Novel insights into mechanisms of glucocorticoid actions and sensitivity in the airway epithelium
AffiliationPharmacology and Therapeutics
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr Danica Prodanovic
Glucocorticoids (GCs) remain the frontline treatment in the management of chronic inflammatory diseases, as they are the most potent and effective anti-inflammatory agents available so far. However, impaired responses to glucocorticoid therapy in some patients with severe disease remain a challenging clinical problem. The airway epithelial function influences inflammation in chronic respiratory diseases. Epithelium, as the site of deposition of inhaled glucocorticoids (ICS), is a key target of GC action. Synthetic GCs, including ICS, exert anti-inflammatory effects in airway epithelium by transactivation of genes and by inhibition of release of pro-inflammatory cytokines. Emerging evidence suggests that physiological GC, cortisol, might act as a partial agonist at the glucocorticoid receptor (GR) in the airway epithelium. However, whether cortisol can be a limiting factor to beneficial effects of synthetic GCs, remains to be established. Therefore, through a better understanding of the impact of cortisol on the effects of synthetic GCs in vitro and in vivo, as well as of novel individual mediators of GC actions in the airway epithelium, new strategies may arise for restoring GC responsiveness. Data presented within this thesis has provided evidence that cortisol acts like a partial agonist at the glucocorticoid receptor, limiting GC-induced GC Receptor-dependent transcription in the BEAS-2B human bronchial epithelial cell line. Cortisol also limited the inhibition of granulocyte macrophage colony-stimulating factor (GM-CSF) release by synthetic GCs in TNFα-activated BEAS-2B cells. The relevance of these findings is supported by observations on tracheal epithelium obtained from mice treated for 5 days with systemic GC, showing limitations in selected GC effects, including inhibition of pro-inflammatory cytokine IL-6. Moreover, gene transactivation by synthetic GCs was compromised by standard air-liquid interface (ALI) growth medium cortisol concentration of 1.4 µM in the ALI differentiated organotypic culture of primary human airway epithelial cells. These findings suggest that endogenous corticosteroids may limit certain actions of synthetic pharmacological GCs and contribute to GC insensitivity, particularly when corticosteroid levels are elevated by stress. Data obtained during these thesis studies also highlight the potential of the transcriptional repressor, promyelocytic leukaemia zinc finger (PLZF) to mediate selected glucocorticoid effects in the airway epithelium, including the induction of targets important in mediating physiological effects on the normal lung development and of ones with relevance to the distinct glucocorticoid effects on the epithelial restitution following inflammation and injury. This thesis has provided novel insights into mechanisms of glucocorticoid action and insensitivity in the airway epithelium, allowing the development of strategies for improved treatment of chronic airway inflammatory diseases.
Keywordsglucocorticoids; corticosteroids; epithelium; airway epithelium; asthma; inflammation
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