Die Rolle von Cathelizidin und des Transkriptionsfaktors NF-kB bei Asthma und COPD

Asthma und COPD sind zwei komplexe Lungenkrankheiten. Sowohl Asthma als auch COPD besitzen eine starke entzündliche Komponente, bei der jeweils verschiedene Teile des Immunsystems und der Lunge involviert sind. NF-κB ist ein wichtiger Transkriptionsfaktor, der die Aktivität vieler Gene des Immunsyst...

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Bibliographic Details
Main Author: Klescz, Frank Friedhelm
Contributors: Bals, Robert (Prof. Dr. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2010
Online Access:PDF Full Text
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Asthma and chronic obstructive pulmonary disease (COPD) are two complex diseases of the lung. Asthma as well as COPD have a strong inflammatory component in which different parts of the immune system and the lung are involved. NF-κB is an important transcription factor which controls the expression of many immune genes. Antimicrobial peptides are effector molecules of innate immunity and involved in host defense and inflammation. Since cathelicidins have antimicrobial as well as immunmodulatory functions they could also be involved in asthma and COPD. The aim of the present study was to evaluate the role of the murine cathelicidin CRAMP and the transcription factor NF-κB in asthma and COPD. Analysis of the bronchoalveolar lavage (BAL), lung cytokines and serum-IgE showed that cathelicidin plays no role in experimentally induced acute asthma. In the model of chronic asthma, cathelicidin had a complex effect since CRAMP-/- mice had a slightly higher total cell count and more eosinophils in their BAL than wildtype (WT) mice but the load of serum-IgE and TH2 cytokines in the lungs of serum-IgE of CRAMP-/- mice was lower than in WT mice after experimental induced acute asthma. During short-term exposure to cigarette smoke CRAMP had an anti-inflammatory effect as the BAL of CRAMP-/- mice contained more cytokines than identically treated wild type mice. In the chronic COPD model, CRAMP also had an anti-inflammatory effect since the BAL of CRAMP-/- mice contained more cells and more cytokines than identically treated wild type mice. In experimental acute asthma, this work showed that the p65-mediated NF-κB signaling pathway plays an important role. Activation of p65-mediated myeloid NF-κB resulted in an neutrophilic phenotype and had a partly anti-inflammatory effect contrary to a constitutive inhibition of the p65-mediated myeloid NF-κB signaling pathway leading to a partly proinflammatory effect. During short-term exposure to cigarette smoke the p65-mediated NF-κB signaling pathway played no role regarding the investigated parameters. In contrast to the chronic model of COPD the activation of myeloid p65 had an anti-inflammatory effect. The results of this work show that the murine cathelicidin CRAMP also has immunmodulatory functions in addition to its antimicrobial functions. CRAMP has an anti-inflammatory effect in COPD and in asthma CRAMP acts as a proasthmatic factor. The NF-κB signaling cascade of myeloid cells leads to partly anti-inflammatory and partly proinflammatory effects. In case of experimentally induced COPD, myeloid p65 acts as an anti-inflammatory factor and in case of experimentally induced asthma myeloid NF-κB has proinflammatory and anti-inflammatory effects. Cathelicidin and NF-κB interfer with the complex genesis of inflammatory lung diseases.