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Title: Molecular & pharmacological approach for the optimisation of combination therapy of a long-acting β2 agonist and a corticosteroid in chronic obstructive pulmonary disease
Author: Rossios, Christos
ISNI:       0000 0004 2702 837X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Combination inhalers of long-acting β2 agonists (LABAs) with inhaled corticosteroids (ICSs) are now widely used for the treatment of asthma. However, corticosteroid (CS) insensitivity can be a major barrier for the treatment of chronic obstructive pulmonary disease (COPD). Existing ICSs are less beneficial on the decline of lung function in the long term. Even at the cellular level, CSs are less effective in primary cells, peripheral blood mononuclear cells (PBMCs) obtained from COPD patients compared to PBMCs from healthy volunteers. High levels of oxidative stress in COPD have been reported to be involved in CS insensitivity. In addition, oxidative stress has been reported to affect the β2 adrenergic receptor (β2AR) signalling itself. Here I hypothesise that oxidative stress affects the function of CSs and LABAs and/or their combination. Clarifying the molecular mechanism of this defect, will give new insights for the optimisation of the ideal CS/LABA combination therapy for the treatment of COPD. Primarily, pharmacological effects of fluticasone furoate (FF), a novel CS, were evaluated in various inflammation systems in respiratory cells and compared with those of currently available fluticasone propionate (FP) and budesonide (Bud). In the course of this study, FF was found to be a potent and long-acting CS. More importantly, the anti-inflammatory effects of FP were reduced under oxidative stress, whereas the effects of FF were not affected by oxidative stress. FF was also more effective on inhibiting cytokine release in PBMCs from COPD patients. Hence, this study demonstrated that FF is an oxidative stress insensitive CS. Furthermore, effects of oxidative stress on the function or signalling of LABAs were investigated. Salmeterol (SM)-induced cyclic AMP (cAMP) production was reduced under H2O2 treatment, while the effects of formoterol (FM) were not affected by H2O2. Under conditions of oxidative stress, SM also induced β2AR internalisation, whereas FM did not. Cell signalling analysis showed that FM partially inhibited H2O2-induced Akt phosphorylation, a footprint of phosphoinositide-3 kinase (PI3K) activation, whereas SM did not. Furthermore, add-on treatment with FM could improve sensitivity of either Bud or FP in U937 cells, under simulative conditions of oxidative stress or PBMCs from COPD patients, but SM did not improve it. Moreover, vilanterol trifenatate (VT), also known as GW642444, a novel ultra LABA showed similar effects with FM, under oxidative stress. Thus, FM (and VT) is more robust than SM under oxidative stress conditions. Finally, the outcome of H2O2 on the anti-inflammatory effects of CS/LABA combination was evaluated. As concluded from the results above, FF and FM (or VT) were oxidative stress insensitive compounds. In fact, the combination of FF and VT, as well as a combination of mometasone furoate (MF) with FM showed the most potent anti-inflammatory effects under oxidative stress and in PBMCs from COPD patients. Consequently, the findings from this thesis might give new insights and support the development of new combination therapies for the treatment of chronic inflammatory airway diseases, where high levels of oxidative stress are seen.
Supervisor: Ito, Kazuhiro ; Barnes, Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral