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Title: Predicting response to Azithromycin therapy in asthma
Author: Slater, Mariel
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2015
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Macrolide antibiotics, including Azithromycin (AZM), can improve clinical symptoms in asthma regardless of infection status. Mechanisms underlying these beneficial effects are yet to be fully elucidated. Asthma is associated with a defective airway epithelium with reduced expression of structural proteins and aberrant repair responses. In vitro, AZM has shown anti-inflammatory and anti-viral actions, as well as enhancement of airway cell barrier integrity. Therefore, it was hypothesised that the beneficial effects of AZM in asthma may involve barrier reinforcement. The main aims were to determine the effects of AZM on airway epithelial function in vitro, in vivo and ex vivo. Primary normal human bronchial epithelial cells (HBEC) were differentiated in vitro through an air liquid interface. Severe asthma patients were administered 250mg daily AZM for 6 weeks, with clinical outcome measures and bronchoscopy pre- and post-AZM. Addition of AZM to HBEC in vitro enhanced the development of a differentiating epithelial barrier over 14 days, which was accompanied by reduced permeability, increased thickness, reduced mucin expression and suppressed endogenous release of MMP-9. Importantly, MMP-9 levels inversely correlated with barrier integrity, providing a putative mechanism. Clinical measures from 10 asthma patients were heterogeneous both pre- and post-AZM. Overall, symptoms, lung function and inflammation did not significantly alter and there was no association between clinical measures and the epithelial barrier of bronchial biopsies. The current findings suggest that AZM aids in HBEC barrier formation in vitro. This novel finding may relate to the beneficial effects of AZM reported in vivo e.g. through reducing susceptibility to damage and inflammation during re-epithelisation. This could not be confirmed in vivo due to the low number of samples obtained. The current findings add further evidence towards the beneficial non-antibacterial effects of AZM and may have implications for the prospective targeting of the epithelium for clinical benefit in asthma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: WF Respiratory system