Measurement and treatment of oxidative stress in chronic obstructive pulmonary disease

Abstract

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 reproducible.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.