Phagocytic cells respond to activation by a variety of stimuli by generating oxygen-derived free radicals. The characteristics of the production of superoxide anion and hydrogen peroxide by human neutrophils has been compared with that produced by human monocytes. The majority of work in this thesis is concerned with the employment of an assay which measures hydrogen peroxide produced by stimulated human neutrophils in vitro, but which also has been found to detect the generation of another peroxide, the identity of which is uncertain. The use of cyclooxygenase, lipoxygenase and phospholipase A2 pathway inhibitors has provided indirect evidence for the identification of the unknown peroxide as 5-hydroperoxyeicosatetraenoic acid (5-HPETE). These inhibitors have also provided the opportunity to investigate differences in the oxidative metabolism of human neutrophils induced by various stimuli. In addition, the effects of two cyclooxygenase inhibitors, diclofenac and piroxicam, on neutrophil activity in vivo has been investigated. Whilst neutrophil activity of some individuals was inhibited, this was not consistent and not significant. Incubation of a variety of analogues of the cyclooxygenase inhibitors diclofenac and fenclofenac with stimulated neutrophils in vitro has allowed an insight into the structure-activity relationships of these drugs' effects on neutrophil activity. It was found that the position of substitution of various groups in the ring structure remote from the acid group had the biggest single influence on activity. Finally, the oxidative metabolism of neutrophils from patients with progressive systemic sclerosis, rheumatoid arthritis and peripheral vascular disease has been compared with that of neutrophils from healthy controls. The neutrophils from the progressive systemic sclerosis group were found to have increased activity both ex vivo and following incubation with heat-aggregated IgG. This has been shown to be associated with enhanced expression of Fc receptors on these cells.
|Date of Award||1985|