Die pathophysiologische Rolle des Atemwegepithels und dessen zielgerichtete Freisetzung kleiner nicht-kodierender RNAs in extrazellulären Vesikeln bei Asthma bronchiale

Asthma bronchiale ist eine chronisch entzündliche Erkrankung mit heterogener Pathophysiologie. Das Atemwegsepithel nimmt eine zentrale pathophysiologische Rolle ein. Atemwegsepithelzellen weisen eine hohe strukturelle und funktionelle Diversität und Plastizität auf, die abhängig von den unterschiedl...

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Bibliographic Details
Main Author: Schindler, Viktoria Elisabeth Maria
Contributors: Garn, Holger (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2023
Online Access:PDF Full Text
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Bronchial asthma is a chronic inflammatory disease with a diverse pathophysiology. The airway epithelium plays a central part in the pathophysiology of Asthma. Airway epithelial cells display high structural and functional diversity and plasticity, each of which varies depending on the different asthma phenotypes and disease stages. Pathophysiologically, they are not only passively affected by inflammatory events, but actively participate in immunological activities. An important form of intercellular communication between epithelial cells and other immune cells in this context is the exchange of information by extracellular vesicles (EVs). EVs are produced by almost every cell in the body. They transfer molecules from the cell of origin, such as proteins, lipids, and ribonucleic acids, to the recipient cell and can thus directly influence it. MicroRNA are small non-coding RNA involved in gene regulation via post-transcriptional modification. Through transportation in EVs, they can immunologically influence the target cell by modifying protein translation as well as through direct receptor interaction. In this cumulative dissertation, the pathophysiological role of the airway epithelium in bronchial asthma will be explained on the basis of two publications. In particular, the focus will be on the targeted release of small non-coding miRNA by airway epithelial cells. In the review "Role of airway epithelial cells in the development of different asthma phenotypes", the differences in the functional and structural properties of airway epithelial cells are presented based on the different asthma phenotypes and disease stages. In the attached experimental article "Side-Directed Release of Differential Extracellular Vesicle-associated microRNA Profiles from Bronchial Epithelial Cells of Healthy and Asthmatic Subjects", vesicular miRNA profiles of EVs produced by airway epithelial cells are analyzed depending on their site of secretion. It is demonstrated that EVs can be isolated from both the apical and basolateral domains and differ from each other based on their concentration, size, and surface marker expression. Additionally, vesicular miRNA profiles show significant differences in the two domains. Furthermore, vesicular miRNA profiles of healthy and asthmatic subjects varied within the same compartment. Differentially expressed miRNA were associated with different signaling pathways depending on the site of secretion. In summary, this work outlines the central role of the airway epithelium in the development and maintenance of bronchial asthma. In particular, it was demonstrated that the vesicular profile of small noncoding RNAs differed in healthy individuals and asthmatics. The identification and characterization of different asthma phenotypes will be important for the future establishment of novel individualized therapeutic strategies. Complex vesicular miRNA profiles can contribute to the identification and phenotyping of asthma as well as be used to detect disease stages and treatment predictors. Thus, they hold great diagnostic and therapeutic potential in the detection and treatment of bronchial asthma.