leukotriene-d4 and Chronic-Disease

Topics: Acetates; Administration, Oral; Animals; Asthma; Chromones; Chronic Disease; Cyclopropanes; Humans; Leukotriene Antagonists; Leukotriene D4; Lung; Quinolines; Sulfides

Cysteinyl leukotrienes mediate signs and symptoms of asthma. In a double-blind, placebo-controlled, crossover study, a new potent and specific cysteinyl leukotriene (LTD4) receptor antagonist, montelukast (MK-0476), was evaluated for tolerability and clinical efficacy in patients with chronic asthma (receiving and not receiving inhaled corticosteroids).. Twenty-nine nonsmoking patients with asthma (15 treated concomitantly with inhaled corticosteroids) with FEV1 percent predicted values between 50% to 80% received MK-0476, 200 mg, or placebo three times daily for 10 1/3 days (31 doses) in a random, crossover manner, after a 2-week, open, baseline period. Comparisons in FEV1 (mean percent change from baseline after the first and last dose), mean daily daytime asthma and nocturnal awakening scores, and mean daily beta-agonist use were made between treatment periods.. Montelukast, compared with placebo, caused improvements in FEV1 (mean percentage point difference of the percentage change from baseline) 3 and 4 hours after dosing on day 1 (hour 3, 9.0%; 95% confidence interval [CI] 0.53, 18.72; hour four, 10.9%; 95% CI -0.25, 20.20) and day 11 (hour 3, 14.0%; 95% CI 0.76, 31.43; hour 4, 13.4%; 95% CI 1.24, 28.83). Reductions were observed in mean daily beta-agonist use (1.0 puff/day [95% CI -1.61, -0.26]), mean daytime symptom scores, and nocturnal awakenings over the 10 1/3 day treatment period. There were no important differences between the groups receiving and those not receiving inhaled corticosteroids. Montelukast was well tolerated with no serious clinical adverse events reported.. In this study Montelukast, 200 mg, administered three times daily for 10 1/3 days, compared with placebo, was generally well tolerated and resulted in significant improvement in chronic asthma, irrespective of the presence of inhaled corticosteroids.

Topics: Acetates; Adolescent; Adrenal Cortex Hormones; Adult; Asthma; Chronic Disease; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Leukotriene Antagonists; Leukotriene D4; Male; Membrane Proteins; Middle Aged; Quinolines; Receptors, Leukotriene; Sulfides

Eosinophils are multifunctional granulocytes capable of releasing various cytokines, chemokines, and lipid mediators. We previously reported dysregulated fatty acid metabolism in peripheral blood-derived eosinophils from patients with severe asthma. However, functional characteristics of eosinophils present in allergic inflammatory tissues remain largely uncharacterized.. We established a method for isolating CD69. Lipidomic analysis revealed impaired synthesis of prostaglandins and 15-lipoxygenase (15-LOX)-derived mediators, and selective upregulation of leukotriene D. Inflammatory tissue-derived eosinophils possess a specific phenotype with dysregulated fatty acid metabolism that may be targeted therapeutically to control eosinophilic inflammatory diseases.

Topics: Adult; Arachidonate 15-Lipoxygenase; Blood Donors; Cells, Cultured; Chronic Disease; Cytokines; Eosinophils; Fatty Acids; Female; gamma-Glutamyltransferase; Humans; Leukotriene D4; Male; Middle Aged; Nasal Polyps; Phenotype; Prostaglandin-Endoperoxide Synthases; Proteome; Rhinitis; Signal Transduction; Sinusitis; Transcriptome

Both histamine and leukotrienes are implicated in the pathogenesis of allergic rhinitis (AR), although the pattern and severity of the nasal response to these two potent inflammatory mediators may differ, which has not been adequately studied in patients with persistent AR.. We sought to compare the differential effects of nasal challenge with leukotriene D. An open-label, crossover study was performed in 25 persistent AR patients (AR group) and 16 healthy subjects (control group). Participants randomly underwent histamine and LTD. Nasal airway resistance (NAR) increased significantly after both LTD. LTD

