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Title: Macrophage plasticity in chronic obstructive pulmonary disease
Author: Day, Amy
ISNI:       0000 0004 7657 1969
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Macrophages respond to their microenvironment by altering phenotype. In response to chronic pro-inflammatory signals, such as those in chronic obstructive pulmonary disease (COPD) macrophages can become skewed towards a pro-inflammatory phenotype. However, macrophages are important in the resolution of inflammation and consequently need to alter their phenotype to maintain homeostasis. COPD is a chronic inflammatory condition and therefore the hypothesis of this thesis is that macrophages from COPD patients have lost their ability to alter phenotype and lack plasticity. This thesis used monocyte derived macrophages (MDM) from non-smokers, smokers and COPD patients differentiated in either GM-CSF (GM-MDM) or M-CSF (M-MDM). It also explored plasticity of these cells through manipulation of culture environment. The response of these cells to LPS and IL-4 stimulation showed GM-MDM were more pro-inflammatory and less able to phagocytose bacteria compared with M-MDM in non-smokers. It also showed that MDM from COPD patients were more pro-inflammatory and less phagocytic regardless of environment. However, cell surface receptors alone were insufficient at defining phenotype. While MDM from non-smokers were able to alter phenotype in response to environmental change, MDM from COPD patients only became more pro-inflammatory, demonstrating unidirectional plasticity. Analysis of monocyte subsets within whole blood showed no significant differences between subject groups, suggesting differences in MDM phenotype occur during differentiation. MDM from COPD patients expressed higher levels of pro-inflammatory-linked transcription factors compared with non-smokers and were less able to alter this expression in response to environmental changes, again demonstrating a lack in plasticity in these cells. MDM from COPD patients lack ability to alter phenotype in response to environmental change, demonstrating a lack of plasticity which accentuates the pro-inflammatory COPD phenotype.
Supervisor: Donnelly, Louise Sponsor: National Heart and Lung Institute
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral