montelukast and Inflammation

This meta-analysis aimed to compare the efficacy of montelukast (MKST) combined with budesonide (BUD) and BUD alone in the treatment of pulmonary inflammation and pulmonary function in children with cough variant asthma (CVA). Five electronic databases were searched for studies about MKST+BUD therapy and BUD alone therapy on inflammation and pulmonary function in CVA children from inception to November 23, 2021. Twenty-two articles were included. The results showed that, compared with BUD alone, the combination treatment could achieve better improvement of pulmonary function and lower levels of inflammation (MKST+BUD group: FEV1: SMD = 2.77, 95% CI: 2.07, 3.46; FVC: SMD = 2.54, 95% CI: 1.82, 3.27; PEF: SMD = 2.27, 95% CI: 1.79, 2.75; IgE: SMD = -7.95, 95% CI: -9.66, -6.25; TNF-α: SMD = -4.67, 95% CI: -6.04, -3.31; IL-8: SMD = -8.18, 95% CI: -11.46, -4.90; BUD alone group: FEV1: SMD = 1.83, 95% CI: 1.34, 2.31; FVC: SMD = 1.39, 95% CI: 0.93, 1.84; PEF: SMD = 1.51, 95% CI: 1.13, 1.89; IgE: SMD = -4.93, 95% CI: -6.14, -3.72; TNF-α: SMD = -2.78, 95% CI: -3.76, -1.80; IL-8: SMD = -4.94, 95% CI: -7.10, -2.79). To conclude, compared with BUD alone, MKST+BUD therapy was found to be more effective in improving pulmonary function and reducing inflammation in CVA children. Key Words: Montelukast, Budesonide, Cough variant asthma, Children, Pulmonary function, Inflammatory markers, Meta-analysis.

Topics: Asthma; Budesonide; Child; Cough; Humans; Immunoglobulin E; Inflammation; Interleukin-8; Tumor Necrosis Factor-alpha

Parkinson's disease (PD) is a neurodegenerative disorder where misfolded alpha-synuclein-enriched aggregates called Lewy bodies are central in pathogenesis. No neuroprotective or disease-modifying treatments are currently available. Parkinson's disease is considered a multifactorial disease and evidence from multiple patient studies and animal models has shown a significant immune component during the course of the disease, highlighting immunomodulation as a potential treatment strategy. The immune changes occur centrally, involving microglia and astrocytes but also peripherally with changes to the innate and adaptive immune system. Here, we review current understanding of different components of the PD immune response with a particular emphasis on the leukotriene pathway. We will also describe evidence of montelukast, a leukotriene receptor antagonist, as a possible anti-inflammatory treatment for PD.

Topics: Acetates; Anti-Inflammatory Agents; Astrocytes; Cyclopropanes; Humans; Inflammation; Leukotriene Antagonists; Lewy Bodies; Microglia; Parkinson Disease; Quinolines; Receptors, Leukotriene; Sulfides

Approximately one-half of children with asthma present with symptoms before 3 years of age. The typical history describes recurrent episodes of wheezing and/or cough triggered by a viral upper respiratory infection (URI), activity, or changes in weather. When symptoms occur after a viral URI, children with asthma often take longer than the usual week to fully recover from their respiratory symptoms. Wheezing and coughing during exercise or during laughing or crying, and episodes triggered in the absence of infection suggest asthma. A trial of bronchodilator medication should show symptomatic improvement. The goal of asthma therapy is to keep children "symptom free" by preventing chronic symptoms, maintaining lung function, and allowing for normal daily activities. Avoidance of triggers identified by a history, such as second-hand cigarette smoke exposure, and allergens identified by skin-prick testing can significantly reduce symptoms. According to the 2007 National Asthma Education and Prevention Program (NAEPP) report, if impairment symptoms are present for >2 days/week or 2 nights/month, then the disease process is characterized as persistent, and, in all age groups, inhaled corticosteroids (ICS) are recommended as the preferred daily controller therapy. Montelukast is approved for children ages ≥ 12 months and is often used for its ease of daily oral dosing. Long-acting beta-2 adrenergic agonists should only be used in combination with an ICS. For more-severe or difficult-to-control phenotypes, biologic therapy has been developed, which targets the type of inflammation present.

Topics: Acetates; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Child; Child, Preschool; Cough; Cyclopropanes; Humans; Inflammation; Pediatrics; Quinolines; Respiratory Sounds; Sulfides

Allergic rhinitis (AR) clinically expressed by sneezing, rhinorrhea, nasal itching and congestion is an allergen-driven mucosal inflammatory disease which is modulated by immunoglobulin E. Epidemiological studies have indicated that prevalence of AR continues to increase, and it has been a worldwide health problem that places a significant healthcare burden on individuals and society. Given the evolving understanding of the process by which an allergen is recognized and the roles of mediators which account for AR progress, the pathogenesis of AR has become clearer. Current studies have demonstrated local allergic rhinitis (LAR) that patients with both sug- gestive symptoms of AR and a negative diagnostic test for atopy may have local allergic inflammation is a prevalent entity in patients evaluated with rhinitis, but further research remains needed. Management of AR includes aller- gen avoidance, pharmacological treatment and allergen-specific immunotherapy. Recently montelukast has exhibited previously undocumented anti-inflammatory properties, leukotriene receptor antagonists therefore may serve a more important role in the treatment of AR. Not only has immunotherapy proved its efficacy, but also been able to alter disease course and thereby mitigate progression to asthma. Thus immunotherapy can be initiated while receiving pharmacotherapy, especially in children with AR. As clinical guidelines, the ARIA (Allergic Rhinitis and its Impact on Asthma) provides basic principles of effective treatment of AR. Besides, choosing an appropriate treatment strategy should be based on the severity and chronicity of patient's symptom. The aim of this review was to provide an update mainly on the pathophysiology, epidemiology, and management of AR.

Topics: Acetates; Allergens; Anti-Inflammatory Agents; Asthma; Child; Cyclopropanes; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Immunotherapy; Inflammation; Leukotriene Antagonists; Prevalence; Quinolines; Rhinitis, Allergic; Sulfides

Anti-inflammatory preventive treatment is recommended in cases of persistent asthma. Besides inhaled corticosteroids (ICS), which represent the mainstay of treatment, other therapeutic options are available, of which only antileukotrienes are approved for all age groups.. Given as a substitute of low-dose ICS, montelukast prevents exacerbations as efficiently and for a longer period than long-acting β2-agonists. Montelukast is as efficient as doubling the dose of ICS on asthma symptoms in cases of inadequate control with low-dose ICS. Combined with ICS, it can lead to better control of asthma and potentially to ICS sparing.. Given the efficacy, tolerance and long-term treatment compliance of montelukast in mild persistent asthma in adults and children, montelukast, given as a substitute or combined with ICS, could contribute to enhanced control of asthma, especially in children.

Topics: Acetates; Adrenal Cortex Hormones; Adult; Airway Remodeling; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Child; Cyclopropanes; Cytokines; Drug Therapy, Combination; France; Humans; Inflammation; Leukotriene Antagonists; Leukotrienes; Models, Biological; Practice Guidelines as Topic; Prevalence; Quinolines; Randomized Controlled Trials as Topic; Receptors, Leukotriene; Sulfides

Patients with multiple traumas are at high risk of developing respiratory complications, including pneumonia and acute respiratory distress syndrome. Many pulmonary complications are associated with systemic inflammation and pulmonary neutrophilic infiltration. Leukotriene-receptor antagonists are anti-inflammatory and anti-oxidant drugs subsiding airway inflammation. The present study investigates the effectiveness of montelukast in reducing pulmonary complications among trauma patients.. This randomized, double-blind, placebo-control trial was conducted in patients with multiple blunt traumas and evidence of lung contusion detected via CT scan. We excluded patients if they met at least one of the following conditions: < 16 years old, history of cardiopulmonary diseases or positive history of montelukast-induced hypersensitivity reactions. Patients were allocated to the treatment (10 mg of montelukast) or placebo group using permuted block randomization method. The primary measured outcome was the volume of pulmonary contusion at the end of the trial. The secondary outcomes were intensive care unit and hospital length of stay, ventilation days, multi-organ failure, and the in-hospital mortality rate.. In total, 65 eligible patients (treatment = 31, placebo = 34) were included for the final analysis. The treatment group had more pulmonary contusion volume (mean (SD), mm. Administrating montelukast has no preventive or therapeutic effects on lung contusion or its complications.

Topics: Adolescent; Contusions; Humans; Inflammation; Lung Injury; Pneumonia; Respiratory Distress Syndrome; Tablets; Thoracic Injuries; Thoracic Wall; Treatment Outcome; Wounds, Nonpenetrating

Whether cysteinyl-leukotriene receptor antagonists (LTRAs) have a similar antitussive effect to inhaled corticosteroids and long-acting β2-agonist (ICS/LABA), and that LTRA plus ICS/LABA is superior to LTRAs alone or ICS/LABA alone in treating cough variant asthma (CVA) remain unclear. This study aimed to investigate and compare the efficacy of montelukast alone, budesonide/formoterol alone and the combination of both in the treatment of CVA.. Ninety-nine CVA patients were assigned randomly in a 1:1:1 ratio to receive montelukast (M group: 10 mg, once daily), budesonide/formoterol (BF group: 160/4.5 μg, one puff, twice daily), or montelukast plus budesonide/formoterol (MBF group) for 8 weeks. The primary outcomes were changes in the cough visual analogue scale (VAS) score, daytime cough symptom score (CSS) and night-time CSS, and the secondary outcomes comprised changes in cough reflex sensitivity (CRS), the percentage of sputum eosinophils (sputum Eos%) and fractional exhaled nitric oxide (FeNO). CRS was presented with the lowest concentration of capsaicin that induced at least 5 coughs (C5). The repeated measure was used in data analysis.. Montelukast alone, budesonide/formoterol alone and a combination of both were effective in improving cough symptom, decreasing cough reflex sensitivity and alleviating eosinophilic airway inflammation in patients with CVA, and the antitussive effect and anti-eosinophilic airway inflammation were similar. Trial registration ClinicalTrials.gov, number NCT01404013.

Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Antitussive Agents; Asthma; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Capsaicin; Cough; Cyclopropanes; Formoterol Fumarate; Humans; Inflammation; Leukotriene Antagonists; Quinolines; Sulfides

The aim of this study was to explore the clinical effect of montelukast sodium chewable tablets combined with inhaled budesonide in the treatment of pediatric asthma and its influence on inflammatory factors. One hundred and thirty-five asthmatic children were randomly divided into montelukast sodium group, budesonide group and combined group. Clinical symptoms, lung function, inflammatory factors and immune related indices of patients in each group were observed and recorded. After treatment, the times to disappearance of wheezes, dyspnea, asthma and hospital stay in the combined group were significantly shorter than those in the single-drug group (all p < 0.001). Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), peak expiratory flow (PEF) were significantly higher than those before treatment, and in the combined group value were significantly higher than in the single-drug group in the same period (all p < 0.001). Tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-8 and hypersensitive C-reactive protein (hs-CRP) were significantly lower than before treatment, and the combined group was significantly lower than the single-drug group in the same period (all p < 0.05). The number of CD4

Topics: Acetates; Administration, Inhalation; Administration, Oral; Anti-Asthmatic Agents; Asthma; Budesonide; Child; Child, Preschool; Cyclopropanes; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Inflammation; Male; Quinolines; Respiratory Function Tests; Sulfides; Tablets; Treatment Outcome

The efficacy of montelukast (MONT), a cysteinyl leukotriene receptor antagonist, in nonasthmatic eosinophilic bronchitis (NAEB), especially its influence on cough associated life quality is still indefinite. We evaluated the efficacy of MONT combined with budesonide (BUD) as compared to BUD monotherapy in improving life quality, suppressing airway eosinophilia and cough remission in NAEB.. A prospective, open-labeled, multicenter, randomized controlled trial was conducted. Patients with NAEB (aged 18-75 years) were randomized to inhaled BUD (200 μg, bid) or BUD plus oral MONT (10 μg, qn) for 4 weeks. Leicester cough questionnaire (LCQ) life quality scores, cough visual analog scale (CVAS) scores, eosinophil differential ratio (Eos), and eosinophil cationic protein (ECP) in induced sputum were monitored and compared.. The control and MONT groups contained 33 and 32 patients, respectively, with similar baseline characteristics. Significant with-in group improvement in CVAS, LCQ scores, Eos, and ECP was observed in both groups during treatment. After 2-week treatment, add-on treatment of MONT was significantly more effective than BUD monotherapy for CVAS decrease and LCQ scores improvement (both P < 0.05). Similar results were seen at 4-week assessment (both P < 0.05). 4-week add-on therapy of MONT also resulted in a higher percentage of patients with normal sputum Eos (<2.5%) and greater decrease of ECP (both P < 0.05).. MONT combined with BUD was demonstrated cooperative effects in improvement of life quality, suppression of eosinophilic inflammation, and cough remission in patients with NAEB.

Topics: Acetates; Adolescent; Adult; Aged; Aged, 80 and over; Bronchitis; Budesonide; Cough; Cyclopropanes; Female; Humans; Inflammation; Male; Middle Aged; Quality of Life; Quinolines; Sulfides; Young Adult

Our aim was to investigate the effectiveness of montelukast in recurrently wheezy infants. We randomised 113, 6-24-month-old children with recurrent wheezing to receive either placebo or montelukast daily for an 8-week period. The primary end-point was symptom-free days. The secondary aims were to evaluate the effect of montelukast on rescue medication, on lung function, airway responsiveness and exhaled nitric oxide fraction (FeNO). Clinical response and FeNO were determined, the functional residual capacity (FRC) and specific airway conductance (sGaw) were measured using an infant whole-body plethysmograph, the maximal flow at functional residual capacity (V'max,FRC) was recorded using the squeeze technique and airway responsiveness was evaluated by performing a dosimetric methacholine challenge test. There was no significant difference in changes in weekly symptom-free days between the montelukast and the placebo group (3.1-3.7 days versus 2.7-3.1 days, p = 0.965). No significant differences were detected in the secondary end-points, i.e. use of rescue medication, FRC, sGaw, V'max,FRC, FeNO or airway responsiveness between groups. Montelukast therapy did not influence the number of symptom-free days, use of rescue medication, lung function, airway responsiveness or airway inflammation in recurrently wheezy, very young children.

Topics: Acetates; Anti-Asthmatic Agents; Bronchial Provocation Tests; Child, Preschool; Cyclopropanes; Female; Humans; Infant; Inflammation; Lung; Male; Nitric Oxide; Plethysmography; Quinolines; Respiration; Respiratory Function Tests; Respiratory Sounds; Sulfides; Treatment Outcome

It has been demonstrated that Leukotriene modifiers reduce rhinitis symptoms, but montelukast preventive effect on inflammatory cells pattern in intranasal challenge studies has not been already assessed. This pilot study has been designed to explore the montelukast effects in preventing early/late inflammatory cells response to specific allergen challenge in persistent rhinitis. After a 4 week wash-out period, patients were randomised to receive montelukast/placebo for 4 weeks. Pre-post treatment nasal washing and scraping before and after specific nasal challenge were performed. No difference in baseline inflammatory cells count before and after treatment was shown between groups. Despite at a basal level a decrease of inflammatory cells in active group after treatment was observed, the statistical significance was not reached. The generalised mixed model showed that, after therapeutic interventions, the inflammatory cells increased 30' and 6 hour after challenge but, only in the active group the cells amounting was less for eosinophils (-34%), macrophages (-56%), lymphocytes (-45%) and neutrophils (-46%; p = 0.001). The longitudinal generalised linear model with just one time variable showed a decrease of all inflammatory cellular types although a significant relevance was reached only for macrophages (p = 0.038) and neutrophils (p = 0.001). The modulatory effect on neutrophils and macrophages could lead to montelukast still unexplored effects. Specific trials, sized according to the results of this pilot exploratory study, could add relevant evidences concerning the leukotrienes receptors antagonist treatment of specific rhinitis and asthma phenotypes.

Topics: Acetates; Adult; Cell Count; Cyclopropanes; Double-Blind Method; Eosinophils; Female; Humans; Hypersensitivity; Inflammation; Leukotriene Antagonists; Lymphocytes; Macrophages; Male; Neutrophils; Pilot Projects; Quinolines; Rhinitis, Allergic, Perennial; Sulfides

Extra-fine particle formulations of hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) exhibit clinical effects comparable with conventional particle formulations of chlorofluorocarbon beclometasone dipropionate (CFC-BDP) at half the dose. There is little data comparing their effects on inflammation. We have evaluated the effects of HFA-BDP and CFC-BDP on pulmonary and systemic markers of asthmatic inflammation.. A double-blind randomized crossover trial was undertaken comparing the anti-inflammatory effects of HFA-BDP (100 and 400 microg/day) and CFC-BDP (200 and 800 microg/day). Treatment with montelukast was evaluated as add-on to the higher dose of BDP.. Compared with baseline after withdrawal of usual asthma therapy, 100 microg of HFA-BDP significantly attenuated serum eosinophilic cationic protein levels (0.61-fold change, 95% CI 0.49-0.77; a 39% reduction, P < 0.001), but 200 microg of CFC-BDP did not (0.87-fold change, 95% CI 0.63-1.23; P = 1). A dose of 800 microg of CFC-BDP and 400 microg of HFA-BDP led to reductions in exhaled nitric oxide (0.57-fold change, 95% CI 0.44-0.73; a 43% reduction, P < 0.001 and 0.65-fold change, 95% CI 0.47-0.91; a 35% reduction, P = 0.008, respectively); and peripheral eosinophils (-74 cells/microl, 95% CI -146 to -2; P = 0.020 and -77 cells/microl, 95% CI -140 to -14; P = 0.012, respectively). Montelukast further reduced exhaled nitric oxide (0.81-fold change, 95% CI 0.66-0.98; P = 0.028) with 400 microg HFA-BDP and eosinophils (-44 cells/microl, 95% CI -80 to -8; P = 0.012) with 800 microg CFC-BDP, but not vice versa.. Chlorofluorocarbon beclometasone dipropionate and HFA-BDP have differential effects on pulmonary and systemic inflammation, which dictate the additive effects of montelukast.

Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Chemistry, Pharmaceutical; Chlorofluorocarbons; Cyclopropanes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Eosinophils; Humans; Hydrocarbons, Fluorinated; Inflammation; Nitric Oxide; Particle Size; Quinolines; Sulfides

The aim of the study was to investigate the effect of addition of montelukast to inhaled fluticasone propionate (FP) therapy, compared with FP therapy alone (100 microg twice a day) on airway immunopathology in individuals with mild asthma. Twenty-eight subjects received FP (100 microg twice a day) or FP (100 microg twice a day) plus montelukast (10 mg at night) for 8 weeks and were then crossed over to the alternate treatment for a further 8 weeks. Physiological measurements and bronchial biopsies were obtained at +/- 2 days before treatment and +/- 2 days at the end of each treatment period. A two-period crossover analysis was performed and the mean and SE were calculated. There was no significant difference in percent predicted FEV1 (p = 0.51) or PC20 mg/ml (p = 0.81) between the two treatment regimes after 8 weeks of therapy. There was no difference in the efficacy of either treatment in decreasing T cell (p = 0.97), CD45RO+ (p = 0.37), mast cell (p = 0.37), or activated eosinophils (p = 0.55) numbers in bronchial biopsies. There was no significant difference in the percentage area stained for IFN-gamma (p = 0.76) or interleukin-4 (p = 0.61) between treatments. Reduction of inflammatory cell numbers in the bronchial mucosa achieved with FP plus montelukast was not significantly different from the reduction observed with FP alone in individuals with mild asthma.

Topics: Acetates; Administration, Inhalation; Administration, Topical; Adult; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Biopsy; Bronchi; Bronchodilator Agents; Cross-Over Studies; Cyclopropanes; Data Interpretation, Statistical; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Immunohistochemistry; Inflammation; Interferon-gamma; Interleukin-4; Leukotriene Antagonists; Male; Middle Aged; Placebos; Quinolines; Sulfides; Time Factors

Inhaled corticosteroids are effective antiinflammatory therapy for asthma; however, they do not completely abolish allergen-induced airway inflammation. Leukotriene modifiers attenuate both early and late allergen responses and have antiinflammatory properties. We reasoned that treatment with budesonide and montelukast in combination might provide greater antiinflammatory effects than either drug alone, and the purpose of this study was to compare the effects of treatment with budesonide and montelukast, alone or in combination, on outcome variables after allergen inhalation. Ten subjects with asthma with dual responses after allergen inhalation were included in this randomized, double-blind, crossover study. Outcomes included early and late asthmatic responses, and changes in airway responsiveness and sputum eosinophilia, measured before and after challenge. Treatment with montelukast attenuated the maximal early asthmatic response compared with placebo (p < 0.001) and budesonide (p = 0.002). Both budesonide and montelukast, alone and in combination, attenuated the maximal late asthmatic response compared with placebo (p < 0.01). Budesonide and montelukast, alone and in combination, afforded protection against allergen-induced airway hyperresponsiveness (p < 0.05), although the treatment effect of budesonide was greater than that of montelukast (p < 0.05). Treatment with budesonide and montelukast, alone and in combination, also attenuated allergen-induced sputum eosinophilia. Thus, montelukast and budesonide attenuated allergen-induced asthmatic responses, airway hyperresponsiveness, and sputum eosinophilia, although combination treatment did not provide greater antiinflammatory effects than either drug alone.

Topics: Acetates; Administration, Inhalation; Administration, Oral; Anti-Inflammatory Agents; Asthma; Budesonide; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Humans; Inflammation; Leukotriene Antagonists; Prospective Studies; Quinolines; Respiratory Hypersensitivity; Respiratory System; Sulfides

Immune-mediated inflammation contributes to progressive pulmonary damage in cystic fibrosis (CF). Sputum cysteinyl leukotriene levels, eosinophil cationic protein (ECP), and interleukin-8 (IL-8) are significantly related to disease severity.. The aim of this study was to evaluate the anti-inflammatory and clinical effects of the cysteinyl leukotriene receptor antagonist montelukast in children with CF.. A double-blind, randomized, crossover design was used. Patients received montelukast (6 to < or = 14 years, 5 mg; > 14 years, 10 mg) or placebo as a once-daily tablet for 21 days and then, after a washout period of at least 4 weeks, crossed over to receive the alternative treatment. Blood and native nasal fluid were taken on days 1 and 21 of each treatment block, and WBC count, ECP, and IL-8 were analyzed using a chemiluminescent immunometric assay.. Sixteen CF patients (10 boys, 6 girls; age, 5 to 18 years, median 9.5 years) completed the trial. There was a significant (P < or = 0.02) reduction of serum ECP (median reduction: montelukast 7.7 microg/L vs placebo 0.15 microg/L) and eosinophils (P < or = 0.027; median reduction: montelukast 85/microL vs placebo 0/microL). There was no significant change in nasal ECP, IL-8, or serum IL-8 after a 21-day course of montelukast. Clinical symptom scores did not change significantly.. Montelukast reduces eosinophilic inflammation in CF patients. Multicenter trials providing more patients to create more data to prove the hypothesis that montelukast is an effective tool to cut down disease severity in CF patients are needed.

Topics: Acetates; Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Blood Proteins; Child; Cross-Over Studies; Cyclopropanes; Cystic Fibrosis; Double-Blind Method; Eosinophil Granule Proteins; Eosinophilia; Humans; Inflammation; Interleukin-8; Leukocyte Count; Leukotriene Antagonists; Membrane Proteins; Pilot Projects; Quinolines; Receptors, Leukotriene; Respiratory Function Tests; Ribonucleases; Sulfides; Treatment Outcome

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.

Topics: Acetates; Adult; Asthma; Bronchi; Bronchial Hyperreactivity; Cell Count; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Eosinophils; Humans; Inflammation; Leukotriene Antagonists; Middle Aged; Quinolines; Respiratory Function Tests; Sputum; Sulfides

Montelukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1) that protects against inflammation and oxidative stress. However, the function of montelukast in liver fibrosis remains unknown. In this study, we examined whether the pharmacological inhibition of CysLTR1 could protect mice against hepatic fibrosis.. Carbon tetrachloride (CCl. Montelukast suppressed CCl

Topics: Animals; Carbon Tetrachloride; Diet; Fibrosis; Hepatic Stellate Cells; Humans; Inflammation; Liver; Liver Cirrhosis; Methionine; Mice; Racemethionine; Signal Transduction; Transforming Growth Factor beta1

Neuroinflammation plays an important role in brain injury and repair. Regulation of post-stroke inflammation may be a reasonable strategy to treat ischemic stroke. The present study demonstrates that montelukast sodium protected brain tissue by regulating the post-stroke inflammatory reaction.. Adult male mice underwent distal occlusion of the middle cerebral artery (d-MCAO) surgery, followed by intraperitoneal injection of montelukast sodium or equivalent saline, from day 0-7 after the operation. On the 7th day, Rotarod and adhesive-removal test were performed. M AP2 staining, and Iba1, CD206, and CD16/32 co staining were performed. BV2 microglial cell lines were co-cultured with different concentrations of montelukast sodium with or without lipopolysaccharide (LPS). Real-time polymerase chain reaction (rt-PCR) and enzyme linked immunosorbent assay (ELISA) were used to detect the mRNA expression of M1 and M2 phenotypic microglia markers and the release of cytokines representing from different phenotypes of microglia cells.. Montelukast sodium prolonged the time that d-MCAO mice remained on the rotating bar, shortened the time to remove the sticker on the opposite claw, and reduced the infarct volume, promoting the transformation of microglial cells/macrophages around the infarct to the M2 phenotype. Montelukast sodium increased the mRNA expression of Arg-1, CD206, TGF-β, and IL-10 in BV2 microglial cell lines stimulated by LPS, while decreased the expression of iNOS, TNF-α, and CD16/32.. Montelukast sodium can protect against focal cerebral ischemic injury by regulating inflammatory reaction via promoting microglia polarization.

Topics: Animals; Brain Injuries; Brain Ischemia; Infarction; Infarction, Middle Cerebral Artery; Inflammation; Lipopolysaccharides; Male; Mice; Microglia; RNA, Messenger; Stroke

Montelukast, a cysteinyl leukotriene receptor (CysLTR)1 antagonist, is emerging as an attractive strategy to curtail diabetic complications; however, its role in aortic and testicular tissues is unknown. This study investigated the effect of CysLTR1 antagonism by montelukast on toll-like receptor (TLR)4 and nuclear factor kappa B (NF-κB) pathways in diabetes-induced aortic and testicular injury.. Adult male Sprague-Dawley rats were made diabetic with Streptozotocin (STZ, 55 mg/kg). Following this, Streptozotocin-induced diabetic (SD) rats were administered montelukast (10 and 20 mg/kg, orally) for 8 weeks. Blood glucose, serum malondialdehyde (MDA), inflammatory markers, and histopathology were evaluated.. Montelukast showed protection against diabetic complications, as evidenced by the ameliorative effect against STZ-induced alterations in oxidative stress as indicated by serum MDA levels. Moreover, montelukast conferred a significant decrease in the aortic and testicular levels of CysLTR1, TLR4, and NF-κB with a subsequent decrease in the levels of NOD-like receptor family pyrin domain containing (NLRP)3, caspase 1, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α. Additionally, administration of montelukast resulted in autophagy stimulation, as shown by decreased p62/Sequestosome (SQSTM)1 levels. Finally, montelukast protection resulted in normal thickness of whole aortic wall, regular tunica (t.) intima, mild vacuolation of smooth muscle fibers in aorta, increased size of seminiferous tubules, and increased spermatogenesis in testis as demonstrated by histopathology.. The protective effect of montelukast against diabetes-induced aortic and testicular injury is due to its antioxidant, anti-inflammatory, and autophagy stimulation characteristics.

Topics: Animals; Aorta; Diabetes Complications; Diabetes Mellitus; Inflammation; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Streptozocin; Tumor Necrosis Factor-alpha

Burns are severe injuries often associated with impaired wound healing. Impaired healing is caused by multiple factors, including dysregulated inflammatory responses at the wound site. Interestingly, montelukast, an antagonist for cysteinyl leukotrienes and U.S. Food and Drug Administration approved for treatment of asthma and allergy, was previously shown to enhance healing in excision wounds and to modulate local inflammation.. In this study, the authors examined the effect of montelukast on wound healing in a mouse model of scald burn injury. Burn wound tissues isolated from montelukast- and vehicle-treated mice at various times after burn injury were analyzed for wound areas ( n = 34 to 36), reepithelialization ( n = 14), inflammation ( n = 8 to 9), and immune cell infiltration ( n = 3 to 6) and proliferation ( n = 7 to 8).. In contrast to previously described beneficial effects in excision wounds, this study shows that montelukast delays burn wound healing by impairing the proliferation of keratinocytes and endothelial cells. This occurs largely independently of inflammatory responses at the wound site, suggesting that montelukast impairs specifically the proliferative phase of wound healing in burns. Wound healing rates in mice in which leukotrienes are not produced were not affected by montelukast.. Montelukast delays wound healing mainly by reducing the proliferation of local cells after burn injury.. Although additional and clinical studies are necessary, our study suggests that burn patients who are on montelukast may exhibit delayed healing, necessitating extra observation.

Topics: Acetates; Animals; Burns; Cyclopropanes; Endothelial Cells; Inflammation; Leukotrienes; Mice; Quinolines; Sulfides; Wound Healing

Accumulative data links inflammation and immune dysregulation to the pathophysiology of mental disorders; little is known regarding leukotrienes' (LTs) involvement in this process. Circumstantial evidence suggests that treatment with leukotriene modifying agents (LTMAs) such as montelukast (MTK) may induce adverse neuropsychiatric events. Further methodic evaluation is warranted.. This study aims to examine behavioral effects, as well as inflammatory mediator levels of chronic MTK treatment in male and female rats.. Depression-like phenotypes were induced by exposing male and female rats to a chronic unpredictable mild stress (CUMS) protocol for four weeks. Thereafter, rats were treated (intraperitoneally) once daily, for two weeks, with either vehicle (dimethyl sulfoxide 0.2 ml/rat) or 20 mg/kg MTK. Following treatment protocols, behavioral tests were conducted and brain regions were evaluated for inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and prostaglandin (PG) E2.. Overall, MTK did not invoke negative behavioral phenotypes (except for an aggression-inducing effect in males). Numerous positive behavioral outcomes were observed, including reduction in aggressive behavior in females and reduced manic/hyperactive-like behavior and increased sucrose consumption (suggestive of antidepressant-like effect) in males. Furthermore, in control males, MTK increased IL-6 levels in the hypothalamus and TNF-α in the frontal cortex, while in control females it generated a robust anti-inflammatory effect. In females that were subjected to CUMS, MTK caused a prominent reduction in TNF-α and IL-6 in brain regions, whereas in CUMS-subjected males its effects were inconsistent.. Contrary to prior postulations, MTK may be associated with select beneficial behavioral outcomes. Additionally, MTK differentially affects male vs. female rats in respect to brain inflammatory mediators, plausibly explaining the dissimilar behavioral phenotypes of sexes under MTK treatment.

Topics: Acetates; Animals; Anti-Inflammatory Agents; Antidepressive Agents; Cyclopropanes; Depression; Dimethyl Sulfoxide; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Male; Prostaglandins; Quinolines; Rats; Sucrose; Sulfides; Tumor Necrosis Factor-alpha

Encephalopathy of prematurity (EoP) affects approximately 30% of infants born < 32 weeks gestation and is highly associated with inflammation in the foetus. Here we evaluated the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist widely used to treat asthma in children, to ameliorate peripheral and central inflammation, and subsequent grey matter neuropathology and behaviour deficits in a mouse model of EoP. Male CD-1 mice were treated with intraperitoneal (i.p.) saline or interleukin-1beta (IL-1β, 40 μg/kg, 5 μL/g body weight) from postnatal day (P)1-5 ± concomitant montelukast (1-30 mg/kg). Saline or montelukast treatment was continued for a further 5 days post-injury. Assessment of systemic and central inflammation and short-term neuropathology was performed from 4 h following treatment through to P10. Behavioural testing, MRI and neuropathological assessments were made on a second cohort of animals from P36 to 54. Montelukast was found to attenuate both peripheral and central inflammation, reducing the expression of pro-inflammatory molecules (IL-1β, IL-6, TNF) in the brain. Inflammation induced a reduction in parvalbumin-positive interneuron density in the cortex, which was normalised with high-dose montelukast. The lowest effective dose, 3 mg/kg, was able to improve anxiety and spatial learning deficits in this model of inflammatory injury, and alterations in cortical mean diffusivity were not present in animals that received this dose of montelukast. Repurposed montelukast administered early after preterm birth may, therefore, improve grey matter development and outcome in EoP.

Topics: Acetates; Animals; Brain Diseases; Disease Models, Animal; Female; Gray Matter; Humans; Infant, Newborn; Inflammation; Male; Mice; Premature Birth; Quinolines

Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group 2 innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia.. Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia.. Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.

