Zur Initiation, Progression und Chronifikation des allergischen Asthma bronchiale

Das allergische Asthma ist eine chronisch entzündliche Erkrankung der Atemwege, die mit einer erhöhten Mukusproduktion, verschiedenen strukturellen Veränderungen der Atemwege und der Entwicklung einer Atemwegshyperreagibilität einhergeht. Die Vielfalt der Faktoren, die zur Initiation, Progression un...

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Bibliographic Details
Main Author: Wegmann, Michael
Contributors: Renz, Harald (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2005
Online Access:PDF Full Text
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Allergic bronchial asthma is a chronic inflammatory disease of the airways that is characterized by increased mucus production, airway remodeling and development of airway hyperreactivity. The variety of factors contributing to the initiation, progression and chronification of this disease is as complex as its phenotype. Epidemiological studies identified genetic as well as environmental factors such as live and hygiene standards involved in the development of the disease. Furthermore few factors were identified that are associated with an abased risk for the development of allergic asthma. This observation led to the formation of the hygiene-hypothesis. Especially the role of viral infections of the airways mainly by respiratory syncytial virus (RSV) and rhino viruses is discussed controversially within this context. These infections represent the main cause of exacerbation when asthma has already been established, however, when appearing during early childhood they are associated with protective as well as with triggering effects on asthma development. Possibly viral toll-like receptors (TLRs) such as single or double stranded viral RNA play an important role within this context. It was part of this study to characterize the effects of viral TLR-3 or TLR-7 ligands on allergic sensitization as well as on allergic inflammation. In a murine model of allergic asthma the allergic sensitization could be completely suppressed by systemic application of synthetic TLR-3 and TLR-7 ligands. In already sensitized animals systemic application of synthetic TLR-ligands resulted in significant reduction of the secondary allergic reaction after allergen-rechallenge as characterized by diminished infiltration of eosinophils and lymphocytes into airway tissue and normalisation of airway reactivity to metacholine. Furthermore, hints on the initiation of a TH1-immune response could be identified. Because peritoneal macrophages produced large amounts of interleukin 12 (IL-12) after intra-peritoneal application of synthetic TLR3 as well as TLR-7 ligands, the role of IL-12 was further elucidated. The systemic application of synthetic TLR-3 as well as TLR-7 ligands did neither result in reduction of allergic airway inflammation nor in normalization of airway reactivity. Therefore, the protective effect of viral infections during early childhood may base upon a TLR ligand induced TH1 immune-response counterbalancing the allergen-specific TH2-immune response. This effect seems to be in parts mediated by IL-12. For the identification of factors contributing to the chronification of allergic bronchial asthma it was further scope of this study to establish an animal model that is able to reflect the human phenotype of this disease as close as possible. A chronic allergic airway inflammation was induced in sensitized animals by allergen exposure for about twelve weeks. This inflammation mainly consists of lymphocytes that persist in the airway mucosa even without allergen contact. Chronic airway inflammation was further associated with considerably stuctural changes of the airway wall as characterized by subepithelial fibrosis, goblet cell hyperplasia and increased numbers of fibroblasts and myofibroblasts. In contrast to other animal models of chronic allergic asthma airway hyperresonsiveness did not resolve over time and a persistant airflow limitation was observed. To further elucidate the mechanisms underlying the observed chronification of the asthmatic phenotype a CCR-3 antagonist was applied systemically for at least eight weeks starting after for weeks of allergen challenge. Antagonisation of CCR-3 resulted in marked reduction of the eosinophil infiltration in airway tissue as well as in broncho-alveolar lumen und was further associated with lack of subepithelial fibrosis. Besides, CCR-3 antagonist treated animals revealed complete normalisation of airway reactivity to metacholine. Therefore, eosinophils seem to play a major role within the process of chronification of allergic bronchial asthma, that lead to airway remodelling as well as to increased airway reactivity.