Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and
mortality worldwide. Oxidative stress in the lung has been associated with the
pathogenesis of this disease. Monitoring of the degree of oxidative stress and
subsequent inflammation in the lung through non invasive collection of induced
sputum and exhaled breath condensate (EBC) may improve our understanding of
this disease process. Treatment to reduce oxidative stress in COPD may improve
health status and lung function.
This thesis covers three studies. First of all the reproducibility of non invasive
biomarkers was assessed and then a cross sectional study of these biomarkers
was carried out. Finally a study of the impact of an inhaled anti oxidant on health
status and non invasive biomarkers in subjects with COPD was carried out.
The reproducibility of differential cells counts and pro inflammatory cytokines IL-1G,
IL-6, IL-8 and VEGF in induced sputum was assessed in 47 subjects. Total cell
counts and macrophage differential counts were reproducible but not neutrophil
and eosinophil differentials. IL-8 and VEGF but not IL-1R. and IL-6 demonstrated
reproducibility in induced sputum supernatant. Exhaled breath condensate was
measured in 24 subjects. 8-lsoprostane but not hydrogen peroxide was
Exhaled breath condensate was collected in 78 with COPD and 61 controls.
Groups were subdivided into current and ex-smokers. Levels of 8-lsoprostane and
hydrogen peroxide were measured. No significant differences were seen between
the mean levels of these two biomarkers measured in COPD and control groups.
Levels of oxidative stress biomarkers were compared to health status, symptom
scores and lung spirometry in the COPD population. No significant associations
were noted in the current smokers. COPD ex-smokers from the lowest quartile
(Q1) of 8-lsoprostane measured had lower health status and exacerbation
frequency compared to the highest quartile (Q4). Lung function was worse in the
highest 8-lsoprostane quartile. Hydrogen peroxide levels in EBC did not relate to
health status or symptom scores.
Fifty-eight subjects with moderate to severe COPD participated in a 12 week
double blind placebo controlled trial of an inhaled lyseine salt of N-Acetylcysteine.
Fewer of the subjects in the low dose treatment arm of the study had clinically
significant exacerbations compared with placebo. The low dose treatment arm also
demonstrated improvements in terms of diary card reporting of breathlessness
when compared with placebo.
In summary, some non invasive biomarkers of oxidative stress in COPD are
reproducible. However the overall utility of EBC 8-lsoprostane and hydrogen
peroxide measurement in COPD appears limited. 8-lsoprostane levels in exsmokers with COPD may reflect disease activity. Treatment with low dose inhaled
antioxidant demonstrated some improvement in health status.