Cigarette smoke-induced oxidative stress in COPD: Effects on mitochondrial function, the lipidome and glucocorticoid responsiveness in airway epithelium

Roland Frederik Hoffmann

    Research output: ThesisThesis fully internal (DIV)

    1483 Downloads (Pure)

    Abstract

    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.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Heijink, Irene, Supervisor
    • van Oosterhout, Antoon, Supervisor
    • ten Hacken, Nicolaas, Co-supervisor
    Award date29-Feb-2016
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-6299-301-3
    Publication statusPublished - 2016

    Cite this