Modulation der angeborenen Immunität der Lunge durch Umwelteinflüsse und allergische Entzündung
Die Atemwege des Menschen sind von einem mehrzelligen Epithel ausgekleidet. Dieses Atemwegsepithel ist nicht nur eine physikalische Barriere für Pathogene, sondern auch aktiv an der angeborenen Immunität beteiligt. Ziel der vorliegenden Arbeit war es, Komponenten der angeborenen Immunantwort des Res...
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Format: | Doctoral Thesis |
Language: | German |
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Philipps-Universität Marburg
2005
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Online Access: | PDF Full Text |
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The respiratory tract is shielded by a multi-component host defense system that involves structural, physical and functional mechanisms. Secretions of the airways contain proteins and peptides that directly kill pathogens or modulate the inflammatory response. It was the aim of this study to investigate the innate immune response of the respiratory tract and of bronchiolar epithelial cells to bacterial infections under the influence of cigarette smoke and allergic inflammation. First, the innate immune response of human bronchiolar epithelial cells (HBEC) was characterized in vitro. Toll-like receptors could be detected in HBEC. Furthermore, HBEC could be activated by pathogens and parts of pathogens like flagellin. This activation resulted in increased expression of cytokines, chemokines and antimicrobial peptides (AMP). Next, the concentration of the two AMP LL-37/hCAP18 and human β-defensin 2 (hBD-2) was measured in airway secretions of patients with community acquired pneumonia and patients with chronic obstructive pulmonary disease (COPD). In the case of COPD patients there was a corellation between the level of inflammation and the concentration of AMP. During an exacerbation significantly increased concentrations of AMP could be detected. Smoking increases the susceptibility to pulmonary infection and is the most important risk factor for the development of COPD. Chronic infection likely contributes to the development of COPD. In this study is postulated that cigarette smoke inhibits the activation of components of the innate immune system in response to a bacterial infection. With sensitive ex-vivo analysis the level of hBD-2 in pharyngeal washing fluids of patients with community acquired pneumonia was measured. Current or former smoking was associated with a significant suppression of hBD-2 levels. In vitro experiments showed that exposure of differentiated airway epithelium to smoke inhibits the induction of hBD-2 by bacteria and that this effect is mediated by reactive oxygen species. These findings show that smoke suppresses the induction of innate immune functions and implicate this mechanism in the pathogenesis of pneumonia and COPD. The allergic inflammation of the respiratory tract is associated with incresead levels of Th2-cytokines. In the present study is shown that Th2-cytokines suppress defensin expression of HBEC in vitro. Furthermore, in vivo studies with a murine asthma model showed that the allergic inflammation leads to a defect in the defense of a bacterial infection. This defect was connected with a delayed clearence of the bacterial infection, with a reduced release of pro-inflammatory cytokines, an inhibited influx of neutrophils into the lung and a reduced release of the AMP CRAMP into the lung. The present study shows that airway epithelium is an active player in the innate immune response of the lung and that cigarette smoke and allergic inflammation inhibit the activation of components of the innate immune system in response to bacterial infections.