Airway Epithelial Cells as Targets of Glucocorticoid Therapy in Inflammatory Lung Diseases

Glucocorticoids (GCs) have been a mainstay in the treatment of various autoimmune and allergic diseases for many decades due to their potent anti-inflammatory activities. The beneficial effects of GCs are mediated by the glucocorticoid receptor (GR) mainly through modulation of target gene expression via transactivation or transrepression. Despite their therapeutic potency, the use of GCs is limited as their broad activity profile may lead to the development of severe side effects. Therefore, a better understanding of the precise mode and site of GC-action could help to improve this therapeutic regimen. Allergic airway inflammation (AAI) as a model of asthma was induced in GRdim mice to dissect the molecular mechanisms of GCs. These mice carry a point mutation that impairs GR-dimerization and thus interferes with gene transactivation. Treatment of AAI with dexamethasone (Dex) failed to diminish clinical symptoms in the airways of GRdim mice, indicating that an intact GR-dimerization interface was essential for therapeutic efficacy in this disease model. As previous data had revealed that GCs presumably target structural cells of the lung in the treatment of AAI rather than immune cells, it was tested whether airway epithelial cells (AECs) were essential targets. Hence, AAI was induced in GRspc mice that specifically lack the GR in alveolar type II epithelial (AT-II) cells. Dex repressed AAI in GRspc mice only partially, highlighting that AT-II cells play a crucial role for the efficacy of GC-therapy. Notably, GC-treatment of acute lung injury (ALI), another pulmonary disease, was not impaired in GRspc mice. A potential link between GC-target site and mode of action was confirmed by expression analysis of various inflammatory genes in the lung, which revealed that GRdim and GRspc mice behaved similarly with regard to transcriptional control. Furthermore, antibody-conjugated betamethasone nanoparticles were investigated as a novel vehicle for AT-II cell-directed delivery of GCs in AAI but did not show any efficacy in improving disease symptoms. Taken together, the findings reported in this thesis bring about a novel concept of GC-therapy of allergic asthma, indicating that its efficacy depends on GR-dependent gene regulation in AECs. This notion paves the way for a future cell-directed delivery of GCs as an interesting approach for the improvement of GC-therapy in allergic asthma with fewer side effects