leukotriene-d4 and Rhinitis

Twenty five years after the structure elucidation of slow reacting substance of anaphylaxis, antileukotrienes are established as a new therapeutic modality in asthma. The chapter reviews the biochemistry and pharmacology of leukotrienes and antileukotrienes with particular focus on the different usage of antileukotrienes for treatment of asthma and rhinitis in Europe and the US. Further research needs and new areas for leukotriene involvement in respiratory diseases are also discussed.

Topics: Acetates; Animals; Asthma; Clinical Trials as Topic; Cyclopropanes; Humans; Hydroxyurea; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lipoxygenase Inhibitors; Membrane Proteins; Quinolines; Receptors, Leukotriene; Respiratory System; Rhinitis; Sulfides

Aspirin is not only one of the best-documented medicines in the world, but also one of the most frequently used drugs of all times. In addition to its role as an analgesic, aspirin is being increasingly used in the prophylaxis of ischemic heart disease and strokes. The prevalence of aspirin intolerance is around 5 to 6%. Up to 20% of the asthmatic population is sensitive to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) and present with a triad of rhinitis, sinusitis, and asthma when exposed to the offending drugs. This syndrome is referred to as aspirin-induced asthma (AIA). The pathogenesis of AIA has implicated both the lipoxygenase (LO) and the cyclooxygenase (COX) pathways. By inhibiting the COX pathway, aspirin diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of prostaglandin (PG) E(2), the anti-inflammatory PG, along with an increase in the synthesis of cysteinyl leukotrienes (LTs). Evidence suggests that patients with AIA have increased activity of LTC(4) synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, in their bronchial biopsy specimens, thereby tilting the balance in favor of inflammation. LT-modifying drugs are effective in blocking the bronchoconstriction provoked by aspirin and are used in the treatment of this condition. Aspirin desensitization has a role in the management of AIA, especially in patients who need prophylaxis from thromboembolic diseases, myocardial infarction, and stroke. This review covers the latest understanding of pathogenesis, clinical features, and management of AIA.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Aspirin; Asthma; Bronchial Hyperreactivity; Cyclooxygenase Inhibitors; Desensitization, Immunologic; Dinoprostone; Drug Hypersensitivity; Glutathione Transferase; Humans; Leukotriene Antagonists; Leukotriene D4; Lipoxygenase; Rhinitis; Sinusitis

Topics: Acetates; Asthma; Bronchi; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotriene D4; Lipoxygenase Inhibitors; Membrane Proteins; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Rhinitis; Sinusitis; Sulfides; Sulfonamides; Tosyl Compounds

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

Histamine and cysteinyl leukotrienes are pivotal mast cell mediators which contribute considerably and likely complementary to the symptoms of allergic rhinitis. Currently, we sought to explore the direct actions of histamine and leukotriene D(4) (LTD(4)), a cysteinyl leukotriene, on porcine nasal arteries and veins. We also studied combined blocks of histamine and cysteinyl leukotrienes using loratadine and montelukast in an in vivo model of allergy-mediated nasal inflammation.. For the evaluation of the action of histamine and LTD(4) on arteries and veins, porcine nasal mucosa was isolated and cut into slices (100-300 microm thick). Real-time images of the nasal arteries and veins were recorded and vessel activities estimated by changes in cross-sectional area before and after the tested drugs. For the in vivo studies, the effect of loratadine and montelukast given alone and in combination was examined on upper airway inflammation in ovalbumin-sensitized and -challenged Brown Norway rats.. Both histamine (0.001-10 micromol/l) and LTD(4) (0.001-10 micromol/l) produced a concentration-dependent increase in the lumen area of nasal mucosa arteries and veins. Histamine (0.01 micromol/l) alone produced a 24 and 12% increase in cross-sectional areas of arteries and veins, respectively. LTD(4) (0.001 micromol/l) alone increased artery and vein dilation by about 17 and 9%, respectively. Combination treatment with histamine (0.01 micromol/l) and LTD(4) (0.001 micromol/l) increased vessel dilation by 65% (arteries) and 26% (veins). In our in vivo Brown Norway rat studies, oral loratadine (0.01-10 mg/kg) and montelukast (0.01-10 mg/kg) significantly reduced antigen-induced total nasal inflammatory cell infiltration in a dose-dependent manner. The antiinflammatory dose-response curve of loratadine was shifted to the left when studied in combination with montelukast (0.01 mg/kg). Similarly, the dose-response characteristics of montelukast (0.01-10 mg/kg) was shifted in the presence of loratadine (0.01 mg/kg).. Our studies support the position that histamine and cysteinyl leukotrienes may act collaboratively to elicit allergic nasal pathologies such as upper airway inflammation and nasal vessel dilation (which may translate into increased nasal mucosal engorgement). Furthermore, the current results are supportive of the hypothesis that combined treatment of allergic rhinitis with an H(1) receptor antagonist and a CysLT(1) receptor antagonist may have greater benefit than sole treatment with these agents alone.

Topics: Acetates; Animals; Cyclopropanes; Cysteine; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Histamine; Histamine H1 Antagonists, Non-Sedating; Hypersensitivity; In Vitro Techniques; Leukotriene Antagonists; Leukotriene D4; Leukotrienes; Loratadine; Male; Nasal Mucosa; Neutrophil Infiltration; Quinolines; Rats; Rats, Inbred BN; Rhinitis; Sulfides; Sus scrofa