montelukast and Pneumonia

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

Airway remodeling is believed to be important in the pathophysiology of asthma, and myofibroblasts are increased in the airways of asthmatic individuals 24 h after allergen challenge. Leukotriene receptor antagonists exert antiinflammatory activity in asthma, but it is unknown whether they influence indices of airway remodeling. In the present study, we evaluated the effect of montelukast on airway myofibroblasts following low-dose allergen challenge (LDAC).. Stable subjects with mild asthma were included in a two-center, randomized, parallel-group study. A 2-week run-in period was followed by LDAC and endobronchial biopsy. Subjects were then randomized to receive either montelukast, 10 mg/d, or placebo (n = 10 in each group) for 8 weeks in a double-blind manner; at the end of the treatment period, subjects underwent a second LDAC and endobronchial biopsy. The effect of treatment on myofibroblasts, fibroblasts, and inflammatory cells was examined using electron microscopy techniques.. Treatment with montelukast showed no significant difference by comparison with placebo but did show a significant within-group treatment-related decrease in airway wall myofibroblasts not seen in the placebo group. In addition, the montelukast-treated group also showed a significant within-group reduction in lymphomononuclear cells and increased neutrophils.. The results suggest that montelukast has an inhibitory effect on airway structural cells that play a key role in airway remodeling in allergic airway inflammation, and that montelukast may be a useful therapy to attenuate airway remodeling in asthma.

Topics: Acetates; Adult; Anti-Asthmatic Agents; Asthma; Bronchial Provocation Tests; Cyclopropanes; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fibroblasts; Forced Expiratory Volume; Humans; Male; Muscle, Smooth; Pneumonia; Quinolines; Respiratory System; Sulfides

Leukotriene receptor antagonists appear to exert anti-inflammatory activity in asthma. We undertook the present study to evaluate the effect of montelukast on levels of exhaled nitric oxide (ENO) and two inflammatory markers, hydrogen peroxide (H(2)O(2)), and cysteinyl leukotrienes (cys-LTs), in the exhaled breath condensate of subjects with mild asthma.. Twenty stable subjects with mild asthma (15 women and 5 men; mean [+/- SD] age, 34.8 +/- 12.6 years) were included in the study.. A 1-week run-in period was followed by 2 weeks of treatment (with montelukast or placebo) that was administered in randomized, double-blind, crossover fashion. One week of washout followed each treatment arm.. Montelukast significantly reduced the levels of ENO from baseline (median, 52.5 parts per billion [ppb]; 25th to 75th percentile, 37.8 to 101.8 ppb) during the entire treatment period (ie, day 1 to day 14), with the effect measurable as early as day 1 (median, 45.9 ppb; 25th to 75th percentile, 29.3 to 92.5 ppb) and with the maximal effect being observed on day 7 (median, 35.7 ppb; 25th to 75th percentile, 27.6 to 66.6 ppb). The levels of ENO did not change significantly with placebo therapy. Montelukast improved symptom score and reduced peak expiratory flow (PEF) variability. Changes in PEF variability correlated positively with changes in ENO (r = 0.46; p = 0.04). No significant changes in FEV(1) or concentration of H(2)O(2) in the exhaled breath condensate were observed. Levels of cys-LTs were undetectable in the exhaled breath condensate.. We concluded that montelukast reduces the levels of ENO in patients with mild asthma, a finding that is compatible with an anti-inflammatory effect of montelukast, and that ENO appears to be more sensitive in detecting this effect than FEV(1) and H(2)O(2) levels in the exhaled breath condensate.

