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Title: Corticosteroid insensitivity in severe asthma
Author: Hew, Mark Ji-Liang
Awarding Body: University of London
Current Institution: Imperial College London
Date of Award: 2007
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Severe asthmatic patients continue to have poorly controlled disease despite the use of anti-inflammatory medication such as corticosteroids. The aims of this thesis were to determine whether severe asthma is associated with corticosteroid insensitivity, and to begin an exploration of the cellular mechanisms involved. In this study, severe asthmatics had more severe airway obstruction and greater airway inflammation despite the use of high dose inhaled or oral corticosteroids. In peripheral blood mononuclear cells, relative corticosteroid insensitivity was present, evidenced by impaired steroid-regulated suppression of lipopolysaccharide-induced cytokine release. These cells also had diminished histone deacetylase activity, and this was linked with the degree of asthma severity, airway inflammation and corticosteroid insensitivity. Conversely, an associated reduction in histone acetyltransferase activity was related to the use of corticosteroid therapy rather than disease severity. Relative corticosteroid insensitivity was also detected in alveolar macrophages of severe asthmatic patients. This was seen in conjunction with impaired MAP kinase phosphatase-l (MKP-l) induction by dexamethasone in the presence of lipopolysaccharide, and exaggerated p38 mitogen activated protein (MAP) kinase activation by lipopolysacharide. This suggests that dysregulation of the p38 MAP kinase pathway may be an important determinant of corticosteroid insensitivity in alveolar macrophages of these severe asthmatic patients. In summary, this study has demonstrated the presence of relative corticosteroid insensitivity in both circulating peripheral blood mononuclear cells as well as alveolar macrophages from the airways of severe asthmatic patients. This corticosteroid insensitivity is linked to diminished histone deacetylase activity, and also to dysregulation of p38 MAK kinase activation. Overcoming corticosteroid insensitivity by targeting these pathways may offer a new strategy in the treatment of severe asthma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available