Topics: Acetates; Animals; Antigens, Dermatophagoides; Class I Phosphatidylinositol 3-Kinases; Cyclopropanes; Cytokines; Eosinophils; Female; Goblet Cells; Hypersensitivity; Inflammation; Interleukin-33; Interleukin-5; Lymphocytes; Mice; Mice, Inbred BALB C; Pyroglyphidae; Quinolines; Respiratory System; Sulfides; Th2 Cells

Montelukast is a leukotriene receptor antagonist that is known to prevent allergic rhinitis and asthma. Blocking the Cysteinyl leukotriene receptor (CysLTR1), one of the primary receptors of leukotrienes, has been demonstrated to be efficacious in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through disrupting chemotaxis of infiltrating T cells. However, the role of CysLTR1 in the pathogenesis of MS is not well understood. Here, we show that MS patients had higher expression of CysLTR1 in the circulation and central nervous system (CNS). The majority of CD4

Topics: Acetates; Adoptive Transfer; Animals; Anti-Inflammatory Agents; Cell Differentiation; Cyclopropanes; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Inflammation; Leukotriene Antagonists; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Multiple Sclerosis; Quinolines; Receptors, Leukotriene; Signal Transduction; Sulfides; Th17 Cells

We hypothesized that oral montelukast treatment could inhibit cholesteatoma formation in an experimental animal model.. Inflammation and excessive proliferation have been described in the histopathology of cholesteatoma. The aim of this study was to determine the effect of oral montelukast on cholesteatoma development.. Eighteen healthy female Wistar albino rats weighing 250 g were chosen for the study. The animals were divided into two groups: group 1 received montelukast and group 2 was the control group. Intratympanic propylene glycol injection was administered into the left ears and physiologic serum was instilled into the right ears of the animals on the first, eighth, and fifteenth days. The effects of montelukast administration were evaluated by histological examination of the tympanic membrane and middle ear.. Group 1 (montelukast group) showed significant differences in terms of cholesteatoma formation, granulation, epithelial invagination, and inflammation. Cholesteatoma formation in the left ear was observed in 2 (22%) and 8 (89%) rats in groups 1 and 2, respectively (p = 0.015).. Development of cholesteatoma and inflammation was significantly lower in the montelukast-administered group. Thus, oral montelukast was found effective in preventing cholesteatoma formation.

Topics: Acetates; Animals; Cholesteatoma, Middle Ear; Cyclopropanes; Female; Inflammation; Models, Animal; Quinolines; Rats; Rats, Wistar; Sulfides

Alzheimer's disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling-more specifically, the leukotriene receptors-has been recognized as a potential drug target to ameliorate AD pathology. Here, we analyzed the effects of the leukotriene receptor antagonist montelukast (MTK) on hippocampal gene expression in 5xFAD mice, a commonly used transgenic AD mouse model. We identified glial activation and neuroinflammation as the main pathways modulated by MTK. The treatment increased the number of Tmem119+ microglia and downregulated genes related to AD-associated microglia and to lipid droplet-accumulating microglia, suggesting that the MTK treatment targets and modulates microglia phenotypes in the disease model compared to the vehicle. MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma. Finally, MTK treatment resulted in improved cognitive functions. In summary, we provide a proof of concept for MTK to be a potential drug candidate for AD and provide novel modes of action via modulation of microglia and CD8+ T-cells. Of note, 5xFAD females showed a more severe pathology, and in consequence, MTK treatment had a more pronounced effect in the females compared to the males. The effects on neuroinflammation, i.e., microglia and CD8+ T-cells, as well as the effects on cognitive outcome, were dose-dependent, therefore arguing for the use of higher doses of MTK in AD clinical trials compared to the approved asthma dose.

Topics: Acetates; Alzheimer Disease; Animals; Brain; CD8-Positive T-Lymphocytes; Cognition; Cyclopropanes; Inflammation; Leukotriene Antagonists; Mice; Mice, Transgenic; Quinolines; Sulfides

Hemorrhagic cystitis (HC) is a major urotoxic complication of cyclophosphamide (CPA) therapy. This study investigated the uroprotective effect of montelukast on CPA-induced HC, compared to the efficacy of 2-mercaptoethane sulfonate sodium (MESNA).. Male albino rats were pretreated with MESNA (40 mg/kg/day, IP) or montelukast (10 mg/kg/day, orally) for three days then received a single dose of CPA (200 mg/kg, IP), 1 h after the last dose, and compared to CPA-treated rats receiving drug vehicle. Age-matched rats were used as controls. Bladders of rats were assessed biochemically, macroscopically and microscopically by light and electron microscope 24 h later.. CPA injection contributed to increased bladder weight, urothelial ulceration, vascular congestion, hemorrhage, increased collagen deposition and mast cell infiltration, compared to control rats. Montelukast preconditioning suppressed mast cell infiltration and inflammatory mediators to greater extent than MESNA. Also, montelukast enhanced autophagosomes formation in detrusor myocytes and up-regulated the autophagy-related proteins (beclin-1 & LC3-II), likely through inhibition of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Montelukast preconditioning offset the up-regulation of transient receptor potential vanilloid 4 (TRPV4) in urothelial tissue of CPA-treated rats, to greater extent than MESNA.. These results demonstrate the uroprotective effect of montelukast on CPA-induced HC, which appears to be more superior to MESNA. These findings suggest that montelukast can emerge as a novel strategy to protect against CPA-induced urotoxicity.

Topics: Acetates; Animals; Apoptosis; Autophagy; Cyclophosphamide; Cyclopropanes; Cystitis; Hemorrhage; Inflammation; Male; Mast Cells; Mesna; Oxidative Stress; Phagocytosis; Phagosomes; Quinolines; Rats; Signal Transduction; Sulfides; TRPV Cation Channels; Urinary Bladder; Urothelium

Male reproductive dysfunction is one of the overlooked findings of diabetes mellitus (DM) that deserves greater scientific attention. This study is designed to explore the therapeutic potential of metformin and montelukast, in combination with Lactobacillus, for modulation of intestinal flora and suppression of oxidative stress in testicular and liver damage in diabetic male rats. A DM model was induced by streptozotocin (STZ)which caused functional, biochemical, and inflammatory injuries to the testicular and liver tissues. The experimental panel included nine rat groups: normal control, normal control plus metformin, normal control plus montelukast, DM control, DM plus montelukast, DM plus a combination of metformin and Lactobacillus, DM plus a combination of montelukast and Lactobacillus, and DM plus a combination of metformin and montelukast. In parallel, clinical evaluation of microscopic examination scoring, and hepatic and testicular injuries, were evaluated. Biochemical markers including glucose level, lipid profile, inflammatory markers (tumor necrosis factor- (TNF-α) and interleukin-17 (IL-17), Caspase-3, and Bax proteins expressions were measured. The change in the microbiota abundance was investigated using conventional and real-time PCR. The current study revealed a significant difference in the relative abundance of microbiota, where DM is associated with an enormous increase of Bacteroides spp., Clostridium spp., E. coli, and Fusobacterium spp., and a significant decrease in Bifidobacteria spp., and Lactobacillus spp., in contrast with normal control. Metformin and montelukast, in combination with Lactobacillus, significantly reversed the testicular and liver damage caused by STZ. Moreover, the drugs significantly reduced the oxidative, inflammatory, and apoptotic activities induced by STZ.

Topics: Acetates; Animals; Cyclopropanes; Cytochrome P-450 CYP1A2 Inducers; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Therapy, Combination; Gastrointestinal Microbiome; Hypoglycemic Agents; Inflammation; Lactobacillus; Male; Metformin; Oxidative Stress; Quinolines; Rats; Rats, Sprague-Dawley; Sulfides

Montelukast, a cysteinyl leukotriene receptor antagonist, exhibits antiinflammatory action. We tested whether exposure to montelukast plus nonsteroidal antiinflammatory drugs (NSAIDs) elicits better control of paw inflammation in the rat formalin test and improves associated gastric damage.. A total of 46 adult male rats were used in the study.. We evaluated separate and combined effects of montelukast (20 mg/kg), celecoxib (COX2 inhibitor, 10 mg/kg), and diclofenac (nonselective COX1/COX2 inhibitor, 10 mg/kg) on paw and gastric damage in the rat formalin test.. Individual pretreatments of rats with montelukast, diclofenac, or celecoxib partly reduced formalin-induced increases in (i) paw edema, fibrosis, and inflammatory cells, (iii) serum interleukin-6 (IL-6) and leukotrienes (LTB4 and LTD4), and (iv) paw expressions of inducible nitric oxide synthase (iNOS) and COX2. These effects were accentuated in rats treated with montelukast plus diclofenac or montelukast plus celecoxib. Alternatively, montelukast or celecoxib, but not diclofenac, alleviated formalin-evoked gastric damage and increments in tumor necrosis factor-α and decrements in prostaglandin-E. While montelukast equally enhances antiinflammatory action of diclofenac or celecoxib via downregulating iNOS/COX2/LTs/IL-6 signaling, its gastroprotective action is preferentially potentiated by celecoxib.

Topics: Acetates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase 2; Cyclopropanes; Diclofenac; Formaldehyde; Inflammation; Male; Nitric Oxide Synthase Type II; Quinolines; Rats; Rats, Wistar; Risk; Signal Transduction; Stomach; Sulfides

Asthma in elderly patients causes excessive suffering and inconvenience. Regimens with better efficacy and less adverse events are still in need of researches.. To investigate the effect of montelukast sodium plus budesonide on lung function, inflammatory factors, and immune levels in elderly asthma patients.. A total of 180 patients with asthma were assigned into the control group and the observation group. The control group was given aerosol inhalation of budesonide suspension, while the observation group was given budesonide inhalation and oral montelukast sodium. The treatment effect, lung function (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF)%), inflammatory factors (interleukin (IL)-4, IL-6, and tumor necrosis factor-α (TNF-α)), and immune level (immunoglobulin (Ig) A, and IgE) were analyzed and compared between the two groups.. After treatment, the effective rate was significantly higher in the observation group. The lung function and serum inflammatory factors were improved in both groups. The FEV1, FVC, and PEF% in the observation group were better, and the inflammatory factors IL-4, IL-6, and TNF-α were lower. Patients in both groups showed elevated IgA level and reduced IgE level, and the improvements were more significant in the observation group. There was no significant difference between the two groups in terms of adverse reaction.. Montelukast sodium plus budesonide has a promising clinical effect on asthma in elderly patients, effectively improves lung function and immunocompetence, and controls inflammatory response, without increasing the adverse reaction.

Topics: Acetates; Aged; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Budesonide; Cyclopropanes; Female; Humans; Inflammation; Male; Middle Aged; Quinolines; Respiratory Function Tests; Sulfides

It has been hypothesized that Montelukast, a cysteinyl leukotriene (cysLT) receptor antagonist, with effects of anti-inflammatory, suppress oxidative stress and reduce affect cytokine production, may limited progression of the disease on COVID-19 infection.

Topics: Acetates; Anti-Inflammatory Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cyclopropanes; Cytokines; Disease Progression; Humans; Inflammation; Oxidative Stress; Pandemics; Pneumonia, Viral; Quinolines; Receptors, Leukotriene; SARS-CoV-2; Sulfides

It is widely believed that infection with the SARS-CoV-2 virus triggers a disproportionate immune response which causes a devastating systemic injury, particularly in individuals with obesity, itself a chronic, multi-organ inflammatory disease. Immune cells accumulate in visceral adipose tissue and together with paracrine adipocytes release a wide range of biologically active cytokines (including IL-1β, IL5, IL6 and IL8) that can result in both local, pulmonary and systemic inflammation. A more intense 'cytokine storm' is postulated as the mechanism behind the extreme immune response seen in severe COVID-19. It is striking how dangerous the combination of obesity and COVID-19 is, resulting in a greater risk of ICU admission and a higher mortality. Furthermore, patients from a BAME background appear to have increased mortality after SARS-CoV-2 infection; they also have a higher prevalence of central obesity and its metabolic complications. In the absence of an effective vaccine, the therapeutic potential of immune-modulating drugs is a priority, but the development of new drugs is expensive and time-consuming. A more pragmatic solution would be to seek to repurpose existing drugs, particularly those that might suppress the heightened cytokine activity seen in obesity, the major risk factor for a poor prognosis in COVID-19. Montelukast is a cysteinyl leukotriene receptor antagonist licensed to treat asthma and allergic rhinitis. It has been shown to diminish pulmonary response to antigen, tissue eosinophilia and IL-5 expression in inflammatory cells. It has also been shown to decrease elevated levels of IL-1β and IL8 in humans with viral upper respiratory tract infections compared with placebo-treated patients. In addition, in silico studies have demonstrated a high binding affinity of the montelukast molecule to the terminal site of the virus's main protease enzyme which is needed for virus RNA synthesis and replication. Montelukast, which is cheap, safe and widely available would appear to have the potential to be an ideal candidate drug for clinical trials, particularly in early stage disease before irreparable tissue damage has already occurred. HYPOTHESIS: Through a direct anti-viral effect, or by suppression of heightened cytokine release in response to SARS-CoV-2, montelukast will reduce the severity of immune-mediated multiorgan damage resulting from COVID-19, particularly in patients with central obesity and metabolic syndrome.

Topics: Acetates; Antiviral Agents; Betacoronavirus; Coronavirus 3C Proteases; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cyclopropanes; Cysteine Endopeptidases; Cytokine Release Syndrome; Drug Repositioning; Humans; Immunologic Factors; Inflammation; Leukotriene Antagonists; Obesity; Pandemics; Pneumonia, Viral; Quinolines; SARS-CoV-2; Sulfides; Viral Nonstructural Proteins

Identification of the characterization of cysteinyl leukotrienes receptor (CysLTRs) could facilitate our understanding of these receptors' role in asthma. We aimed to investigate the localization and interactions of CysLTRs using a mouse model of asthma. BALB/c mice were administered ovalbumin (OVA) to induce allergic asthma. Some mice were administered the antagonists of CysLTR1, CysLTR2, and purinergic receptor P2Y12 (P2Y12R) (montelukast, HAMI 3379 and clopidogrel, respectively). The expression levels of CysLTR1, CysLTR2, and P2Y12R on lung tissues and inflammatory cells were evaluated by western blot, flow cytometry, and immunochemistry. CysLTR1 and P2Y12R were significantly up-regulated in lung tissues (P < 0.05 for each) from mouse after being sensitized and challenged with OVA (OVA/OVA). The ratio of CysLTR1: CysLTR2: P2Y12R in lungs of negative control (NC) mice was shifted from 1:0.43:0.35 to 1:0.65:1.34 in OVA/OVA mice. Montelukast significantly diminished the up-regulation of CysLTR1, CysLTR2, and P2Y12R (P < 0.05 for each), while the effects of HAMI 3379 and clopidogrel were predominant on the expression of CysLTR2 and P2Y12R, respectively. Montelukast predominantly diminished the cell count, while clopidogrel potently inhibited the release of interleukin (IL)-4, IL-5, and IL-13. Our study demonstrated the interactions between CysLTRs, thereby highlighting the potential synergistic effects of CysLTR antagonists in asthma treatment.

Topics: Acetates; Animals; Asthma; Clopidogrel; Cyclohexanecarboxylic Acids; Cyclopropanes; Disease Models, Animal; Drug Therapy, Combination; Eosinophils; Female; Inflammation; Interleukins; Leukotriene Antagonists; Mice; Mice, Inbred BALB C; Ovalbumin; Phthalic Acids; Purinergic P2Y Receptor Antagonists; Quinolines; Receptors, Leukotriene; Receptors, Purinergic P2Y12; Sulfides; Th2 Cells

Topics: Acetates; Animals; Anti-Bacterial Agents; Cefazolin; Cyclopropanes; Cytokines; Disease Models, Animal; Inflammation; Leukotriene Antagonists; Male; Nasal Septum; Quinolines; Rats; Rats, Wistar; Rhinitis; Sinusitis; Staphylococcal Infections; Staphylococcus aureus; Sulfides; Treatment Outcome; Turbinates

Chronic inflammation and oxidative stress are critical components in the pathogenic cascade of early diabetic retinopathy, characterized by neuronal and vascular degeneration. We investigated pharmacologic inhibition of the proinflammatory leukotriene cascade for therapeutic benefit in early diabetic retinopathy. Using the streptozotocin-induced diabetes mouse model, we administered montelukast, a leukotriene receptor antagonist, and diabetes-related retinal pathology was assessed. Early biochemical and cellular function measures were evaluated at 3 months' diabetes duration and included vascular permeability, superoxide production, leukotriene generation, leukocyte-induced microvascular endothelial cell death, and retinal function by electroretinography. Histopathology assessments at 9 months' diabetes duration included capillary degeneration and retinal ganglion cell loss. Leukotriene receptor antagonism resulted in a significant reduction of early, diabetes-induced retinal capillary leakage, superoxide generation, leukocyte adherence, and leukotriene generation. After 9 months of diabetes, the retinal microvasculature from untreated diabetic mice demonstrated a nearly threefold increase in capillary degeneration compared with nondiabetic mice. Montelukast inhibited the diabetes-induced capillary and neuronal degeneration, whether administered as a prevention strategy, immediately after induction of diabetes, or as an intervention strategy starting at 4.5 months after confirmation of diabetes. Pharmacologic blockade of the leukotriene pathway holds potential as a novel therapy to prevent or slow the development of diabetic retinopathy.

Topics: Acetates; Animals; Capillary Permeability; Cyclopropanes; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Electroretinography; Inflammation; Leukotriene Antagonists; Male; Mice; Quinolines; Retina; Retinal Vessels; Sulfides; Superoxides; Treatment Outcome

Topics: 5-Lipoxygenase-Activating Proteins; Acetates; Animals; Asthma; Cell Movement; Chemokines; Cyclopropanes; Epoxide Hydrolases; Humans; Inflammation; Leukotriene B4; Lipid Metabolism; Molecular Targeted Therapy; Neutrophil Activation; Neutrophils; Quinolines; Sulfides; T-Lymphocytes

Airway inflammation in chronic obstructive pulmonary disease (COPD) is refractory to corticosteroids and hence COPD treatment is hindered and insufficient. This study assessed the effects of oral treatment with Montelukast (10 and 30 mg/kg) or dexamethasone (20 mg/kg) for 20 days on COPD model induced by chronic exposure to lipopolysaccharide (LPS). Six groups of male guinea pigs were studied. Group 1: naïve group, group 2: exposed to saline nebulization. Groups 3, 4, 5, and 6: exposed to 9 nebulizations of LPS (30 μg/ml) for 1 hour, 48 hours apart with or without treatment with Montelukast or dexamethasone. Airway hyperreactivity (AHR) to methacholine (MCh), histopathological study and bronchoalveolar lavage fluid (BALF) as well as lung tissue analyses were performed 48 hours after the final exposure to LPS (day 20). LPS-induced pulmonary dysfunction was associated with increased neutrophil count, leukotriene (LT) B4, and tumor necrosis factor (TNF)-α in BALF. Moreover, there was an increase in malondialdehyde (MDA) level and a decrease in histone deacetylases(HDAC) activity in the lung tissue. Both Montelukast (10 or 30 mg /kg) and dexamethasone significantly reduced neutrophil count in BALF and inflammatory cells in lung parenchyma as well as TNF-α, and MDA levels. However, dexamethasone was more effective (p < 0.05). Montelukast, at a dose of 30 mg /kg, significantly reduced specific airway resistance after the 9th LPS exposure, attenuated AHR to MCh, decreased LTB4 and increased HDAC activity in comparison to dexamethasone. These results suggest that treatment with Montelukast can be useful in chronic airway inflammatory diseases including COPD poorly responsive to glucocorticoids.

Topics: Acetates; Animals; Bronchoalveolar Lavage Fluid; Chronic Disease; Cyclopropanes; Dexamethasone; Disease Models, Animal; Glucocorticoids; Guinea Pigs; Histone Deacetylases; Inflammation; Leukocyte Count; Leukotriene Antagonists; Leukotriene B4; Lipopolysaccharides; Lung; Male; Malondialdehyde; Neutrophils; Pulmonary Disease, Chronic Obstructive; Quinolines; Respiratory Hypersensitivity; Sulfides; Tumor Necrosis Factor-alpha

Asthma guidelines allow anti-leukotriene medications to be used as an alternative to inhaled corticosteroids (ICS) in second-step intensity therapy. The aim of the study was to analyze the risk factors of exacerbations, particularly inflammatory markers, during the 12-month period following therapy reduction from an ICS to montelukast in young patients with mild asthma.. A total of 84 patients (aged 7-18 years old) with mild asthma controlled by low-dose ICS, had their treatment switched to montelukast. Exhaled nitric oxide (eNO), sputum eosinophils (sEos), and bronchial hyperreactivity (BHR) were assessed at the beginning and then every three months throughout the one-year period. The patients with asthma exacerbations (first severe or third mild) were discontinued from the study.. Over the study period, 22 patients (26%) discontinued montelukast due to asthma exacerbations. An increased risk of exacerbations was noted among patients with initial sEos above 2.5% (relative risk, RR 36.6; 95% CI: 7.1-189.3; p < 0.001), as well as those with augmented BHR (RR 9.5; 2.8-31.6; p < 0.001), or eNO greater than 20 ppb (RR 3.7; 95% CI: 1.3-10.7; p = 0.013). An increase in BHR and eNO was observed during the last visit before exclusion.. After switching treatment from a low-dose ICS, montelukast maintained control of asthma symptoms in 75% of patients. High sEos before the treatment change was the strongest exacerbation risk factor. In patients with asthma controlled by low-dose ICS and low inflammatory markers, treatment could be safely switched to montelukast.

Topics: Acetates; Administration, Inhalation; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Child; Cyclopropanes; Eosinophils; Female; Follow-Up Studies; Glucocorticoids; Humans; Inflammation; Leukotriene Antagonists; Male; Nitric Oxide; Practice Guidelines as Topic; Prospective Studies; Quinolines; Risk Factors; Sputum; Sulfides

The potency of acute montelukast treatment, a leukotriene receptor antagonist, has been demonstrated as tocolytic on in vitro myometrial contractility. This study assessed the ability of a 48h montelukast treatment to modify in vitro contractions under inflammatory conditions in a pregnant rat model.. Pregnant Sprague-Dawley rats were injected intraperitoneally (gestational days 20-22) with lipopolysaccharides (LPS) 200μg/kg (4 treatments at 12h intervals) alone or combined with montelukast 10mg/kg/day or a saline solution for a 48h period. Uterine rings (n=72) were obtained by median laparotomy at day 22. Spontaneous contractile activities were compared using pharmacological compounds (oxytocin, nifedipine) along with assessment of contractile parameters. Myometrial subcellular fractions were also analyzed by Western blot to quantify oxytocin, cysteinyl leukotriene receptors and inflammation markers.. In in vitro experiments, the area under the curve, the amplitude and the duration of phasic contractions were significantly reduced following 48h of LPS+montelukast treatment comparatively to the LPS group. Moreover, in this same group, oxytocin (10. Our results strongly suggest that montelukast treatment could facilitate a relative uterine quiescence by decreasing its sensitivity to uterotonic agent or by increasing tocolytic efficiency under proinflammatory conditions.

