Improvement of animal models of COPD and identification of new therapeutic intervention principles therein

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality worldwide. It is listed as the fourth leading cause of death and is projected to be the third by 2020. COPD is characterised by chronic infiltration of inflammatory cells especially neutrophils into the lungs followed by pulmonary tissue destruction. Exacerbations, a major cause of mortality, represent a serious burden in COPD management and are most commonly triggered by viral or bacterial infections. The underlying pathomechanism of COPD is still poorly understood. Therefore, the need for suitable in vivo models is crucial for the investigation of the pathogenesis and for the characterisation of new COPD treatment options. The first aim of this thesis was to examine new approaches to mimic COPD-like changes in vivo by combining different inflammatory stimuli. Furthermore, there is still a large unmet medical need for anti-inflammatory therapy of COPD. Thus, a second aim of this work was to investigate new treatment strategies for COPD by using anti-inflammatory drugs for known but non-COPD indications.The first part of this thesis describes the improvement of murine models for COPD. In order to establish a model for acute exacerbations, different approaches with diverse inflammatory stimuli such as lipopolysaccharide (LPS), cigarette smoke (CS) or poly (I:C) were used alone or in combinatorial setups. The combination of 4 days of CS exposure with a single poly (I:C) challenge on day 4, proved to be the most suitable approach for modelling exacerbations in mice. This combination had additive effects on the induction of neutrophil infiltration in the lung compared to the single stimuli. However, poly (I:C) challenge alone induced a higher increase of cytokines in the lung than the combination of CS and poly (I:C). Thus, it is assumed that by combining both stimuli, a mixed inflammatory process developed, composed of chronologically diverse time points within an inflammatory process. In conclusion, the combination of constant CS exposure and repeated poly (I:C) challenge would be a suitable approach to create a short- to mid-term model for COPD with exacerbations.The second part of the thesis focuses on the investigation of new therapeutic intervention principles for COPD. Anti-inflammatory drugs for non-COPD indications were characterised for their beneficial effects on neutrophilia in the acute CS mouse model. Statins, PPARγ agonists and cannabinoid receptor agonists showed no efficacy on the CS-induced neutrophilia. In contrast, the non-selective sphingosine-1-phosphate (S1P) receptor agonist FTY720 was highly effective in reducing neutrophilia and total cell levels in the lung of CS-exposed mice. Similar results were observed for the S1P1-specific receptor agonist CYM5442. Furthermore, the putative anti-inflammatory mode of action of FTY720 was examined. Neither pulmonary vascular barrier function nor lymphocyte trafficking seemed to be involved in the mode of action of FTY720 or CYM5442 in the acute CS model. In contrast, S1P receptor agonism resulted in an increase in apoptotic cells in the lung, increased the number of neutrophils in the blood and reduced levels of the neutrophil chemoattractant KC in the lung. In conclusion, the anti-inflammatory mechanism of FTY720 in CS-induced neutrophilia might provide a new intervention principle for the therapy of COPD.