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Title: The role of macrophage migration inhibitory factor in airways disease
Author: Russell, Kirsty
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Chronic obstructive pulmonary disease (COPD) and severe asthma are progressive chronic inflammatory diseases of the airways. Both diseases are characterised by airflow limitation and share some pulmonary symptoms. However they have distinct inflammatory cell signatures and differ in response to corticosteroid (CS) treatment. Most asthmatic patients control their disease with CS, with a few showing a relative CS resistance; however COPD patients show little or no improvement with CS and are CS insensitive. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory mediator whose function is yet to be fully elucidated. MIF has been shown to counter-act the immunosuppressive action of CS. MIF is elevated in chronic diseases such as asthma and atherosclerosis. The role of MIF in COPD has not been investigated and its role in asthma is not fully understood. MIF inhibition attenuated ozone-induced airway inflammation and lung function in vivo but did not affect CS sensitivity. MIF expression did not vary between stable COPD patients and controls. Pro-inflammatory effects of MIF were investigated in THP-1 monocytes and primary cells. There was no clear role for MIF in LPS-induced inflammation. MIF modulated the transactivation functions of CS in THP-1 cells. Finally I took an unbiased approach to generate new hypotheses for MIF function using proteomic and transcriptomic techniques. The RIG-I-like pathway was identified by proteomics as a novel target pathway and was investigated in THP-1 cells and human BAL macrophage samples following viral infection. The role of MIF in airway inflammation remains unclear and results demonstrated here show MIF function does not necessarily translate from mouse to humans. MIF does not seem to have a role in the inflammation of stable disease. The proteomic data suggests that the association between viral infection, MIF and CS in regulating CS sensitivity in COPD and severe asthma should be investigated.
Supervisor: Adcock, Ian; Barnes, Peter; Durham, Andrew Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available