Topics: Acetates; Animals; Cyclopropanes; Female; Inflammation; Leukotriene Antagonists; Myometrium; Pregnancy; Quinolines; Rats; Rats, Sprague-Dawley; Sulfides; Tocolytic Agents; Uterine Contraction; Uterus

Cysteinyl leukotrienes (CysLTs) propagate inflammatory reactions that result from allergen exposure in asthma. Montelukast, a CysLT type-1 receptor antagonist, disrupts mediator-receptor interactions and minimizes inflammatory response. In this study, we have evaluated anti-asthmatic efficacy of inhalable montelukast-loaded large porous particulate formulations in ovalbumin-induced rat airway inflammation model that mimics asthma.. The anti-inflammatory effects of a montelukast-loaded formulation were investigated in rats by measuring the total protein content, levels of injury markers and number of inflammatory cells in the bronchoalveolar lavage fluid (BALF). The histopathological studies assessed the morphological and structural changes that occur in asthmatic lungs. Animals were also challenged with methacholine to examine the airway hyper-reactivity.. Compared with healthy animals, asthmatic animals showed a 3.8- and 4.77-fold increase in the protein content and number of inflammatory cells in BALF, respectively. Intratracheal montelukast particles reduced the protein content by 3.3-fold and the number of inflammatory cells by 2.62-fold. Also, montelukast particles reduced the lactate dehydrogenase (LDH) and myeloperoxidase (MPO) levels by a 4.87- and 6.8-fold in BALF, respectively. Montelukast particles reduced the airway wall thickness by 2.5-fold compared with untreated asthmatic lungs. Further, particulate formulation protected the lungs against methacholine-induced bronchial provocation (p < 0.05).. Respirable large porous particles containing montelukast alleviated allergen-induced inflammatory response in an animal model and prevented histological changes associated with asthma. Thus montelukast-loaded large porous polylactic acid (PLA) particles could be an aerosolized delivery approach for administration of currently available oral montelukast.

Topics: Acetates; Aerosols; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cysteine; Disease Models, Animal; Inflammation; L-Lactate Dehydrogenase; Lactic Acid; Leukotrienes; Lung; Ovalbumin; Peroxidase; Polyesters; Polymers; Quinolines; Rats; Rats, Sprague-Dawley; Sulfides

Compare the effects of montelukast or dexamethasone in distal lung parenchyma and airway walls of guinea pigs (GP) with chronic allergic inflammation.. GP have inhaled ovalbumin (OVA group-2x/week/4weeks). After the 4th inhalation, GP were treated with montelukast or dexamethasone. After 72 hours of the 7th inhalation, GP were anesthetised, and lungs were removed and submitted to histopathological evaluation.. Montelukast and dexamethasone treatments reduced the number of eosinophils in airway wall and distal lung parenchyma compared to OVA group (P < 0.05). On distal parenchyma, both treatments were effective in reducing RANTES, NF- κ B, and fibronectin positive cells compared to OVA group (P < 0.001). Montelukast was more effective in reducing eotaxin positive cells on distal parenchyma compared to dexamethasone treatment (P < 0.001), while there was a more expressive reduction of IGF-I positive cells in OVA-D group (P < 0.001). On airway walls, montelukast and dexamethasone were effective in reducing IGF-I, RANTES, and fibronectin positive cells compared to OVA group (P < 0.05). Dexamethasone was more effective in reducing the number of eotaxin and NF- κ B positive cells than Montelukast (P < 0.05).. In this animal model, both treatments were effective in modulating allergic inflammation and remodeling distal lung parenchyma and airway wall, contributing to a better control of the inflammatory response.

Topics: Acetates; Administration, Inhalation; Animals; Chronic Disease; Cyclopropanes; Dexamethasone; Disease Models, Animal; Guinea Pigs; Hypersensitivity; Inflammation; Leukotriene Antagonists; Lung; Ovalbumin; Quinolines; Sulfides

The leukotrienes and prostaglandins are biologically active metabolites derived from arachidonic acid. The leukotrienes have a role in inflammatory diseases such as allergic rhinitis, inflammatory bowel disease and asthma. Montelukast, a cysteinyl leukotriene receptor antagonist, is claimed to be effective in asthma. The present study aimed to assess the role of cysteinyl leukotriene receptor antagonist on peripheral inflammation and whether montelukast treatment enhances the anti-inflammatory effect of indomethacin. Anti-inflammatory response was measured using a plethysmometer. Histopathologic examination for leukocyte accumulation was done. Montelukast (0.5-2mg/kg, i.p.) produced a significant anti-inflammatory effect in dose dependent manner against formalin-induced rat paw oedema at 1h but not in 3 and 5 h. When indomethacin (5 mg/kg, i.p) was co-administered with montelukast (1 mg/kg, i.p), the anti-inflammatory effects of indomethacin were significantly increased as compared to the per se effect at 3 and 5 hour after formalin challenge. In histopathology it has been found that combination therapy significantly decreased migration of leucocytes into the site of inflammation. These results show that montelukast has anti-inflammatory properties in peripheral tissue and markedly potentiates the anti-inflammatory activity of indomethacin at 3 and 5 h. It is expected that combination of montelukast with cyclooxygenase inhibitor would prove to be a novel approach to manage complex inflammatory conditions.

Topics: Acetates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclopropanes; Dose-Response Relationship, Drug; Drug Synergism; Formaldehyde; Indomethacin; Inflammation; Male; Quinolines; Rats; Rats, Wistar; Sulfides

This study examined the effect of montelukast and beclomethasone on airway remodeling in murine model of asthma. Mice were sensitized by i.p. injection of ovalbumin (OVA) on days 0 and 14, and then challenged by nebulization of 1% OVA 3 days/week for 6 or 10 weeks. Results of 6-week OVA-challenged group showed moderate inflammation, but the 10-week OVA-challenged group exhibited mild inflammation. The OVA challenge (6 and 10 weeks) exhibited marked airway fibrosis, illustrated by significant increase in goblet cell hyperplasia and epithelial thickness, increased lung content of collagen and transforming growth factor-β(1), together with a decrease in nitric oxide production; also, there was an increase in bronchoalveolar lavage fluid level of interleukin-13. Administration of montelukast or beclomethasone before each OVA challenge was capable of restoring most of the measured parameters to near normal levels. Inhalation of beclomethasone has a similar role in airway remodeling as montelukast, but its effects in regulating inflammatory changes is less pronounced than montelukast.

Topics: Acetates; Administration, Inhalation; Airway Remodeling; Animals; Anti-Asthmatic Agents; Asthma; Beclomethasone; Cyclopropanes; Disease Models, Animal; Inflammation; Male; Mice; Ovalbumin; Quinolines; Severity of Illness Index; Sulfides; Time Factors

Gastrointestinal eosinophilic (EG) is a rare and heterogeneous condition characterized by patchy or diffuse eosinophilic infiltration of gastrointestinal tissue. Pharmacological study so far has demonstrated that montelukast, an oral leukotriene receptor antagonist, might be considered in patients with this disease. The aim of this study was to evaluate the effect of montelukast on oral ovalbumin (OVA) allergen induced EG inflammation in mice and to suggest some mechanisms underlying this effect. Twenty-four mice were divided into three experimental groups: PBS control, OVA group, and montelukast treated group. The mice were sensitized intraperitoneally and challenged intragastrically with OVA, and were treated with montelukast. Gastrointestinal symptoms were observed after challenged intragastrically with OVA. Eosinophils count in blood, serum OVA specific IgE and gastrointestinal histology were evaluated. Montelukast could significantly reduce the severity of oral allergen-induced eosinophilic inflammation, villous atrophy, and associated symptoms of weight loss associated with diarrhea. Montelukast also could ameliorate OVA-induced gastrointestinal pathological lesions, which was associated with the decrease of IgE and LTD4 levels, and this might be one of the important mechanisms of montelukast that protected gastrointestinal injury from EG. These findings indicated that montelukast therapy may be a novel therapeutic approach for EG and other eosinophil-mediated diseases.

Topics: Acetates; Animals; Body Weight; Cyclopropanes; Enteritis; Eosinophilia; Eosinophils; Female; Gastric Mucosa; Gastritis; Gastroenteritis; Immunoglobulin E; Inflammation; Jejunum; Leukotriene D4; Mice; Mice, Inbred BALB C; Ovalbumin; Quinolines; Stomach; Sulfides

Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301-treated mice compared with vehicle-treated mice. Presumably, these therapeutic effects of ONO-1301 are attributable to the up-regulation of production of hepatocyte growth factor (HGF) in lung tissue, because the neutralization of HGF by antibodies prevented the effects of ONO-1301 on AHR and airway remodeling. Mice administered ONO-1301 showed similar levels of AHR and airway remodeling as mice administered montelukast, a cysteinyl-leukotriene-1 receptor antagonist, and lower levels were observed in mice administered dexamethasone. These data suggest that ONO-1301 exerts the effect of reversing airway remodeling, at least in part through an elevation of HGF in the lungs, and may be effective as an anti-remodeling drug in the treatment of asthma.

Topics: Acetates; Airway Remodeling; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cyclopropanes; Dexamethasone; Epoprostenol; Female; Goblet Cells; Hepatocyte Growth Factor; Inflammation; Lung; Metaplasia; Mice; Mice, Inbred BALB C; Muscle, Smooth; Ovalbumin; Pulmonary Fibrosis; Pyridines; Quinolines; Receptors, Leukotriene; Sulfides; Thromboxanes; Up-Regulation

Non-steroidal anti-inflammatory drugs (NSAIDS) are the first line of therapy in acute gouty arthritis. NSAIDs inhibit the cyclooxygenase pathway, but not the lipooxygenase activity and can have many adverse effects and thus have a limited effect on the control of inflammation in this disease. In this work we studied the effect of montelukast on the cellular inflammatory infiltrate in a model of murine arthritis induced by sodium monourate crystals (SMU), using a subcutaneous air cavity (air pouch) in BALB/c mice. Seven groups of BALB/c mice (n = 4) were distributed into five experimental groups and two inflammatory control groups, a positive and a negative one. Previous to SMU exposure, the experimental groups received montelukast (1 and 0.01 mg/Kg/w) and/or indomethacine (2.5 mg/Kg/w), followed by administration of SMU in the air pouch. The total and differential counts of inflammatory cells were analyzed after 2, 6, 12 and 24 hours. Montelukast, significantly reduced the total number of cells (p < 0.05), with a predominant impact on polymorphonuclear over mononuclear cells, especially after 12 hours of the medication. The montelukast/indometacine combination showed an additive effect. Our data show that montelukast has an anti-inflammatory effect in the model of gouty arthritis. Consequently, anti-leukotrienes could represent a new and effective therapy, either isolated or combined with conventional therapy of gouty arthritis.

Topics: Acetates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Gouty; Cell Migration Assays, Leukocyte; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Indomethacin; Inflammation; Leukocytes, Mononuclear; Leukotriene Antagonists; Male; Mice; Mice, Inbred BALB C; Neutrophils; Premedication; Quinolines; Sulfides; Uric Acid

Little is known about the role of the cysteinyl leukotriene (cysLT) 2 receptor in the pathophysiology of asthma. The aim of this study is to investigate the effects of a cysLT1 receptor antagonist (montelukast) and a dual cysLT1/2 receptor antagonist (BAY-u9773) on airway hypersensitivity and airway inflammation induced by antigen challenge in ovalbumin (OVA)-sensitized guinea pigs.. Male Hartley guinea pigs sensitized with OVA were intraperitoneally administered 0.1, 1, or 10 mg/kg of montelukast or 0.1 mg/kg of BAY-u9773 and then challenged with inhaled OVA. Airway reactivity to acetylcholine, inflammatory cells in bronchoalveolar lavage (BAL) fluid, and eosinophil infiltration in airway walls after OVA challenge were evaluated.. Pretreatment with 1 or 10 mg/kg, but not 0.1 mg/kg, of montelukast significantly suppressed airway hypersensitivity and eosinophil infiltration into the BAL fluid. Moreover, 0.1 mg/kg of BAY-u9773 significantly suppressed the development of these markers. The suppressive effects of BAY-u9773, although not significantly different, trended toward being greater than those of montelukast. Although all of the doses of montelukast tested and 0.1 mg/kg of BAY-u9773 significantly suppressed eosinophil infiltration in airway walls, the suppressive effect of BAY-u9773 was significantly greater than that of 0.1 mg/kg of montelukast.. Signaling may contribute to the pathophysiology of asthma via the cysLT1/2 receptor.

Topics: Acetates; Acetylcholine; Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Cyclopropanes; Eosinophils; Guinea Pigs; Inflammation; Leukotriene Antagonists; Lung; Male; Ovalbumin; Quinolines; Receptors, Leukotriene; SRS-A; Sulfides

Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators and are considered to play a key role in inflammatory diseases such as asthma. Antagonists targeting the receptor of CysLTs (CysLT1) are currently used as antiasthmatic drugs. CysLTs have also been implicated in other inflammatory reactions. In this study, we report that in experimental autoimmune encephalomyelitis animals, CysLT1 is upregulated in immune tissue and the spinal cord, and CysLT levels in the blood and cerebrospinal fluid are also higher than in normal mice. Two clinically used antiasthma drugs, montelukast and zafirlukast, both targeting CysLT1, effectively block the CNS infiltration of inflammatory cells and thus reduce the incidence, peak severity, and cumulative clinical scores. Further study indicated that CysLT1 signaling does not affect the differentiation of pathogenic T helper cells. It might affect the pathogenesis of experimental autoimmune encephalomyelitis by increasing the secretion of IL-17 from myelin oligodendrocyte glycoprotein-specific T cells, increasing the permeability of the blood-brain barrier and inducing chemotaxis of T cells. These effects can be blocked by CysLT1 antagonists. Our findings indicate that the antiasthmatic drugs against CysLT1 can also be used to treat multiple sclerosis.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Blood-Brain Barrier; Blotting, Western; Cell Separation; Cyclopropanes; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Fluorescent Antibody Technique; Indoles; Inflammation; Mice; Mice, Inbred C57BL; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Spinal Cord; Sulfides; Sulfonamides; Tosyl Compounds

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.. To determine the effects of montelukast (MK), a cysteinyl leukotriene (cysLT) receptor antagonist, in primary and secondary RSV-infected newborn and adult mice.. 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.. RSV infection induced cysLT release in bronchoalveolar lavage fluid. MK decreased RSV-induced AHR, airway inflammation, and increased IFN-gamma 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.. 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.

Topics: Acetates; Animals; Animals, Newborn; Anti-Asthmatic Agents; Bronchiolitis, Viral; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cysteine; Disease Models, Animal; Inflammation; Interferon-gamma; Leukotriene Antagonists; Leukotrienes; Mice; Mice, Inbred BALB C; Quinolines; Recurrence; Respiratory Hypersensitivity; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Sulfides

Montelukast and S-carbocysteine have been used in asthmatic patients as an anti-inflammatory or mucolytic agent respectively. S-carbocysteine also exhibits anti-inflammatory properties.. Ovalbumin (OVA) sensitized BALB/c mice were challenged with OVA for 3 days followed by single OVA re-challenge (secondary challenge) 2 weeks later. Forty-eight hours after secondary challenge, mice were assessed for airway hyperresponsiveness (AHR) and cell composition in bronchoalveolar lavage (BAL) fluid. Suboptimal doses of 10 mg.kg(-1) of S-carbocysteine by intraperitoneal injection (ip), 20 mg.kg(-1) of montelukast by gavage, the combination of S-carbocysteine and montelukast or 3 mg.kg(-1) of dexamethasone as a control were administered from 1 day before the secondary challenge to the last experimental day. Isolated lung cells were cultured with OVA and montelukast to determine the effects on cytokine production.. Treatment with S-carbocysteine or montelukast reduced both AHR and the numbers of eosinophils in BAL fluid. Neutralizing IFN-gamma abolished the effects of S-carbocysteine on these airway responses. Combination of the two drugs showed further decreases in both AHR and eosinophils in the BAL fluid. Goblet cell metaplasia and Th2-type cytokines, interleukin (IL)-4, IL-5 and IL-13, in BAL fluid were decreased with montelukast treatment. Conversely, S-carbocysteine increased Th1-type cytokines, IFN-gamma and IL-12 in BAL fluid.. The combination of two agents, montelukast and S-carbocysteine, demonstrated additive effects on AHR and airway inflammation in a secondary allergen model most likely through independent mechanisms of action.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Carbocysteine; Cyclopropanes; Dexamethasone; Drug Synergism; Drug Therapy, Combination; Eosinophils; Female; Inflammation; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Ovalbumin; Quinolines; Sulfides

To investigate the sensitizing effects of the cysteinyl leukotrienes (CysLTs) C(4) and D(4) on the proinflammatory responses of chemoattractant-activated human neutrophils in vitro.. Neutrophils were isolated from venous blood taken from healthy, adult, human volunteers.. Cells were exposed to LTC(4) and LTD(4) (50-300 nM) prior to activation with 1 microM of N-formyl-L-methionyl- L-leucyl-L-phenylalanine (fMLF).. A fura-2/AM-based spectrofluorimetric procedure, lucigenin-enhanced chemiluminescence (LECL), a colourimetric method and an ELISA procedure, were used to measure Ca(2+) mobilization, superoxide production, elastase and MMP-8 release respectively following activation of LTC(4)/ D(4)-primed neutrophils with fMLF. Superoxide generation was also measured in the presence and absence of the CysLT receptor 1 antagonist, montelukast (100 nM).. Exposure of neutrophils to either LTC(4) or LTD(4) alone had modest effects on Ca(2+) mobilization, while superoxide generation and elastase release were unaffected. However, relative to the responses of neutrophils activated with fMLF in the absence of the CysLTs, pre-treatment of the cells with either LTC(4)or LTD(4) resulted in significant, augmentation of fMLF-activated elastase and MMP-8 release and superoxide generation, which was attenuated by montelukast.. These previously undocumented sensitizing interactions of LTs C(4) and D(4) with neutrophils may contribute to the activation of these cells in acute and chronic inflammation of both atopic and non-atopic aetiology, while identifying a role for montelukast in regulating neutrophil reactivity.

Topics: Acetates; Adult; Chemotactic Factors; Cyclopropanes; Fluorescent Dyes; Fura-2; Humans; Inflammation; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Matrix Metalloproteinase 8; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pancreatic Elastase; Quinolines; Sulfides; Superoxides

We recently demonstrated that the T-helper type 1 (Th1) immune response plays an important role in the development of non-eosinophilic inflammation induced by airway exposure of an allergen plus double-stranded RNA (dsRNA). However, the role of lipoxygenase (LO) metabolites in the development of Th1 inflammation is poorly understood.. To evaluate the role of LO metabolites in the development of Th1 inflammation induced by sensitization with an allergen plus dsRNA.. A Th2-allergic inflammation mouse model was created by an intraperitoneal injection of lipopolysaccharide-depleted ovalbumin (OVA, 75 microg) and alum (2 mg) twice, and the Th1 model was created by intranasal application of OVA (75 microg) and synthetic dsRNA [10 microg of poly(I : C)] four times, followed by an intranasal challenge with 50 microg of OVA four times. The role of LO metabolites was evaluated using two approaches: a transgenic approach using 5-LO(-/-) and 15-LO(-/-) mice, and a pharmacological approach using inhibitors of cysteinyl leucotriene receptor-1 (cysLTR1), LTB4 receptor (BLT1), and 15-LO.. We found that the Th1-allergic inflammation induced by OVA+dsRNA sensitization was similar between 5-LO(-/-) and wild-type (WT) control mice, although Th2 inflammation induced by sensitization with OVA+alum was reduced in the former group. In addition, dsRNA-induced Th1 allergic inflammation, which is associated with down-regulation of 15-hydroxyeicosateraenoic acids production, was not affected by treatment with cysLTR1 or BLT1 inhibitors, whereas it was significantly lower in 12/15-LO(-/-) mice compared with WT control mice. Moreover, dsRNA-induced allergic inflammation and the recruitment of T cells following an allergen challenge were significantly inhibited by treatment with a specific 15-LO inhibitor (PD146176).. 15-LO metabolites appear to be important mediators in the development of Th1-allergic inflammation induced by sensitization with an allergen plus dsRNA. Our findings suggest that the 15-LO pathway is a novel therapeutic target for the treatment of virus-associated asthma characterized by Th1 inflammation.

Topics: Acetates; Allergens; Alum Compounds; Animals; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Cyclopropanes; Disease Models, Animal; Fatty Alcohols; Fluorenes; Glycols; Hypersensitivity; Inflammation; Leukotriene Antagonists; Lipoxygenase Inhibitors; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Poly I-C; Quinolines; Receptors, Leukotriene; Receptors, Leukotriene B4; RNA, Double-Stranded; Sulfides; Th1 Cells; Th2 Cells

Clinical manifestations suggest that air pollution may induce deterioration of respiratory health. Some air pollutants, including sulfite, may play a role in the exacerbation of asthma. Sulfites are formed at bronchial mucosa from inhaled sulfur dioxide. It has been previously reported that sodium sulfite (Na(2)SO(3)) has pro-inflammatory properties and enhances neutrophil adhesion to A549 cells. Interleukin-8 (IL-8) plays a critical role in attracting inflammatory cells and is an excellent marker of pulmonary cell activation. To date, there have not been any reports on the effect of asthma drugs on the suppression of IL-8 production induced by sulfite in A549 cells or the involvement of specific signal transduction pathways. Thus, our study assessed the effects of salmeterol, fluticasone, and montelukast on human epithelial lung cell inflammation as well as the inhibitors in different signal transduction pathways.. A549 human lung epithelial cells were cultured under the following conditions: (1) treated with sodium sulfite (0, 100, 500, 1000, 2500 uM) for 16 hours; (2) cultured for 1 hour in the presence of SB203580, PD98059, SP600125, or wedeloactone, then co-incubated with sodium sulfite for another 16 hours; (3) cultured for 4 hours in the presence of salmeterol, fluticasone, or montelukast, then stimulated with sodium sulfite at a concentration of 1000 uM for 16 hours. We collected the supernatants from the above conditions and performed enzyme-linked immunosorbent assay (ELISA) to measure the IL-8 concentration.. IL-8 production increased after treatment with sodium sulfite at 1000 to 2500 uM (p

Topics: Acetates; Air Pollutants; Albuterol; Androstadienes; Anti-Asthmatic Agents; Cell Line; Cell Survival; Cyclopropanes; Dose-Response Relationship, Drug; Epithelial Cells; Fluticasone; Humans; Inflammation; Interleukin-8; Lung; Quinolines; Salmeterol Xinafoate; Signal Transduction; Sulfides; Sulfites

Increased cough reflex sensitivity is found in patients with allergic rhinitis and may contribute to cough caused by rhinitis. We have reported that cough to citric acid is enhanced in the guinea pig model of allergic rhinitis. Here we address the hypothesis that the cough reflex sensitivity is increased in this model. The data from our previous studies were analyzed for the cough reflex sensitivity. The allergic inflammation in the nose was induced by repeated intranasal instillations of ovalbumin in the ovalbumin-sensitized guinea pigs. Cough was induced by inhalation of doubling concentrations of citric acid (0.05-1.6 M). Cough threshold was defined as the lowest concentration of citric acid causing two coughs (C2, expressed as geometric mean [95% confidence interval]). We found that the cough threshold was reduced in animals with allergic rhinitis. C2 was 0.5 M [0.36-0.71 M] and 0.15 M [0.1-0.23 M] prior and after repeated intranasal instillations of ovalbumin, respectively, P<0.01, n=36). C2 was not affected in control animals (n=29). We have reported that the selective leukotriene cys-LT1 receptor antagonist montelukast inhibited cough enhancement in this model. We found that this was accompanied by inhibition of the changes in cough reflex sensitivity. C2 was reduced in animals with allergic rhinitis treated orally with vehicle (0.57 M [0.28-1.1] vs. 0.09 M [0.04-0.2 M], P<0.05, n=8), but not in animals treated with montelukast (0.57 M [0.22-1.4 M] vs. 0.52 M [0.17-1.6 M], NS, n=8). We conclude that the cough reflex sensitivity is increased in the guinea pig model of allergic rhinitis. Our results suggest that guinea pig is a suitable model for mechanistic studies of increased cough reflex sensitivity in rhinitis.

Topics: Acetates; Allergens; Animals; Anti-Asthmatic Agents; Citric Acid; Cough; Cyclopropanes; Guinea Pigs; Inflammation; Leukotriene Antagonists; Male; Nasal Mucosa; Ovalbumin; Quinolines; Reflex; Rhinitis, Allergic, Seasonal; Sulfides

5-lipoxygenase (5-LO) is the key enzyme in leukotriene (LT) biosynthesis from arachidonic acid (AA). Here, we examined the role of the 5-LO-product, cysteinyl-LT (Cys-LT), with a 5-LO inhibitor (zileuton) and a Cys-LT, receptor antagonist (montelukast), in the inflammatory response and tissue injury associated with spinal cord injury (SCI).. SCI was induced in mice by the application of vascular clips to the dura via a two-level T6 to T7 laminectomy for 1 min. Cord inflammation was assessed histologically and by measuring inflammatory mediators (ELISA) and apoptosis by annexin V, TUNEL, Fas ligand staining and Bax and Bcl-2 expression (immunohistochemistry and western blots). Motor function in hindlimbs was assessed by a locomotor rating scale, for 10 days after cord injury.. SCI in mice resulted in tissue damage, oedema, neutrophil infiltration, apoptosis, tumour necrosis-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) expression, prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) production, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in injured tissue. Treatment of the mice with zileuton or montelukast reduced the spinal cord inflammation and tissue injury, neutrophil infiltration, TNF-alpha, COX-2 and pERK1/2 expression, PGE(2) and LTB(4) production, and apoptosis. In separate experiments, zileuton or montelukast significantly improved the recovery of limb function over 10 days.. Zileuton and montelukast produced a substantial reduction of inflammatory events associated with experimental SCI. Our data underline the important role of 5-LO and Cys-LT in neurotrauma.

Topics: Acetates; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Cyclooxygenase 2; Cyclopropanes; Cysteine; Dinoprostone; Disease Models, Animal; Gene Expression Regulation; Hydroxyurea; Inflammation; Leukotrienes; Lipoxygenase Inhibitors; Male; Mice; Neutrophil Infiltration; Quinolines; Recovery of Function; Spinal Cord Injuries; Sulfides; Tumor Necrosis Factor-alpha

1. The effect of montelukast or MEN91507, selective leucotriene CysLT1 receptor antagonists, on antigen-induced airway inflammation and bronchoconstriction were compared in anaesthetized guinea-pigs. 2. In sensitized animals, ovalbumin (0.3 mg kg(-1), i.v.)-induced microvascular leakage in trachea, intrapulmonary airways, total lung (parenchyma and intrapulmonary airways) and urinary bladder was reduced by MEN91507 (0.01-1 micromol kg(-1), i.v.), whereas montelukast (0.01-1 micromol kg(-1), i.v.) antagonized the effect of the antigen only in the lung and urinary bladder. 3. Ovalbumin (1 mg kg(-1), i.v.)-induced bronchoconstriction was dose dependently antagonized by MEN91507 (10-30 micromol kg(-1), i.v.), whereas the effect of montelukast (0.1-30 micromol kg(-1), i.v.) was marginal (15-30% inhibition). Neither MEN91507 nor montelukast (30 micromol kg(-1), i.v.) affected the bronchoconstrictor response induced by acetylcholine (0.3 micromol kg(-1), i.v.) in sensitized animals. 4. It is concluded that montelukast and MEN91507 display a differential activity against the effect of endogenous leucotrienes, despite the fact that both compounds show a similar antagonist profile against exogenous leucotrienes acting through CysLT1 receptors.

Topics: Acetates; Animals; Antigens; Benzopyrans; Bronchoconstriction; Cyclopropanes; Dose-Response Relationship, Drug; Evans Blue; Guinea Pigs; Inflammation; Injections, Intravenous; Leukotriene Antagonists; Male; Membrane Proteins; Ovalbumin; Quinolines; Receptors, Leukotriene; Respiratory System; Sulfides; Tetrazoles

Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating adenosine A(1) receptors. Previously, it is reported that a high dose of L-97-1, a water-soluble, small molecule adenosine A(1) receptor antagonist, blocks early and late allergic responses, and bronchial hyper-responsiveness to histamine in a hyper-responsive rabbit model of allergic asthma. Effects of a lower dose of L-97-1 are compared to montelukast, a cysteinyl leukotriene-1 receptor antagonist on early allergic response, late allergic response, bronchial hyper-responsiveness, and inflammatory cells in bronchoalveolar lavage (BAL) fluid following house dust mite administration. Rabbits received intraperitoneal injections of house dust mite extract within 24 h of birth followed by booster house dust mite injections. Hyper-responsive rabbits received aerosolized house dust mite (2500 allergen units), 1 h after intragastric administration of L-97-1 (1 mg/kg) or montelukast (0.15 mg/kg) and lung dynamic compliance was measured for 6 h. Lung dynamic compliance was significantly higher following L-97-1 at all time points and with montelukast at 60-300 min following house dust mite (P<0.05). L-97-1 blocks both early and late allergic responses. Montelukast blocks only the late allergic response. Both L-97-1 and montelukast significantly blocked bronchial hyper-responsiveness at 24 h (P<0.05). Both L-97-1 and montelukast significantly reduced BAL eosinophils at 6 h and neutrophils at 6 and 24 h (P<0.05). L-97-1 significantly reduced BAL lymphocytes at 6 and 24 h (P<0.05). Montelukast significantly reduced BAL macrophages at 6 and 24 h (P<0.05). By blocking both bronchoconstriction and airway inflammation, L-97-1 may be an effective oral anti-asthma treatment.

Topics: Acetates; Adenosine A1 Receptor Antagonists; Animals; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Cyclopropanes; Disease Models, Animal; Eosinophils; Histamine; Inflammation; Leukotriene Antagonists; Lung Compliance; Lymphocytes; Macrophages, Alveolar; Neutrophils; Purines; Pyroglyphidae; Quinolines; Rabbits; Sulfides; Time Factors

Pain is commonly associated with inflammation. Several mediators including prostaglandins have been implicated in pain and inflammation. However, the recent reports indicated the role of leukotrienes as signaling molecules in pain. The present study was aimed to evaluate the effect of 5-LOX inhibitor, zileuton in nociceptive paradigms including inflammatory pain. Acetic acid-induced writhing, tail flick and hot plate tests to assess pain response were used. The effect on carrageenan-induced mechanical hyperalgesia, and acetic acid-induced vascular permeability was also determined. Zileuton (ED50=31.81 mg/kg p.o.), zafirlukast (ED50=6.19 mg/kg p.o.), montelukast (ED50=7.17 mg/kg p.o.) inhibited acetic acid-induced writhing in mice. Further, zileuton and ZK 158252, leukotriene B4 receptor antagonist did not alter basal response against tail flick and hot plate assays. Acetic acid-induced vascular permeability was significantly inhibited by zileuton. Oral administration of zileuton showed efficacy against carrageenan-induced mechanical hyperalgesia and also reversed histological changes in paw biopsies. These data suggest that zileuton, a 5-LOX inhibitor, exhibited antinociceptive effect in paradigms of inflammatory pain.

Topics: Acetates; Acetic Acid; Analgesics; Animals; Capillary Permeability; Carrageenan; Cyclopropanes; Dose-Response Relationship, Drug; Female; Hindlimb; Hydroxyurea; Hyperalgesia; Indoles; Inflammation; Leukotriene Antagonists; Lipoxygenase Inhibitors; Male; Mice; Pain; Pain Measurement; Phenylcarbamates; Quinolines; Rats; Rats, Wistar; Receptors, Leukotriene B4; Sulfides; Sulfonamides; Tosyl Compounds

Topics: Acetates; Asthma; Bronchial Hyperreactivity; Child; Cyclopropanes; Humans; Immune System; Immunotherapy; Inflammation; Leukotriene Antagonists; Quinolines; Sulfides

Airway inflammation and remodeling in chronic asthma are characterized by airway eosinophilia, hyperplasia of goblet cells and smooth muscle, and subepithelial fibrosis. We examined the role of leukotrienes in a mouse model of allergen-induced chronic lung inflammation and fibrosis. BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on Days 0 and 14, received intranasal OVA periodically Days 14-75. The OVA-treated mice developed an extensive eosinophil and mononuclear cell inflammatory response, goblet cell hyperplasia, and mucus occlusion of the airways. A striking feature of this inflammatory response was the widespread deposition of collagen beneath the airway epithelial cell layer and also in the lung interstitium in the sites of leukocytic infiltration that was not observed in the saline-treated controls. The cysteinyl leukotriene(1) (CysLT(1)) receptor antagonist montelukast significantly reduced the airway eosinophil infiltration, mucus plugging, smooth muscle hyperplasia, and subepithelial fibrosis in the OVA-sensitized/challenged mice. The presence of Charcot-Leyden-like crystals in airway macrophages and the increased interleukin (IL)-4 and IL-13 mRNA expression in lung tissue and protein in BAL fluid seen in OVA-treated mice were also inhibited by CysLT(1) receptor blockade. These data suggest an important role for cysteinyl leukotrienes in the pathogenesis of chronic allergic airway inflammation with fibrosis.

Topics: Acetates; Acute Disease; Allergens; Analysis of Variance; Animals; Asthma; Bronchoalveolar Lavage Fluid; Chronic Disease; Cyclopropanes; Disease Models, Animal; Drug Evaluation, Preclinical; Eosinophils; Fibrosis; Glycoproteins; Goblet Cells; Hyperplasia; Inflammation; Leukotriene Antagonists; Leukotrienes; Lysophospholipase; Macrophages, Alveolar; Mice; Ovalbumin; Quinolines; Respiratory Mechanics; Sulfides