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Effects of acute and chronic antigen inhalation on airway inflamation and function and anti-inflammatory drug interventions

Evans, Rhys 2009. Effects of acute and chronic antigen inhalation on airway inflamation and function and anti-inflammatory drug interventions. PhD Thesis, Cardiff University.

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Asthma is a chronic inflammatory disease characterised by airway inflammation, bronchoconstriction, airway hyperresponsiveness AHR and airway remodelling. Most models of asthma focus on acute allergen challenges, where airway remodelling is absent. The thesis aimed to compare acute and chronic allergen challenge models of asthma and analyse the effects of anti-inflammatory drugs on these models. Acute and chronic challenges with ovalbumin in conscious guinea pigs and mice caused impared lung function, measured as specific airway conductance sGaw and enhanced pause Penh , respectively. This was characterised by early EAR and late LAR asthmatic responses, AHR and cellular influx. Multiple challenges with ovalbumin caused airway remodelling distinguished by increased bronchiolar collagen and goblet cells compared to control. No airway remodelling was observed in acute ovalbumin models. Treatment with the corticosteroid, fluticasone propionate FP, attenuated the LAR, AHR and cellular influx in all models. In both chronic ovalbumin models, FP treatment partially reversed airway remodelling, though not to naive levels. This was also the case with treatment with the phosphodiesterase IV inhibitor, roflumilast. However, roflumilast also attenuated the EAR. Treatment with the iNOS inhibitor, GW274150F, reduced the LAR and AHR and showed some inhibition of cellular influx in the acute ovalbumin challenged animals. However, GW274150F was ineffective in chronic ovalbumin models. Lung oedema, assessed by magnetic resonance imaging in acute and chronic ovalbumin challenged guinea pigs, was increased and correlated temporarily with the LAR. Dexamethasone treatment attenuated the level of oedema though not to control levels. Acute ovalbumin challenged models showed airway functional changes which were partially resolved with drug treatment. Chronic ovalbumin challenges provoked lung functional and structural changes which were attenuated by FP and roflumilast but not GW274150F. As GW274150F proved ineffective in clinical trials, the data in this thesis suggests that chronic ovalbumin challenge animals are better pre-clinical models of asthma.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
ISBN: 9781303191718
Date of First Compliant Deposit: 30 March 2016
Last Modified: 02 Oct 2014 13:44

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