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Title: Airway smooth muscle and mast cell interaction modulates corticosteroids sensitivity
Author: Alzahrani, Abdulrahman M.
ISNI:       0000 0004 7655 7120
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2018
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A proportion of patients affected by the severe form of asthma do not adequately respond to corticosteroids, and the underlying mechanisms are unknown. Because infiltration of mast cells in ASM bundle is a defining feature of asthma and as mast cells have been shown to modulate the function of ASM cells including to the anti-asthma therapy drug b2-agonists, I hypothesised that mast cells could regulate corticosteroids responsivenes to ASM. The purpose of this PhD was to test whether healthy ASM cells pre-treated with conditioned media (CM) from non-activated or activated human lung mast cells for either 30 minutes (effect of preformed mediators) or 24 hours (effect of synthesised mediators) would affect the ability of fluticasone to i) repress TNF-a-induced expression of different chemokines including CCL5, CXCL10 and CXCL8 and ii) induce the expression of anti-inflammatory genes. The results show that fluticasone-dependent repression of CXCL10 and CCL5 induced by TNF-α was significantly impaired in cells that were first pretreated with CM from 30-minute and 24-hour activated mast cells. The reduced expression of two fluticasone-inducible genes GILZ and MKP-1 by the CM from 24-hour activated mast cells suggested that transactivation activities were affected by mast cell mediators. The inhibitory effect of activated mast cell CM on fluticasone-induced transactivation was further confirmed using gene array analysis showing a profound reduction of a number of different steroid-inducible genes with anti-inflammatory and anti-asthma properties. The gene array data of changes in expression of four selected genes including GILZ, MKP-1, FKBP5 and PIK3R1 were validated using individual qPCR which demonstrated strong correlations between the two techniques with respect to gene modulation. Together, these studies show for the first time that CM from activated mast cells contains mediators that can regulate the responsiveness of ASM cells to corticosteroids by differentially inhibiting their transactivation properties.
Supervisor: Amrani, Yassine ; Bradding, Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available