Muid, Robert Edward; (1992) The transduction processes of human neutrophil superoxide generation activated by receptor and post-receptor mechanisms. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The generation of toxic oxygen radicals, by activated human neutrophils, is involved not only in microbial killing but has been implicated in tissue injury. The development of improved therapeutic agents necessitates an adequate understanding of the events coupling receptor stimulation with oxygen radical production. At least two signal-transduction pathways appear to be involved in the generation of oxygen radicals. One involves the phospholipase C mediated breakdown of phosphatidylinositol bisphosphate - giving rise to inositol trisphosphate (which mobilizes calcium) and diacylglycerol (which activates protein kinase C). The other pathway involves generation of diradylglycerols from non-inositol containing lipids by the action of phospholipase D. However derived, increased diradylglycerol levels and subsequent protein kinase C activation have been implicated in the generation of superoxide (O2-). Despite this, a controversy still exists as to the involvement of protein kinase C in receptor-mediated O2- production. Superoxide was measured by the reduction of ferricytochrome c initiated by receptor stimuli (fMLP, opsonized zymosan, IgG and heat-aggregated IgG), two direct protein kinase C activators (OAG and DiC8), a calcium ionophore (A23187) and a compound thought to mobilize membrane lipids (y-HCCH). Newly available and reportedly specific protein kinase C inhibitors, and putative inhibitors of diacylglycerol metabolism were used to investigate the transduction mechanisms. The results suggest that contrary to reports in the literature, protein kinase C has a central role in the signal transduction of the respiratory burst. Differences in the transduction pathways for the receptor stimuli were found and an arachidonate pathway may play a role in opsonized zymosan- and IgG-induced O2- generation. This raises the possibility that drugs could be designed which might reduce toxic oxygen radical-mediated tissue damage (such as that caused by immune complexes), without reducing the effectiveness of microbial killing. The ability of the non-steroidal anti-inflammatory drugs (NS AIDs) to modify O2- production was also investigated. Some NSAIDs, namely sodium meclofenamate, mefanamic acid and benoxaprofen, actually exacerbated superoxide release when neutrophils were stimulated by both receptor and post-receptor mechanisms. Indomethacin potentiated post-receptor stimulated O2- generation, but inhibited fMLP, Fe and C3b receptor-mediated O2- production. These results could have clinical relevance.

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