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2015
Master Thesis
Title
Comparative analysis of experimental COPD and allergic asthma in mouse models
Abstract
Chronic obstructive pulmonary disease (COPD) and allergic asthma are complex chronic inflammatory diseases of the airways. They both cause airway obstruction and their incidence is globally increasing coupled with rising mortality. Worldwide approximately 64 million and 235 million people suffer from COPD and asthma, respectively. Despite intensive research both disorders remain incurable. Conventional treatment options and therapies are only symptomatical and often with insufficient effects. All this underlines the urgent demand to develop new drugs and novel therapeutic approaches to combat these diseases. For the preclinical research appropriate animal models are required, which precisely reflect the pathological phenotype of the respective disease. In the present study, two murine models were used to mimic pathophysiological characteristics of COPD and allergic asthma in order to establish reliable in vivo systems for the study of the underlying pathomechanisms of each disease as well as for future drug testing. The models were characterised and examined as well as compared in terms of their disease-like phenotypic expressions. For this purpose, a whole-body exposure system was used to expose C57BL/6JRj male mice with cigarette-smoke (CS) for a period of 9 months to induce a COPD-like phenotype. In the murine asthma model, female BALB/c mice were repeatedly intranasally challenged with house dust mite (HDM) extract in a period of 37 days to induce an allergic asthma-like phenotype. The characterisations were performed by means of functional, histological, immunological, and cytological analyses. The parameters examined in the study included lung function measurements, hemogram analyses, determination of plasma- and bronchoalveolar lavage (BALF)-IgE titres, BALF-IL-6 levels, BALF total cell numbers and the percentages of leukocyte populations, and airway remodelling as well as the assessment of goblet cell hyperplasia in lungs, tracheas, and noses. Using non-invasive lung function testing after 9 months, CS-exposed mice showed airway hyperreactivity to methacholine with an incidence of 37 %, which is comparable to that obtained in COPD patients. The further investigations displayed increased total cell numbers in BAL fluids, which indicated an infiltration of inflammatory cells into the airways of CSexposed mice. However, no COPD-like changes in BALF leukocyte populations could be observed. Also no pathological alterations could be found by histological analyses of lungs, tracheas and noses for infiltration, airway remodelling, and goblet cell hyperplasia in CSexposed mice. Altogether, CS-exposed mice showed only minor COPD-like pathological changes compared to control mice. In contrast to the COPD model, HDM-exposed mice displayed a strong phenotype of allergic asthma. Besides severe airway hyperreactivity on methacholine challenge, mice showed an increase in plasma-IgE titres and elevated BALF-IgE levels. Their BALF total cell numbers were on average almost 5-fold higher than in saline-exposed control mice, and 3-fold higher compared to CS-exposed mice. Differential analysis of BALF leukocyte populations demonstrated a typical clinical picture of allergic asthma in the distribution of leukocyte populations. Infiltration of inflammatory cells into the airways could be confirmed by histological analysis. Furthermore, histological analyses of the lungs displayed evidence of airway remodelling processes in the mice exposed to HDM including fibrosis, goblet cell hyperplasia, and mucus hypersecretion as seen in allergic asthma patients. In addition, goblet cell hyperplasia and mucus hyper-production was also present in tracheas and noses. In conclusion, both murine models showed pathological features of the respective disease-like characteristics found in patients with COPD or allergic asthma. However, the HDM model, used for the induction of asthmatic phenotypes in BALB/c mice, could better reflect the allergic asthma-like hallmarks compared to the CS-model, used for the induction of COPDlike characteristics in C57BL/6JRj mice. The weak presence of a COPD-like phenotype made it difficult to compare the investigated parameters in both murine models. The present HDM murine model for allergic asthma induction can be used for future drug studies or studies addressing the examination of the underlying pathomechanisms. The present CS murine model for COPD induction led to a weak phenotype and is therefore currently not suitable or not particularly suitable for further use in research and improvements need to be carried out.
Thesis Note
Konstanz, Univ., Master Thesis, 2015
Publishing Place
Konstanz