Topics: Acetates; Adult; Anti-Asthmatic Agents; Asthma; Biomarkers; Breath Tests; Cross-Over Studies; Cyclopropanes; Cysteine; Double-Blind Method; Exhalation; Female; Forced Expiratory Volume; Humans; Hydrogen Peroxide; Inflammation Mediators; Leukotrienes; Male; Nitric Oxide; Peak Expiratory Flow Rate; Pneumonia; Quinolines; Severity of Illness Index; Sulfides

Some pro-inflammatory lipids derived from 1 lipooxygenase enzyme are potent neutrophil chemoattractant, a cell centrally involved in acute respiratory distress syndrome (ARDS); a syndrome lacking effective treatment. Considering the beneficial effects of the leukotriene receptor inhibitor, montelukast, on other lung diseases, whether montelukast attenuates inflammation in a mouse model of ARDS, and whether it reduces LPS stimulated activation of human neutrophils was investigated.. Thirty-five C57Bl/6 mice were distributed into control (PBS)+24h, LPS+24h (10μg/mouse), control+48h, LPS+48h, and LPS 48h+Montelukast (10mg/kg). In addition, human neutrophils were incubated with LPS (1μg/mL) and treated with montelukast (10μM).. Oral-tracheal administration of montelukast significantly attenuated total cells (P<.05), macrophages (P<.05), neutrophils (P<.01), lymphocytes (P<.001) and total protein levels in BAL (P<.05), as well as IL-6 (P<.05), CXCL1/KC (P<.05), IL-17 (P<.05) and TNF-α (P<.05). Furthermore, montelukast reduced neutrophils (P<.001), lymphocytes (P<.01) and macrophages (P<.01) in the lung parenchyma. In addition, montelukast restored BAL VEGF levels (P<.05). LTB4 receptor expression (P<.001) as well as NF-κB (P<.001), a downstream target of LPS, were also reduced in lung parenchymal leukocytes. Furthermore, montelukast reduced IL-8 (P<.001) production by LPS-treated human neutrophils.. In conclusion, montelukast efficiently attenuated both LPS-induced lung inflammation in a mouse model of ARDS and in LPS challenged human neutrophils.

Topics: Acetates; Animals; Bronchoalveolar Lavage; Capillary Permeability; Cyclopropanes; Cytokines; Humans; Leukocyte Count; Leukotriene Antagonists; Lipopolysaccharides; Lung; Lymphocytes; Macrophages; Mice; Mice, Inbred C57BL; Neutrophil Activation; Neutrophils; NF-kappa B; Pneumonia; Quinolines; Receptors, Leukotriene B4; Respiratory Distress Syndrome; Sulfides; Time Factors; Vascular Endothelial Growth Factor A

The incidence of overlapping bronchial asthma and chronic obstructive pulmonary disease has increased in recent years. Cysteinyl leukotrienes (CysLTs) play an important role in asthma, and the type 1 CysLT receptor (CysLT1R) is expressed by many inflammatory cells. We evaluated the effect of montelukast, a CysLT1R antagonist, on mouse models of asthma, porcine pancreatic elastase (PPE)-induced emphysema, and asthma combined with emphysema. Mice were sensitized with ovalbumin (OVA) on Days 0 and 14 and subsequently challenged with OVA on Days 28, 29, and 30. Pulmonary emphysema was induced by intratracheal instillation of PPE on Day 25. Mice were treated subcutaneously with montelukast or vehicle from Day 25 to Day 31. Airway hyperresponsiveness (AHR), static compliance; the number of inflammatory cells, the levels of cytokines, chemokines, LTs, and perforin in the bronchoalveolar lavage fluid, and the quantitative morphometry of lung sections were analyzed on Day 32. Treatment with montelukast significantly attenuated the AHR and eosinophilic airway inflammation in OVA-sensitized and OVA-challenged mice. Administration of montelukast significantly reduced the AHR, static compliance, and neutrophilic airway inflammation, while attenuating emphysematous lung changes, in PPE-treated mice. In PPE-treated mice subjected to allergen sensitization and challenges, montelukast significantly suppressed the AHR, static compliance, and eosinophilic and neutrophilic airway inflammation in addition to the development of experimentally induced emphysema in the lungs. Our data suggest that CysLT1R antagonists may be effective in ameliorating the consequences of PPE-induced lung damage and the changes that follow allergen sensitization and challenges.

