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Novel insights into the contribution of IL-13 to the pathogenesis of muco-obstructive lung disease

Christochowitz, Sandra

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Airway mucus obstruction is a key feature of a spectrum of chronic lung diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and asthma. Mucus dehydration and mucin hypersecretion have been implicated in the pathogenesis of airway mucus plugging. However, understanding of relative contributions and combined effects of these abnormalities remain poorly understood. Mucus accumulation in the airways is associated with chronic airway inflammation. The type 2 cytokine interleukin (IL)-13 has been shown to play a crucial role during type 2 airway inflammation. Furthermore, IL-13 mediates mucin overproduction by acting on airway epithelial cells. If the airway epithelium itself contributes to IL-13 production under conditions of muco-obstructive lung disease is not well understood. In this study, the airway epithelium was investigated as a cellular source for IL-13 production in transgenic (Tg) mice with airway-specific overexpression of the β-subunit of the epithelial sodium channel (Scnn1b) exhibiting airway mucus obstruction due to airway surface dehydration and a spontaneous type 2 airway inflammation at juvenile ages. IL-13 protein and gene expression was studied in the airway epithelium from naïve and allergen-treated wild-type (WT) and Scnn1b-Tg mice. In vitro studies were performed to elucidate signaling pathways that induce epithelial IL-13 expression. To better understand the in vivo pathogenesis of airway mucus obstruction, the relative roles of airway surface dehydration and IL-13-mediated mucin hypersecretion were investigated. Therefore, juvenile Scnn1b-Tg mice with genetic deletion of IL-13 (Scnn1b-Tg/Il13-/-) were studied and the phenotypes of Scnn1b-Tg mice were compared to mice with airway-specific overexpression of IL-13 (Il13-Tg). By studying Scnn1b-Tg/Il13-Tg/Il13-/- mice, the combined effect of both defects were investigated. The airway epithelium from Scnn1b-Tg mice was shown to produce increased levels of IL-13. Epithelial IL-13 production was induced by IL-33 via the St2/Myd88/p38 signaling pathway. Furthermore, IL-13 specifically overexpressed in airway epithelial cells (Il13-Tg/Il13-/-) was sufficient to cause muco-obstructive lung disease associated with mucus plugging, severe goblet cell metaplasia (GCM), and airway inflammation. Scnn1b-Tg/Il13-/- mice displayed neither goblet cells nor mucin hypersecretion, but mucus plugging persisted in the airways. In Scnn1b-Tg mice, airway mucus plugging was more severe than in Il13-Tg mice, although Il13-Tg mice demonstrated a pronounced GCM and Muc5ac expression. These differences were associated with an impaired mucociliary transport in Scnn1b-Tg mice and a normal mucociliary transport in Il13-Tg mice. Combination of airway surface dehydration and IL-13-induced mucin hypersecretion produced severe mucus plugging causing neonatal mortality of Scnn1b-Tg/Il13-Tg/Il13-/- mice. In summary, these results demonstrate that the airway epithelium provides a source of IL-13 production in spontaneous and allergen-induced type 2 airway inflammation in juvenile Scnn1b-Tg mice and indicates that IL-33 contributes to this process in vivo. Further, these results suggest that both airway surface dehydration and IL-13-induced mucin hypersecretion have detrimental effects in the in vivo pathogenesis of airway mucus obstruction.

Item Type: Dissertation
Supervisor: Wölfl, Prof. Dr. Stefan
Date of thesis defense: 17 May 2018
Date Deposited: 12 Jul 2018 07:22
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Medizinische Fakultät Heidelberg > Universitätskinderklinik
Subjects: 570 Life sciences
610 Medical sciences Medicine
Controlled Keywords: IL-13, Chronic airway disease, Mucus obstruction
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