The contribution of eosinophils and mediators in allergic inflammation

Sammanfattning: From the Department of Internal Medicine, Division of Respiratory Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden The contribution of eosinophils and mediators in allergic inflammation The aim of the present work was to investigate the development of allergic inflammation. For this purpose human experimental challenge models in skin, nose and bronchi were used as well as pharmacological interventions. A variety of inflammatory cells and mediators have been suggested as important in the pathogenesis of allergic inflammation. Histamine and leukotrienes are able to induce airway obstruction and have been detected in the allergic airways. The dominant mediator-secreting cells in the airways of atopics appear to be mast cells and eosinophils. However, the precise role of eosinophils and the mediators histamine and leukotrienes in causing allergic inflammation has not yet been clarifyed. Therefore it was of special interest to investigate the contribution that the eosinophils and the mediators histamine and leukotrienes make to induced allergic reactions in skin, nose and bronchi . Potential differences between atopics and eight healthy volunteers concerning IgE-mediated cutaneous inflammation were investigated. Significant recruitment of eosinophils to skin chambers was restricted to the atopic group. The skin responsiveness with respect to mediator release and the sizes of anti-lgE- induced wheal, flare and late-phase reactions were similar in the two groups. The ability of the Hl-receptor antagonist loratadine to modify anti-lgE-induced cutaneous wheal and flare and late-phase reactions as well as mediator release in skin chambers was characterized. Loratadine was found to be a highly selective Hl-receptor antagomst without mast cell stabilizing properties or anti-inflammatory effects in allergic skin. To evaluate the predicted value of eosinophil activity markers for bronchial hyperreactivity, twenty- eight patients with asthma-like symptoms were investigated. A higher concentration of eosinophils was found in the hyperreactive group than in the non-reactive. Using one eosinophil activity marker, either serum ECP or EG2, bronchial hyperreactivity was predicted in 70 % of the patients. The predictive value increased to 100 % when any two of the markers serum ECP, EG2 or the eosinophil percentage were combined. Nasal allergic inflammation was induced with two different types of nasal allergen challenge models, a conventional model with rapidly increasing allergen doses and a model with repeated low doses of allergen for 7 days. With the conventional model there was a rise in histamine and ECP in nasal lavage fluid and an increase in eosinophil concentration and ECP in peripheral blood. Use of the low-allergen- dose model resulted in local inflammation in the nasal mucosa measured as increased ECP in nasal lavage fluid despite the absence of clinical symptoms. Eosinophil activity, differences in expression of Iymphocyte surface antigens in peripheral blood and bronchial responsiveness to histamine were studied in atopics before and after repeated low-dose bronchial allergen exposures. No changes in peripheral blood were detected. However, there was a significant increase in bronchial hyperreactivity after seven days of low-dose challenges despite the absence of clinical symptoms. To evaluate the contribution of histamine and leukotrienes to the early - and the late - phase asthmatic reactions bronchial allergen provocations were performed in twelve atopic asthmatics on five occasions. Treatments with an antihistamine (loratadine) or a leukotriene-antagonist (zafirlukast) significantly inhibited both early and late phase asthmatic reactions. In addition combined treatment with loratadine and zafirlukast was significantly more effective than that with either drug alone. The findings from this work provide evidence for the contribution of the eosinophil granulocyte and the mediators histamine and leukotrienes to allergen-induced airway inflammation and the results conclude that histamine and leukotrienes together are the predominant mediators. Challenges with repeated low doses of allergen offer a reproducible and useful alternative to conventional allergen challenges for studying development of local inflammation and bronchial hyperresponsiveness. Key words: allergic inflammation, eosinophils, bronchial hyperresponsiveness, histamine, leukotrienes, antihistamine, leukotriene-antagonist, low-dose challenge ISBN 91-628-2187-3

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