Twomey, Bridget Mary; (1991) A study of non-steroidal anti-inflammatory drugs on human neutrophil toxic oxygen metabolite production. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A study was carried out on the effect of a wide range of nonsteroidal anti-inflammatory drugs (NSAIDs) on the receptor- and postreceptor-mediated respiratory burst in human neutrophils. Superoxide (O2-) - which can give rise to toxic oxygen metabolites known to cause tissue damage - was measured spectrophotometrically by the reduction of ferricytochrome C. It was found that the NSAIDs fell into three categories: 1) those that increased production, 2) those that had no effect and 3) those that decreased production. These findings could have clinical relevance for the therapy of chronic inflammatory diseases such as rheumatoid arthritis. In order to investigate the mode of action of those drugs which potentiated 01 release, a pharmacological study of the transduction mechanisms of the respiratory burst was undertaken. A number of cyclooxygenase and 5-lipoxygenase inhibitors had no effect on the stimulated response, implying that the enhancing effect of the NSAIDs was independent of their effect on arachidonic metabolism. Putative "specific" inhibitors of the diacylglycerol (DAG) metabolizing enzyme, DAG kinase, gave similar results to those obtained with the potentiating NSAIDs (with the exception of RAF), indicating that the NSAID effect could involve increased DAG/protein kinase C (PKC) activity. The role of the DAG/PKC pathway in the respiratory burst was addressed using a novel series of potent PKC inhibitors reported to be selective for PKC over other protein kinases. It was found that these agents inhibited 01 production induced by both receptor and postreceptor stimuli, and also in activation sequences that are reported to be Ca2+-independent. Differences in the order of potency of the PKC inhibitors within the range of stimuli used indicated that there might be different PKC isoenzymes, differentially affected by the inhibitors. The potentiating NSAIDs were tested for an effect on isolated PKC, but none were found to directly activate the enzyme. Inhibition by wortmannin of the response to some stimuli may suggest a role for the phospholipase D pathway of DAG generation. This study supports a role for the DAG/PKC pathway in signal- transduction for the neutrophil respiratory burst.

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