Topics: Adult; Aged; Airway Resistance; Case-Control Studies; Chronic Disease; Cross-Over Studies; Female; Histamine; Humans; Leukotriene D4; Male; Middle Aged; Nasal Provocation Tests; Reference Values; Rhinitis, Allergic; Severity of Illness Index; Young Adult

Histamine-releasing antibodies that act against the epitope of the alpha chain of Fc(epsilon)RI (anti-Fc(epsilon)RI(alpha) antibody) that may affect pathogenesis in serum of patients with chronic urticaria. We assessed the capability of anti-Fc(epsilon)RI(alpha) antibody in sera from patients with chronic urticaria to release histamine and cytokines, and to induce the expression of endothelial cell adhesion molecules. We also assessed the release of inflammatory mediators from cultured foreskin mast cells, and expression of endothelial cell adhesion molecules on human dermal microvascular endothelial cells. Cells were pretreated with mast cell-conditioned media: culture media of mast cells treated with sera from chronic urticaria patients containing anti-Fc(epsilon)RI(alpha) antibody. Histamine release from human foreskin mast cells challenged with sera, increased after both 20 min and 16 h intervals. Leukotriene D4 release also increased at both 20 min and 16 h. Tumor necrosis factor-alpha increased significantly in foreskin mast cell culture challenged with sera of chronic urticaria patients. After the stimulation of human dermal microvascular endothelial cells with the conditioned media, the expression of intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin increased significantly. Treatment of the conditioned media with anti-tumor necrosis factor-alpha monoclonal antibody partially inhibited the expression of intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. The data suggest that sera from patients with chronic urticaria containing anti-Fc(epsilon)RI(alpha) antibody release mediators and tumor necrosis factor-alpha by activating human foreskin mast cells. This release can play a pathogenic role in chronic urticaria by activating endothelial cells, in part due to the actions of tumor necrosis factor-alpha from mast cells.

Topics: Adult; Antibodies, Monoclonal; Autoantibodies; Cell Adhesion Molecules; Cell Separation; Cells, Cultured; Chronic Disease; Culture Media, Conditioned; Dermis; Enzyme-Linked Immunosorbent Assay; Female; Histamine Release; Humans; Interleukin-13; Leukotriene D4; Male; Mast Cells; Middle Aged; Receptors, IgE; Tumor Necrosis Factor-alpha; Urticaria

Chronic sinusitis is a recurrent disorder commonly found in atopic individuals, yet few studies have explored the role of inflammatory mediators in sinusitis. Sinus lavage fluid from ten patients with chronic sinusitis obtained during endoscopic surgery was analyzed for total cell counts and then assayed for histamine, immunoreactive leukotriene C4/D4/E4 (LTC4/D4/E4), and prostaglandin D2 (PGD2). All ten patients had been unresponsive to medical treatment, including oral corticosteroids in most cases. High concentrations of histamine, LTC4/D4/E4 and PGD2 were found in sinus fluid and were comparable to levels seen in nasal secretions of allergic rhinitis patients following allergen challenge. In the sinus fluid, inflammatory cells were predominantly neutrophils with only low percentages of mast cells, basophils or eosinophils. On the basis of the histamine and PGD2 concentrations in sinus fluid, we conclude that mast cell/basophil activation does occur in chronic sinusitis and may contribute to the persistent inflammation present in sinusitis.

Topics: Adolescent; Adult; Aged; Basophils; Body Fluids; Cell Count; Cell Degranulation; Child; Chronic Disease; Female; Histamine; Humans; Leukotriene C4; Leukotriene D4; Leukotriene E4; Male; Mast Cells; Middle Aged; Prostaglandin D2; Sinusitis; Therapeutic Irrigation