrane-expressed receptors elicit secretion from within cell-free human eosinophil granules 
Cysteinyl leukotrienes are recognized to act via receptors (CysLTRs) expressed on cell surface plasma membranes. Agents that block CysLT1R, are therapeutics for allergic disorders. Eosinophils contain multiple preformed proteins stored within their intracellular granules. Cell-free eosinophil granules are present extracellularly as intact membrane-bound organelles in sites associated with eosinophil infiltration, including asthma, rhinitis and urticaria, but have unknown functional capabilities.
We evaluated the expression of CysLTRs on eosinophil granule membranes and their functional roles in eliciting protein secretion from within eosinophil granules.
We studied secretory responses of human eosinophil granules isolated by subcellular fractionation. Granules were stimulated with cysteinyl leukotrienes and eosinophil cationic protein and cytokines were measured in the supernatants. Receptor expression on granule membranes and eosinophils was evaluated by flow cytometry and western blot.
We report that receptors for cysteinyl leukotrienes, CysLT1R, CysLT2R and the purinergic P2Y12 receptor (P2Y12R), are expressed on eosinophil granule membranes. Leukotriene (LT) C4 and extracellularly generated LTD4 and LTE4 stimulated isolated eosinophil granules to secrete eosinophil cationic protein. MRS 2395, a P2Y12R antagonist, inhibited cysteinyl leukotrienes-induced eosinophil cationic protein release. Montelukast, likely not solely as an inhibitor of CysLT1R, inhibited eosinophil cationic protein release elicited by LTC4 and LTD4 as well as by LTE4.
These studies identify previously unrecognized sites of localization, the membranes of intracellular eosinophil granule organelles, and function for cysteinyl leukotriene-responsive receptors that mediate cysteinyl leukotriene-stimulated secretion from within eosinophil granules, including those present extracellularly.
Clinical implications
Cysteinyl leukotrienes elicit cell-free eosinophil granule secretion suggesting new roles, amenable to therapeutic interventions, for these lipid mediators in eosinophil-associated diseases.
PMCID: PMC2824614  PMID: 20159258
granules; cysteinyl leukotriene; eosinophil; allergy; asthma; montelukast
20.  Lung Type 2 innate lymphoid cells express CysLT1R that regulates Th2 cytokine production 
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.
We hypothesized that lung ILC2 may be activated by leukotrienes through CysLT1R.
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.
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.
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.
PMCID: PMC3704056  PMID: 23688412
Asthma; Type 2 Innate Lymphoid Cells; Cysteinyl Leukotrienes; CysLT1R
21.  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.
PMCID: PMC2772391  PMID: 19759251
22.  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
23.  Update on leukotriene receptor antagonists in preschool children wheezing disorders 
Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Anti-inflammatory therapy, mainly consisting of inhaled corticosteroids (ICS), is the cornerstone of asthma management. Since Leukotrienes (LTs) are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs) are traditionally used as potent anti-inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy.
PMCID: PMC3484040  PMID: 22734451
Leukotriene receptor antagonists; Asthma; Preschool children; Wheezing; Bronchiolitis
24.  Adequate Levels of Adherence with Controller Medication Is Associated with Increased Use of Rescue Medication in Asthmatic Children 
PLoS ONE  2012;7(6):e39130.
The role of asthma controller medication adherence and the level of asthma control in children is poorly defined.
To assess the association between asthma controller medication adherence and asthma control in children using routinely acquired prescribing data.
A retrospective observational study of children aged 0–18 years prescribed inhaled corticosteroids only (ICS), leukotriene receptors antagonists (LTRA), or long-acting β2 agonists (LABA) and ICS prescribed as separate or combined inhalers, between 01/09/2001 and 31/08/2006, registered with primary care practices contributing to the Practice Team Information database. The medication possession ratio (MPR) was calculated and associations with asthma control explored. Poor asthma control was defined as the issue of prescriptions for ≥1 course of oral corticosteroids (OCS) and/or ≥6 short-acting β2 agonists (SABA) canisters annually.
A total of 3172 children prescribed asthma controller medication were identified. Of these, 15–39% (depending on controller medication) demonstrated adequate MPR. Adequate MPR was associated with male gender, good socio-economic status, and oral LTRA therapy. Adequate MPR was more likely to be associated with increased use of rescue medication. However logistic regression only identified a significant relationship for ICS only (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.35–2.48; p<0.001), LTRA (OR, 2.11; 95% CI, 1.27–3.48; p = 0.004) and LABA/ICS (OR, 2.85; 95% CI, 1.62–5.02; p<0.001).
Poor adherence was observed for all asthma controller medications, although was significantly better for oral LRTA. In this study adequate adherence was not associated with the use of less rescue medication, suggesting that adherence is a complex issue.
PMCID: PMC3384638  PMID: 22761728
25.  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.
PMCID: PMC3745193  PMID: 23960762
Montelukast; Antioxidant; Free radicals production; Bronchial asthma

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