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Title: The role of p38 mitogen-activated protein kinase in corticosteroid-insensitivity in severe asthma and COPD
Author: Khorasani, Nadia Mohamed
ISNI:       0000 0004 6422 7095
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Severe asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the lung both characterised by airway limitations but with differing pathophysiology. Asthma is normally well controlled with the use of corticosteroids (CS). However in 5 – 10% of all patients with asthma - severe asthmatics - and in most patients with COPD, the response to CS is poor and these patients are relatively CS-insensitive. p38 mitogen-activated protein kinase (MAPK) is a kinase cascade whose heightened activity has been reported in severe asthma and COPD. In this thesis I hypothesised that increased p38 MAPK activity contributes to CS-insensitivity in severe asthma and COPD Induced p38 MAPK activity was increased in peripheral blood mononuclear cells (PBMC) from patients with severe asthma compared with non-severe asthma and in patients with COPD compared with smoking subjects. The ability of dexamethasone to suppress induced pro-inflammatory cytokine release was impaired in PBMC from patients with severe asthma compared with those with non-severe asthma, and in patients with COPD compared with smoking subjects, demonstrating CS-insensitivity in these patients. The inhibition of p38 MAPK activity with GW856553 improved the ability of dexamethasone to suppress induced cytokine release in PBMC from patients with severe asthma or COPD. To investigate the molecular mechanisms by which p38 MAPK activity may be involved in CS-insensitivity, the effect of p38 MAPK inhibition on the phosphorylation of glucocorticoid receptor (GR) at serine 211 residue was determined and was revealed to be p38 MAPK dependent in PBMC from patients with COPD. MAPK phosphatase (MKP)-1 is an anti-inflammatory mediator that is induced by CS and can regulate p38 MAPK activity through dephosphorylation of its serine/threonine residues. Baseline and induced expression of MKP-1 was reduced in PBMC and monocytes from patients with severe asthma compared with non-severe asthma. Impairment of MKP-1 induction by CS may therefore be a mechanism through which CS-insensitivity manifests itself in severe asthma, however, siRNA knockdown of MKP-1 in monocytes from normal subjects resulted in an increase of induced pro-inflammatory cytokines, but it did not reach significance. CS and long-acting β2 agonists (LABA) are used in combination to treat patients with COPD or severe asthma. The effect of fluticasone propionate (FP) or the novel CS, fluticasone furoate (FF), alone or in combination, with a novel ‘ultra-LABA’ vilanterol trifenatate, on suppression of induced cytokine release was examined and compared between severe asthmatics and non-severe asthmatics, and between patients with COPD and healthy smokers. FF, compared with FP, was superior in its ability to suppress induced cytokine release in PBMC from all groups. Moreover, suppressibility of FF in combination with vilanterol, on induced cytokine release, was significantly enhanced, compared with FP in combination with vilanterol, or vilanterol alone, in PBMC from severe asthmatics or COPD.
Supervisor: Bhavsar, Pankaj ; Chung, Kian Fan Sponsor: National Institutes of Health ; Medical Research Council ; GlaxoSmithKline
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral