Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of death today, with a worldwide increase in incidence. It is a progressive disabling respiratory disease characterized by lung inflammation, leading to airflow limitation and accelerated lung function decline. Corticosteroid treatment acts to suppress lung inflammation, however, clinically this treatment is not very effective in COPD. We hypothesized that long-term cigarette smoke exposure induces glucocorticoid unresponsiveness by inducing oxidative stress and mitochondrial dysfunction in airway epithelium of COPD patients. Results from this thesis show that cigarette smoke-induced oxidative stress induces mitochondrial dysfunction and morphological changes in airway epithelial cells in vitro, and that epithelial cells from COPD patients display similar mitochondrial abnormalities. Lung epithelial cells harboring inactive mitochondria displayed loss of suppressive effects of glucocorticoids on pro-inflammatory activity. Our data further demonstrate that inhibition of GSK3β, a redox sensitive protein also involved in regulating several mitochondrial processes, mediates GC-insensitivity in airway epithelial cells, and that levels of inactivated GSK3β are increased in airway epithelial cells from COPD patients. Additionally, we observed higher levels of lipids from the sphingolipid pathway in sputum of smokers with COPD compared with smokers without COPD. This is interesting because mitochondria regulate lipid metabolism and these changes may thus reflect mitochondrial abnormalities in the lung tissue of COPD patients. Collectively, the data from this thesis show that mitochondrial dysfunction may contribute to inflammatory processes and corticosteroid unresponsiveness in COPD.
|Qualification||Doctor of Philosophy|
|Place of Publication||[Groningen]|
|Publication status||Published - 2016|