8588068

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We have recently reported that the 5-lipoxygenase (5-LO) inhibitor, zileuton, alters lung inflammation produced by segmental antigen challenge in ragweed-allergic human subjects. Specifically, zileuton inhibited the urinary excretion of leukotriene E4 produced by antigen challenge, and the significant increase in bronchoalveolar lavage (BAL) eosinophils observed in subjects on placebo was not seen in subjects on zileuton. In this manuscript, we report additional data obtained during that study which provide information about mechanisms important during IgE-mediated inflammatory reactions in the lung. Three different areas are addressed: 1) the time to recovery of the lung from an IgE-mediated inflammatory response; 2) mechanisms related to the generation of cyclooxygenase products in the lung after antigen challenge and the effect of 5-LO inhibition on the production of cyclooxygenase metabolites; and 3) mechanisms responsible for the production of peptide leukotrienes in the lung and lung injury (as shown by albumin influx into the alveolar air space) 24 h after antigen challenge. We observed the following: 1) a significant BAL eosinophilia and basophilia remained 31 days (range 21-48) after segmental antigen challenge and bronchoalveolar lavage; 2) a decreased quantity of BAL cyclooxygenase products, as well as lipoxygenase products, in the presence of 5-LO inhibition; and 3) correlative analyses which suggest that while eosinophils appear most important for the production of peptide leukotrienes and lung injury 24 h after antigen challenge in subjects taking placebo, other effector mechanisms, perhaps those involving basophils and the initial mast cell triggering event, appear to gain in importance when the IgE-mediated inflammatory reaction is blunted by 5-LO inhibition.

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pubmed-meshheading:8588068-Anti-Inflammatory Agents, Non-Steroidal, pubmed-meshheading:8588068-Arachidonate 5-Lipoxygenase, pubmed-meshheading:8588068-Bronchial Provocation Tests, pubmed-meshheading:8588068-Bronchoalveolar Lavage Fluid, pubmed-meshheading:8588068-Bronchoscopy, pubmed-meshheading:8588068-Cross-Over Studies, pubmed-meshheading:8588068-Dinoprost, pubmed-meshheading:8588068-Dinoprostone, pubmed-meshheading:8588068-Double-Blind Method, pubmed-meshheading:8588068-Eosinophils, pubmed-meshheading:8588068-Humans, pubmed-meshheading:8588068-Hydroxyurea, pubmed-meshheading:8588068-Leukotriene B4, pubmed-meshheading:8588068-Leukotriene E4, pubmed-meshheading:8588068-Leukotrienes, pubmed-meshheading:8588068-Lipoxygenase Inhibitors, pubmed-meshheading:8588068-Lung, pubmed-meshheading:8588068-Lung Injury, pubmed-meshheading:8588068-Placebos, pubmed-meshheading:8588068-Prostaglandin D2, pubmed-meshheading:8588068-Prostaglandin-Endoperoxide Synthases, pubmed-meshheading:8588068-Proteins, pubmed-meshheading:8588068-Regression Analysis, pubmed-meshheading:8588068-Respiratory Hypersensitivity, pubmed-meshheading:8588068-Thromboxane B2

Insights into IgE-mediated lung inflammation derived from a study employing a 5-lipoxygenase inhibitor.

Journal Article, Clinical Trial, Research Support, U.S. Gov't, P.H.S., Randomized Controlled Trial, Research Support, Non-U.S. Gov't