The aim of this thesis was to evaluate mechanisms that are of potential interest in the pathogenesis of Chronic Obstructive pulmonary Disease (COPD) and associated symptoms; and subsequently to identify targets that may be relevant in the management of patients with structural and functional abnormalities of the pulmonary and skeletal muscle systems.
Dynamic hyperinflation (DH) is a recognised feature in the aetiology of dyspnoea and exercise limitation in COPD and strategies to improve DH by offsetting intrinsic positive end expiratory pressure (PEEPi) may improve exercise performance. Here the role of the upper airway was evaluated using continuous laryngoscopy during exercise. Increased laryngeal narrowing in COPD patients was associated with markers of disease severity such as lung function, hyperinflation indices and exercise performance, suggesting that patients may use this strategy to create PEEPi thus reducing flow limitation. This novel insight supports potential therapeutic benefits of upper airway strategies to improve gas exchange and act as a gateway to optimising tissue oxygen delivery.
Oxygen uptake (VO2) plays a vital role in maintaining mitochondrial homeostasis and is the measured parameter at the end of a metabolic gas exchange cardio-pulmonary exercise test. Mitochondria play a crucial role in maintaining the cellular oxidant-antioxidant balance. Mitochondrial function in airway and muscle compartments was evaluated in COPD patients and controls; and there was found to be evidence of airway mitochondrial dysfunction in patients with COPD compared to control subjects and a strong association with clinical phenotype. Similar changes were found in the pulmonary system of mice exposed to ozone and these were partially reversed with a mitochondria targeted antioxidant. Skeletal muscle mitochondrial function was not impaired in COPD despite a comparable oxidative stress burden to that found in the pulmonary system. Targeting the mitochondria may provide therapeutic options for airway related symptoms in patients with COPD