Topics: Acetates; Animals; Asthma; Bronchoalveolar Lavage Fluid; Chemokines; Cyclopropanes; Cysteine; Female; Leukotriene Antagonists; Leukotrienes; Lung; Mice; Mice, Inbred BALB C; Pneumonia; Pulmonary Emphysema; Quinolines; Receptors, Leukotriene; Sulfides; Tumor Necrosis Factor-alpha

Foxa2 is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells of the developing and mature lung. Foxa2 is required for normal airway epithelial differentiation, and its deletion causes goblet-cell metaplasia and Th2-mediated pulmonary inflammation during postnatal development. Foxa2 expression is inhibited during aeroallergen sensitization and after stimulation with Th2 cytokines, when its loss is associated with goblet-cell metaplasia. Mechanisms by which Foxa2 controls airway epithelial differentiation and Th2 immunity are incompletely known. During the first 2 weeks after birth, the loss of Foxa2 increases the production of leukotrienes (LTs) and Th2 cytokines in the lungs of Foxa2 gene-targeted mice. Foxa2 expression inhibited 15-lipoxygenase (Alox15) and increased Alox5 transcription, each encoding key lipoxygenases associated with asthma. The inhibition of the cysteinyl LT (CysLT) signaling pathway by montelukast inhibited IL-4, IL-5, eotaxin-2, and regulated upon activation normal T cell expressed and presumably secreted expression in the developing lungs of Foxa2 gene-targeted mice. Montelukast inhibited the expression of genes regulating mucus metaplasia, including Spdef, Muc5ac, Foxa3, and Arg2. Foxa2 plays a cell-autonomous role in the respiratory epithelium, and is required for the suppression of Th2 immunity and mucus metaplasia in the developing lung in a process determined in part by its regulation of the CysLT pathway.

Topics: Acetates; Animals; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Cyclopropanes; Cysteine; Disease Models, Animal; Eosinophils; Goblet Cells; Hepatocyte Nuclear Factor 3-beta; Inflammation Mediators; Leukotriene Antagonists; Leukotrienes; Metaplasia; Mice; Mice, Knockout; Mice, Transgenic; Pneumonia; Quinolines; Signal Transduction; Sulfides; Th2 Cells

We evaluated the effects of anti-iNOS (1400W - W) associated with leukotriene antagonist (montelukast - M) or corticosteroid (dexamethasone - D) on distal lung of guinea pigs (GP) with chronic pulmonary inflammation.. GP were inhaled with ovalbumin (OVA-2×/week/4 weeks), treated with M (OVAM), D (OVAD) and/or W (OVAW, OVADW, OVAMW) and distal lungs were evaluated by morphometry.. Isolated treatments were not sufficient to reduce all parameters. In OVADW, all parameters were reduced with greater reduction in elastic fibers, TIMP-1, IL-4, IL-5, IFN-gamma and PGF2-alpha compared with OVAD (p<0.05). OVAMW potentiated the reduction of actin, elastic fibers, TIMP-1, IL-4, IL-5, TGF-beta, IFN-gamma, iNOS, and PGF2-alpha to a greater extent than OVAM (p<0.05). A reduction of TIMP-1, IL-4, IL-5, TGF-beta, IFN-gamma and iNOS was observed in OVADW compared with OVAMW (p<0.05).. Although anti-iNOS paired with montelukast or dexamethasone yields better results than isolated treatments, the most effective pairing for controlling inflammation, oxidative stress and remodeling in this asthma model was found to be corticosteroids and anti-iNOS.

