Predicting response to Azithromycin therapy in asthma

Slater, Mariel (2015) Predicting response to Azithromycin therapy in asthma. PhD thesis, University of Nottingham.

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Abstract

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.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Shaw, D.E.
Sayers, I.
Keywords: Macrolide antibiotics, Drug treatment for asthma
Subjects: W Medicine and related subjects (NLM Classification) > WF Respiratory system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 14428
Depositing User: EP, Services
Date Deposited: 06 Oct 2015 14:46
Last Modified: 14 Sep 2016 00:44
URI: http://eprints.nottingham.ac.uk/id/eprint/14428

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