Multi-organ dysfunction and therapeutical potentials in COPD

Abstract

Chronic obstructive pulmonary disease (COPD) is a multi-organ disorder. The studies described in this thesis focused on this multi-organ dysfunction with a special focus on intestinal and metabolic (adipose and muscle tissue) responses. The crosstalk between the gut and lung can be noticed by intestinal disease manifestations during respiratory diseases ... read more and vice versa. We found that cigarette smoke exposure with or without LPS (bacterial trigger) affects intestinal health as observed by changes in intestinal histomorphology and immune network for IgA production in mice. Elevated systemic mediators might play a role in this lung-gut crosstalk. In a genome-wide mRNA sequencing experiment where we compared molecular changes in the lung and ileum in a murine model of cigarette smoke-induced COPD with the genes in the lung of COPD patients and genes in the ileum in Crohn’s disease patients. Interestingly, the highly differentially expressed genes in the murine lung were comparable with the altered gene expression in the lungs of COPD patients, while the highly differentially expressed genes in the ileum of cigarette smoke-exposed mice were less comparable with gene expression changes in the ileum of Crohn's disease (CD) patients. In both the lung and the ileum, enrichment in the genes for the cytokine-cytokine receptor interaction pathways and pathways related to adhesion molecules were identified. COPD can also lead to metabolic comorbidities involving alterations in adipose and skeletal muscle tissues. We examined the adaptive and pathological alterations in adipose tissue and skeletal muscle following cigarette smoke exposure using in vivo and in vitro models and observed that cigarette smoke exposure induces loss of whole-body fat mass and adipose atrophy which is likely due to enhanced lipolysis. This adipose tissue loss and parallel deterioration of skeletal muscle function might precede muscle wasting. Last but not least, the effects of a novel pharmacological compound with mito-protective properties and modest antioxidant capacity (called SUL-151) were investigated in a murine cigarette smoke-induced inflammation model. This SUL-151 compound significantly decreased more than 70% and 50% of the cigarette smoke-induced neutrophil influx in BAL fluid after prophylactic and therapeutic administration, respectively. The findings of this research indicate that future COPD research should not only focus on the lung as the target organ, but also consider a broader perspective related to other organs. For instance, therapeutical strategies for COPD should also target the complicated signal interactions between the lungs and the intestine/adipose tissue to reduce systemic disease progression and related co-morbidities. This multi-organ targeted approach might be beneficial for the treatment of COPD, but also for the concomitant co-morbidities. Moreover, targeting mitochondria and oxidative stress by, e.g., the novel mito-protective and anti-inflammatory compound SUL-151, would be a promising approach to combat COPD. show less