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Effect of inhaled corticosteroids on viral and bacterial infection in chronic obstructive pulmonary disease

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Title: Effect of inhaled corticosteroids on viral and bacterial infection in chronic obstructive pulmonary disease
Authors: Singanayagam, Aran
Item Type: Thesis or dissertation
Abstract: Rhinovirus (RV) infections trigger exacerbations of chronic obstructive pulmonary disease (COPD) exacerbations and may precipitate secondary bacterial infections. Inhaled corticosteroids (ICS) are used commonly in COPD but are relatively ineffective in the context of virus-induced exacerbations and may also increase the risk of pneumonia. We hypothesised that, in a mouse model, ICS would suppress anti-viral and anti-bacterial immune responses leading to alteration of the airway microbiota and secondary bacterial infection following RV-induced exacerbation of COPD. Despite extensive optimisation, we were unable to define a representative mouse model of the deficient anti-viral and anti-bacterial responses that are indicative of human COPD. For this reason, and because of difficulties in measuring the airway microbiota in mice, we employed models of primary RV1B and Streptococcus pneumoniae infection as surrogates for viral exacerbation and bacterial colonisation in COPD. Fluticasone propionate (FP) administration prior to RV1B infection suppressed innate and adaptive immune responses leading to impaired virus control, in a dose dependent manner. This effect was causally related to suppression of type I interferon (IFN) as administration of recombinant IFN-β reconstituted IFN-stimulated gene expression and restored virus control. FP suppressed RV-induced airway inflammation but led to enhanced airway mucin production, effects that were unaltered by recombinant IFN-β. FP administration also suppressed innate responses to S. pneumoniae including expression of anti-bacterial cytokines and cathelicidin-related anti-microbial peptide. High dose FP increased lung tissue bacterial loads with the opposite effect observed with lower dose FP despite similar anti-inflammatory effects. Our findings demonstrate beneficial anti-inflammatory effects of ICS during virus-induced COPD exacerbations but reveal some previously unrecognised detrimental effects including increased virus replication and enhanced mucin production. Additionally, we show that high dose ICS administration may increase bacterial loads and thus increase pneumonia risk but lower doses may conversely reduce bacterial loads and therefore could be safer in COPD.
Content Version: Open Access
Issue Date: Jul-2014
Date Awarded: Dec-2014
URI: http://hdl.handle.net/10044/1/24469
DOI: https://doi.org/10.25560/24469
Supervisor: Johnston, Sebastian
Cookson, William
Moffatt, Miriam
Sponsor/Funder: Wellcome Trust (London, England)
Funder's Grant Number: 096382/Z/11/Z
Department: National Heart & Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses

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