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Title: The role of oxidative and nitrative stress and histone de-acetylation in rhinovirus induced acute exacerbations of Chronic Obstructive Pulmonary Disease
Author: Footitt, Joseph
ISNI:       0000 0004 2715 3146
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Acute exacerbations are the major cause of morbidity and mortality in COPD and respiratory virus infection is believed to be a leading aetiology. However mechanisms by which viruses induce acute exacerbations are poorly understood. This study reports the experimental inoculation with rhinovirus (RV) of COPD and non-obstructed smoking and non-smoking control subjects, of whom 9 COPD, 10 smoking and 11 non-smoking controls were later judged to have been successfully infected. The hypothesis tested was that RV infection led to the induction of oxidative and nitrative stress which resulted in degradation of histone deacetylase (HDAC) enzymes in COPD subjects but not controls. Subsequent histone hyperacetylation would then result in prolonged inflammatory gene transcription and therefore generate clinical features of an acute exacerbation. Following experimental RV inoculation the COPD subjects experienced excess lower respiratory tract symptoms and elevated virus load compared to the control groups. There was an associated acute inflammatory response and a greater burden of redox stress measured using the Griess and Potential of Antioxidant assays. HDAC2 activity was found to be reduced only in the COPD subjects following experimental RV infection. These findings would suggest that RV induced oxidative and nitrative stress results in reduced HDAC2 activity in COPD subjects leading to increased inflammation and symptoms consistent with the clinical phenotype of a COPD exacerbation.
Supervisor: Adcock, Ian ; Mallia, Patrick ; Johnston, Sebastian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral