Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality. Despite this, there has been little progress in disease-modifying therapies, partly due to a poor understanding of the definition and mechanisms surrounding the early COPD disease process before it becomes established. COPD develops only in a proportion of smokers, and underlying pathology is likely to progress before the disease can be detected by spirometry. There is also evidence for the role of neutrophils in early disease, which may form a vital biomarker to investigate the pathophysiological processes of early COPD.

This thesis aimed to investigate changes in a group of smokers who may be at risk of COPD by assessing symptom burden, lung physiology, and evidence of emphysema on chest computed tomography (CT) scanning, with a focus on whether the presence of chronic bronchitis (CB) may influence these changes. Changes in peripheral neutrophil function and phenotype among these smokers were also assessed, using peripheral neutrophils from healthy nonsmokers as controls. Smokers with CB had a higher physical and psychological symptom burden than asymptomatic smokers, but no differences were seen between the two groups’ lung physiology and emphysema. However, many smokers had evidence of small airway dysfunction and/or emphysema which may be features of early COPD even when there is no evidence of airflow obstruction on spirometry.

In addition, peripheral neutrophils from CB smokers were observed to have impaired migratory function similar to neutrophils from COPD patients, which may result in increased collateral tissue damage in susceptible smokers. No difference in neutrophil degranulation or cell surface marker expression was seen among CB smokers, asymptomatic smokers, and healthy non-smokers. However, comprehensive neutrophil phenotyping using dimension reduction algorithms suggested subtle phenotype differences among the three groups. In conclusion, many smokers have evidence of clinical, physiological, and radiological features that could indicate early COPD disease process, which may progress to established disease. Altered neutrophil migration found among CB smokers provides further understanding of the role of neutrophils in early disease and merits further investigation.