calcimycin and Asthma--Exercise-Induced

Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, and food additives (FAs) may exacerbate allergic symptoms in patients with chronic idiopathic urticaria and food-dependent exercise-induced anaphylaxis (FDEIA). Augmentation of histamine release from human mast cells and basophils by those substances is speculated to be the cause of exacerbated allergic symptoms. We sought to investigate the mechanism of action of aspirin on IgE-mediated histamine release.. The effects of NSAIDs, FAs or cyclooxygenase (COX) inhibitors on histamine release from human basophils concentrated by gravity separation were evaluated.. Benzoate and tartrazine, which have no COX inhibitory activity, augmented histamine release from basophils similar to aspirin. In contrast, ibuprofen, meloxicam, FR122047 and NS-398, which have COX inhibitory activity, did not affect histamine release. These results indicate that the augmentation of histamine release by aspirin is not due to COX inhibition. It was observed that aspirin augmented histamine release from human basophils only when specifically activated by anti-IgE antibodies, but not by A23187 or formyl-methionyl-leucyl-phenylalanine. When the IgE receptor signaling pathway was activated, aspirin increased the phosphorylation of Syk. Moreover, patients with chronic urticaria and FDEIA tended to be more sensitive to aspirin as regards the augmentation of histamine release, compared with healthy controls.. Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma, Exercise-Induced; Basophils; Benzoates; Calcimycin; Cell Degranulation; Cells, Cultured; Child; Chronic Disease; Cyclooxygenase Inhibitors; Enzyme Activation; Female; Food Hypersensitivity; Histamine Release; Humans; Immunoglobulin E; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Phosphorylation; Protein-Tyrosine Kinases; Signal Transduction; Syk Kinase; Tartrazine; Urticaria; Young Adult

The generation of LTB4 by peripheral blood neutrophils (PMN) isolated before and for as long as 6 h after exercise-induced asthma (EIA) has been analyzed. Three and 6 h after the development of EIA, PMN isolated from 10 asthmatic subjects and stimulated in vitro by 2 x 10(8) and 4 x 10(8) zymosan particles per 2 x 10(6) PMN demonstrated a 12- and 4-fold enhancement, respectively, in the production of immunoreactive LTB4 as compared with PMN isolated before exercise. At 6 h after EIA, there was a redistribution of generated LTB4 such that 30 to 40% of LTB4 produced by zymosan-activated PMN was released extracellularly as compared with 10% before exercise. There was no significant enhancement in the generation of LTB4 by unstimulated PMN at any time point after exercise. Resolution by reverse-phase high performance liquid chromatography (HPLC) of products from [3H]arachidonic-acid-labeled and zymosan-activated PMN demonstrated that, in addition to LTB4, there was enhanced metabolism to 6-trans-LTB4, omega-oxidation metabolites of LTB4 and 5-HETE. Stimulation of PMN with 10 microM A23187 revealed a 2-, 6-, and 5-fold enhancement in the production of LTB4, 6-trans-LTB4, and 5-HETE, respectively, at 6 h after EIA, as measured by integrated ultraviolet absorbance after HPLC. There was no significant enhancement in LTB4 generation by PMN in 6 asthmatic subjects after methacholine-induced bronchospasm, and after exercise in 6 subjects who did not develop asthma. The augmentation of PMN LTB4 generation in EIA correlated with the extent of the early decrease in SGaw.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Airway Resistance; Arachidonate 5-Lipoxygenase; Asthma; Asthma, Exercise-Induced; Bronchial Provocation Tests; Calcimycin; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged; Neutrophils; Stereoisomerism; Zymosan

The hypothesis studied is that increased responsiveness in asthma is not limited to the airways. Forty asthmatic children were analysed for their bronchial responsiveness (BR) to exercise. Twenty patients revealed bronchial obstruction after exercise while the remainder did not. These observations were compared with the responsiveness of leucocytes, which was determined by their histamine 'releasability'. Twenty healthy children served as controls. Release of histamine induced by calcium ionophore-aided calcium influx was significantly higher in both groups of asthmatics than in the healthy children (P less than 0 X 005). Similar findings were obtained by induction of microtubule aggregation due to deuterium oxide (D2O). The S-shaped dose-response relationship with D2O was shifted to the left in the patients with BR to exercise compared to patients without (P less than 0 X 025). The slope was increased in both patient groups compared with the healthy children (P less than 0 X 01). It is concluded that the mean 'releasability' of histamine release due to both stimulants correlated well (P less than 0 X 01). This suggests that the 'releasability' is determined by the responsiveness of the microtubules. This may also apply to allergen-induced histamine release, as was revealed from studies with anti-IgE. The differences in histamine release found in relation to BR due to exercise were also present if the patients were divided according to BR due to histamine. A significant relationship existed between the degree of BR to histamine and the responsiveness of the microtubules (P less than 0 X 02).

Topics: Asthma; Asthma, Exercise-Induced; Bronchial Provocation Tests; Calcimycin; Child; Deuterium; Deuterium Oxide; Dose-Response Relationship, Immunologic; Histamine; Histamine Release; Humans; Leukocytes; Water