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Title: Systemic inflammation in COPD : effects on skeletal muscle and the cardiovascular system
Author: Mohan, Divya
ISNI:       0000 0004 6496 065X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Chronic obstructive pulmonary disease (COPD) is increasingly recognised to be heterogeneous and complex, with several extra-pulmonary manifestations, necessitating categorisation of patients in order to better tailor treatments towards distinct phenotypes. Cardiovascular disease and peripheral skeletal muscle dysfunction are amongst the most important comorbidities in COPD, with systemic inflammation proposed as a potential mechanistic link. Therefore, there is considerable interest in novel anti-inflammatory drugs, as well as understanding underlying mechanisms. An observational study of 729 COPD subjects confirms that cardiovascular co-morbidity and quadriceps weakness affect 46.3% and 43.6% of the study population respectively. However, these comorbidities are present as distinct manifestations, and do not overlap to present as a combined phenotype more often than expected. Markers of systemic inflammation (fibrinogen, white cell count and C-reactive protein), relate neither to arterial stiffness, quadriceps weakness nor to diaphragm weakness as measured via sniff nasal inspiratory pressure (SnIP). Consistent with the above findings, Losmapimod, a novel anti-inflammatory p38-MAPK inhibitor, did not improve cardiovascular or muscle performance, measured as arterial stiffness, SnIP and 6-minute walk distance, in a double-blind, randomized control study of 67 COPD subjects. Definitive evidence of whether inflammatory and/or atrophy pathways are up-regulated in human quadriceps is currently lacking, possibly due to the use of whole muscle samples failing to account for altered fibre type composition amongst COPD subjects. Quadriceps biopsy specimens from 12 COPD and 6 healthy subjects were used to separate type I and type II muscle fibres via laser capture microdissection (LCM). In this pilot study, there was evidence of lower MURF-1 and Atrogin-1 expression in type II fibres of COPD versus control subjects, a difference that was not apparent in whole muscle samples. Therefore LCM can potentially provide a more sensitive, novel method to identify therapeutic targets for skeletal muscle dysfunction.
Supervisor: Polkey, Michael ; Hopkinson, Nicholas ; Kemp, Paul Sponsor: Technology Strategy Board ; National Institute for Health Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral