Mechanisms of glucocorticoid insensitivity in asthma

Jan Zijlstra

    Research output: ThesisThesis fully internal (DIV)

    99 Downloads (Pure)

    Abstract

    Asthma and COPD are obstructive pulmonary diseases, which can be treated with anti-inflammatory drugs like glucocorticoids. This thesis aimed to investigate the circumstances which made that these glucocorticoids sometimes do not work like they should. We started by looking which factors predicted whether a subject with asthma would react properly to glucocorticoids. This study showed that some factor associated with eosinophilic inflammation was associated with a better response to glucocorticoid, unlike a more neutrophilic inflammation.
    Afterwards, we investigated possible mechanisms which could play role. Firstly, we determined that Interleukin-17A reduced the sensitivity of pulmonary epithelial cells to glucocorticoids. Therefore, the attraction of neutrophils remained present for a longer period. We showed the mechanism through which this occurred, which could be a target for future therapies in glucocorticoid insensitive disease.
    Th17 cells are one of the celltypes producing IL-17A and they are attracted by the protein CCL20. Therefore, we investigated the effect of glucocorticoids on CCL20 production. We found that glucocorticoids enhance the amount of CCL20 released by pulmonary epithelial cells. Possibly, this leads to a larger influx of Th17 cells in the lung.
    Furthermore we studied the effect of the damage that cigarette smoke does on inflammation. We found that the cell death caused by cigarette smoke leads to the release of molecules which can promote inflammation. The inhibition of a certain type of cell death, necroptosis, lead to the presence of less inflammatory cells in the lungs of mice after cigarette smoke exposition.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Heijink, Irene, Supervisor
    • van Oosterhout, Antoon, Supervisor
    • ten Hacken, Nick, Co-supervisor
    • Kerstjens, Huib, Assessment committee
    • Dekker, Frank, Assessment committee
    • Koenderman, Leo, Assessment committee, External person
    Award date18-Nov-2020
    Place of Publication[Groningen]
    Publisher
    DOIs
    Publication statusPublished - 2020

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