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Title: Restoration of corticosteroid sensitivity in severe asthma
Author: Mercado, Nicolas
ISNI:       0000 0004 2677 8144
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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Severe asthma accounts for a small number of asthmatics but represents a disproportionate cost to health care systems. The underlying mechanism in severe asthma remains unknown and most of the cost is the result of inadequate treatment. Although the disease presents a very heterogeneous profile it displays a certain degree of resistance to corticosteroid therapy. It is hypothesized that corticosteroid insensitivity can be reversed pharmacologically. We investigated the effects of drugs which are currently used for treatment of asthma on glucocorticoid sensitivity in peripheral blood mononuclear cells (PBMCs) from patients with mild, moderate and severe asthma and healthy volunteers. Long acting β2 receptor agonists (LABAs) were found to be able to reverse corticosteroid insensitivity in some severe asthmatic patients. These patients showed a defect of glucocorticoid receptor (GR) nuclear translocation with hyperphosphorylation of GR. Furthermore, LABAs were found to inhibit GR phosphorylation through inhibition of p38MAPKγ phosphorylation. Other severe asthmatic patients were also found to be 'responders' to theophylline, another current add-on treatment, and showed a defect in histone deacetylase activity. Further studies were conducted in order to find additional molecular abnormalities which may define novel add-on treatments to reverse corticosteroid resistance. Using simple laboratory methods in peripheral blood mononuclear cells (PBMCs) by one blood sampling, analysis of GR nuclear translocation potential, GR dependent transrepression (IL-8, IL-2 inhibition) and GR-dependent transactivation (Histone-4 lysine-5 acetylation, GILZ expression) revealed a heterogeneous population in severe asthma. Low levels of corticosteroid response were associated with a decrease in lung function in severe asthma. The use of possible add-on treatments such as an IKK2 inhibitor, a PI3K inhibitor, macrolides and a p38MAPKα/β inhibitor as well as existing treatments (theophylline and formoterol) confirmed that different molecular mechanisms were involved in severe asthma and is possible to choose the best add-on treatment individually for each patient. Particularly, a p38MAPKα/β inhibitor was broadly effective in severe asthma. This screening might be useful in determining the underlying phenotype of each individual patient. In the last chapter, I evaluated the effects of nortriptyline hydrochloride (NH), which is a well-known compound but recently identified as a novel add-on treatment to corticosteroids. Studies using PBMCs showed that there were 'responders' and 'non-responders' to NH in severe asthma. Analysis by correlation with other compounds suggested that NH can modify PI3K signalling. In fact NH inhibited phosphorylation of Akt, a surrogate marker of PI3K under oxidative stress, and restored HDAC activity defective under oxidative stress. This new combination will be one of choice for the treatment of severe asthma. This thesis gives new insights on phenotyping of severe asthma patients and novel add-on treatments to corticosteroids, possibly leading to future tailor-made treatment.
Supervisor: Ito, Kazuhiro ; Adcock, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral