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Title: Peripheral blood neutrophil activasion markers in severe corticosteriod-dependant asthmatics, and the effect of prednisolone
Author: Mann, Bhupinder Singh
ISNI:       0000 0004 2671 0801
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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Background: Severe asthmatics have increased numbers of airway neutrophils compared to mild asthmatics, and blood neutrophils may be activated in asthmatics. Activated neutrophils may contribute to airway inflammation and tissue damage. Hypothesis: Activation of both eosinophils and neutrophils is important in severe asthmatics, through enhancement of mediator release. The effect of corticosteroids on inhibition of neutrophils from severe asthma may be attenuated. Patients with severe allergic asthma may respond to anti-IgE monoclonal antibody treatment. Methods: The level of expression of baseline and stimulated blood neutrophil surface markers was investigated in severe corticosteroid-dependent asthmatics and compared to normal subjects and milder asthmatics. The effect of adding or increasing maintenance oral prednisolone (30mg/day for one week), on surface molecules, IL-8 and myeloperoxidase levels, neutrophil elastase and oxidative burst in blood was also studied. The level of expression and effect of corticosteroids on histone deacetylase (HDAC) activity from asthmatics was studied. The immediate effect of inhaled fluticasone propionate was also investigated, along with the efficacy of subcutaneous anti-IgE therapy. Results: CD35 and CD11b expression was increased in neutrophils from severe asthmatics compared to normal subjects. Prednisolone inhibited surface marker expression, oxidative burst and IL-8 release from mild but not severe asthmatics. HDAC activity was reduced in alveolar macrophages compared to PBMCs in asthmatics. Prednisolone increased HDAC activity in PBMCs from mild, but not severe asthmatics. HDAC activity was generally reduced in granulocytes compared with PBMCs. Inhaled fluticasone reduced exhaled nitric oxide levels in moderate asthmatics at four hours. Subcutaneous administration of anti-IgE therapy was well tolerated and decreased high affinity IgE receptor levels on basophils and monocytes during treatment. Conclusion: Peripheral blood neutrophils from severe asthmatics show a higher state of activation than normal subjects, and show loss of inhibitory corticosteroid response. Potential alternative treatments for severe asthma include anti-IgE antibody therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available