Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Gungl, A.
INFLAMMATORY PROFILING REVEALS TYPE 2 PREDOMINANT EOSINOPHILIC INFLAMMATION AND ASTHMATIC AIRWAY DISEASE IN THE FRA2 TRANSGENIC MOUSE MODEL
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 108
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Heinemann Akos
- Kwapiszewska-Marsh Grazyna
- Marsh Leigh
- Olschewski Andrea
- Altmetrics:
- Abstract:
- Transgenic mice overexpressing the transcription factor Fos-related antigen 2 (Fra2 TG) exhibit vascular changes, systemic inflammation and fibrosis of skin, lung and other organs, the main hallmarks of systemic sclerosis (SSc). In the recent years, these mice became a commonly used model for SSc and associated pulmonary fibrosis and hypertension. However, a detailed assessment of the time-dependent phenotype of Fra2 TG mice was not conducted. Therefore, this work aimed to assess in detail the pulmonary phenotype of Fra2 TG mice in comparison to WT littermate control mice, including pulmonary function, remodelling and inflammation, to gain a better understanding of the underlying pathomechanisms. Fra2 TG mice had increased vascular remodelling in all investigated time-points (8, 16 and >20 weeks), whereas parenchymal remodelling developed later on in a time-dependent manner, leading to increased collagen deposition and a concomitant decline in lung function in mice older than 20 weeks. Histologically, inflammation was not apparent in the lungs of 8-week-old mice, but at 16 weeks perivascular and peribronchial inflammatory infiltrates were observed which advanced in old mice. Expression analysis of key cytokines of the innate and the adaptive immunity (known to be associated with SSc) revealed increased levels of the Th2 cytokines IL-4 and IL-13, which were confirmed on protein level. At the same time, 16- and >20-week-old Fra2 TG mice had a significant increase of inflammatory cells in bronchoalveolar lavage and lung tissue, with eosinophils as the most predominant cell type in both compartments. As increased levels of Th2 cytokines and eosinophils are hallmarks of allergic airway disease and asthma, the hypothesis that Fra2 TG mice have an asthmatic phenotype was investigated. Indeed, 16-week-old mice showed elevated peribronchial collagen deposition, smooth muscle thickening, mucus production and airway hyperresponsiveness in response to increasing doses of methacholine. Glucocorticoid treatment and blockade of IL-13 via neutralising antibodies partially ameliorated the asthmatic phenotype. In conclusion, by detailed characterisation of the Fra2-induced pulmonary phenotype, Fra2 TG mice were discovered as a novel model for non-allergic asthma that mimics key features of the disease, such as airway inflammation, remodelling and hyperresponsiveness.