Topics: Acetates; Amidines; Animals; Anti-Inflammatory Agents; Benzylamines; Chronic Disease; Cyclopropanes; Cytokines; Dexamethasone; Disease Models, Animal; Enzyme Inhibitors; Eosinophils; Guinea Pigs; Lung; Male; Ovalbumin; Pneumonia; Quinolines; Statistics, Nonparametric; Sulfides

It has been well-documented that leukotrienes (LTs) are released in allergic lung inflammation and that they participate in the physiopathology of asthma. A role for LTs in innate immunity has recently emerged: Cys-LTs were shown to enhance FcgammaR-mediated phagocytosis by alveolar macrophages (AMs). Thus, using a rat model of asthma, we evaluated FcgammaR-mediated phagocytosis and killing of Klebsiella pneumoniae by AMs. The effect of treatment with a cys-LT antagonist (montelukast) on macrophage function was also investigated. Male Wistar rats were immunized twice with OVA/alumen intraperitoneally and challenged with OVA aerosol. After 24 h, the animals were killed, and the AMs were obtained by bronchoalveolar lavage. Macrophages were cultured with IgG-opsonized red blood cells (50:1) or IgG-opsonized K. pneumoniae (30:1), and phagocytosis or killing was evaluated. Leukotriene C(4) and nitric oxide were quantified by the EIA and Griess methods, respectively. The results showed that AMs from sensitized and challenged rats presented a markedly increased phagocytic capacity via FcgammaR (10X compared to controls) and enhanced killing of K. pneumoniae (4X higher than controls). The increased phagocytosis was inhibited 15X and killing 3X by treatment of the rats with montelukast, as compared to the non-treated group. cys-LT addition increased phagocytosis in control AMs but had no effect on macrophages from allergic lungs. Montelukast reduced nitric oxide (39%) and LTC(4) (73%). These results suggest that LTs produced during allergic lung inflammation potentiate the capacity of AMs to phagocytose and kill K. pneumonia via FcgammaR.

Topics: Acetates; Allergens; Animals; Asthma; Cyclopropanes; Cysteine; Disease Models, Animal; Klebsiella pneumoniae; Leukotriene Antagonists; Leukotriene C4; Leukotrienes; Lung; Macrophages, Alveolar; Male; Nitric Oxide; Ovalbumin; Phagocytosis; Pneumonia; Quinolines; Rats; Rats, Wistar; Receptors, IgG; Sulfides

This report describes the Churg-Strauss syndrome (CSS) in a 23-year-old asthmatic man treated with a leukotriene antagonists-montelukast. The Churg-Strauss syndrome is now defined as one of the ANCA-associated vasculitis and is characterised by eosinophilia, asthma, chronic sinusitis, cardiomyopathy, pulmonary infiltrates, cutaneous vasculitis, gastrointestinal complaints and a muliplex neuropathy. The pathogenesis is not clear, but it has been reported in patients treated with leukotriene antagonists. We describe a case of CSS with severe pulmonary and cardiovascular complications.

Topics: Acetates; Adult; Churg-Strauss Syndrome; Cyclopropanes; Humans; Leukotriene Antagonists; Male; Pericarditis; Pneumonia; Quinolines; Sulfides

Allergic inflammation of the airways has a critical role in asthma development. We investigated a suppressive effect of verproside (3,4-dihydroxy catalpol) isolated from the extract of Pseudolysimachion longifolium on asthmatic parameters--such as immunoglobulin E (IgE) level, cytokine release, eosinophilia, airway hyperresponsiveness and mucus hypersecretion--in an OVA-sensitized/challenged mouse model. Verproside significantly inhibited the increase of total IgE and the cytokines IL-4 and IL-13 in plasma and bronchoalveolar lavage fluid, and also effectively suppressed airway hyperresponsiveness, eosinophilia and mucus hypersecretion in OVA-induced asthmatic mice. The efficacy of verproside was comparable to montelukast, an anti-asthmatic drug that is currently available. These results suggest that verproside could be a major marker in herbal medicines that are used for asthma treatment, and could also act as a lead for anti-asthmatic drugs.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Disease Models, Animal; Female; Glucosides; Immunoglobulin E; Interleukin-13; Interleukin-4; Iridoid Glucosides; Iridoids; Lung; Methacholine Chloride; Mice; Mice, Inbred BALB C; Molecular Structure; Mucus; Ovalbumin; Plant Extracts; Pneumonia; Pulmonary Eosinophilia; Quinolines; Sulfides; Veronica