Wellcome Trust Clinical PhD Programme at the University of Liverpool. (360G-Wellcome-086756_Z_08_Z)

Oxidative stress is implicated in the pathology of many lung diseases including chronic obstructive pulmonary disease, pulmonary vascular disorders and asthma. The epidemiological association of respiratory and cardiovascular disease, and high levels of particulate matter in the atmosphere may be explained by dysregulation of redox balance. This project will examine the implications of oxidative stress on human alveolar macrophage (AM) behaviour. Specifically, we wish to explain the extent to which extrinsic oxidative burden may cause intracellular redox imbalance, and the degree to which, in conditions of chronic exposure, enzymatic antioxidant defence protects against detrimental cellular effects. Although studies of lung epithelial lining fluid provide some evidence of extracellular disturbance, the intracellular component in humans is not well studied. Studies will include in vitro and ex vivo observations of macrophage susceptibility to oxidative toxicity from bacterial products, including pneumolysin (a key virulence factor produced by common respiratory pathogen Streptococcus pneumoniae). We will assess to what degree this susceptibility is augmented by redox imbalance secondary to selenium deficiency and smoke exposure (from cigarettes and indoor wood fire) We hypothesise that, in macrophages already under oxidative stress, there will be higher rates of apoptosis, and decreased antibacterial function in terms of oxidative burst and phagocytic capacity. If proved, this would have direct implications for the prevention of pneumonia.