A cigarette smoke induced Drosophila model identifies molecular mechanisms underlying COPD development

Prange, Daniel Ruben ORCID

Chronic Obstructive Pulmonary Disease (COPD) serves as an umbrella term that encompasses a group of chronic lung diseases, which collectively cause obstructive and irreversible airflow limitation and finally lead to premature death. The main cause of COPD is undoubtedly cigarette smoking but with rising air pollution and aging populations COPD is suggested to even increase in incidences. However, detailed cellular mechanisms involved in the development of this disease still remain unclear. This thesis introduces a novel cigarette smoke (CS) induced Drosophila model to elucidate underlying causes of disease development. Exposure of flies to CS reproduced major hallmarks of COPD, such as reduced lifespan, impaired activity or increased antioxidant responses. Detailed transcriptomic analyses revealed crucial processes that were induced by the airway epithelium upon CS exposure. Short-term responses were characterized by the activation of antioxidant responses. The Nrf2 pathway was identified as a crucial mediator of these responses by regulating the glutathione metabolism, which in turn plays a pivotal role in detoxification. Ectopic activation of the Nrf2 pathway during CS exposure resulted in an increased lifespan of the fruit fly. Besides these short-term responses, transcriptomic analyses revealed the immune system to be involved in the chronic response to CS. Long-term CS exposure involved the immune system, which was found to decrease the lifespan of CS exposed flies by a genetic manipulation of the immune response. The immune system responses changed in an age dependent manner and transcriptomic analyses proved the relevance of aging for the development of COPD. These results suggest an abnormal aging of CS exposed airways and provided evidence that COPD can be considered as premature aging of the lung. However, CS cessation could reverse the effects of CS exposure to a certain extend but could not fully rescue the reduced lifespan. Transcriptomic analyses elucidated the immune system and an induction of age-related factors that might underlie this chronic response. Moreover, the influence of nutrition on the lifespan of CS exposed flies, suggested the relevance of dietary intervention in COPD patients. Finally, this thesis provides a pioneer data set for the characterization of adult tracheal epithelial cells. In summary, this thesis proves that Drosophila melanogaster can serve as an effective model for studying CS induced effects, pinpoint potential treatment strategies and relate findings in the invertebrate system to human COPD development.

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Prange, Daniel: A cigarette smoke induced Drosophila model identifies molecular mechanisms underlying COPD development. 2020.

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