The impact of smoking-associated aldehyde exposure on the molecular regulation of mitochondrial function in epithelial cells of the airways and lungs: implications for COPD

The aim of this thesis was to investigate the impact of the aldehydes: acrolein, acetaldehyde and formaldehyde (chemical components present in cigarette smoke) on the function of mitochondria (energy suppliers) in epithelial cells of the airways and lungs, in the context of chronic obstructive pulmonary disease (COPD) development. Several experimental airway models of COPD and exposure models to cigarette smoke or aldehydes were deployed, respectively animal (in vivo) and cell (in vitro) models. Subsequently, read-out parameters related to the molecular regulation of mitochondrial metabolism, mitochondrial content, production and breakdown of mitochondria were evaluated. In addition to the current literature suggesting a (causal) relationship between cigarette smoking, mitochondrial dysfunction and COPD, we observed changes in the abundance of genes and proteins associated with the production and breakdown of mitochondria and mitochondrial metabolism in lung tissue from very severe COPD patients, in primary human bronchial epithelial cells (PBEC) exposed to cigarette smoke, and in rat lung upon acute acrolein exposure. Remarkably, no pronounced impact on the molecular regulation of mitochondrial function was observed in PBEC models from COPD patients, in PBEC following exposure to a mixture of aldehydes or in rat lung upon acrolein exposure for 4 weeks. The variation in results observed in the various studies in this thesis might be explained by the differences in experimental set-up, thus it is important to consider what is the most informative and applicable model matching the research question. In summary, based on our study, it is currently unclear whether aldehydes contribute to the development of COPD via inducing mitochondrial dysfunction. Based on our findings, no conclusive recommendations can be provided regarding future regulation of aldehydes in cigarette smoke as proposed by the WHO.