Non-steroidal anti-inflammatory drugs and the augmented lipoxygenase pathway: conceivable impact on joint conditions

Abstract

Eicosanoid products of arachidonic acid (AA) metabolism are involved in several aspects of immuno-inflammatory processes. Macrophages play a pivotal role in such processes. These cells can readily release both cyclooxygenase and lipoxygenase metabolites and are also equipped with receptors for these products. Hence eicosanoids released from macrophages not only influence surrounding cells, but feeding back on the macrophage also modulate several functions of the macrophage itself, including i.a. lysosomal enzyme secretion, eicosanoid discharge and production of cytokines. Observations indicating that macrophage functions appeared to be positively related to the activity of the lipoxygenase pathway and negatively related to cyclic AMP elevating cycloxygenase metabolites, led in turn to the observation that leukotrienes can stimulate PGE₂ synthesis. This indicated that leukotrienes regulate their own production through a self-induced inhibitor, PGE2. These earlier findings warranted an investigation of the possibility that the lipoxygenase pathway is the target through which PGE2 suppresses and cyclo-oxygenase inhibitors stimulate macrophage functions. In this article we give abrief account of the most salient results which show that inhibition of cyclo-oxygenase by NSAIDs leads to stimulation of lysosomal enzyme release and augmented activity of the lipoxygenase pathway in macrophages.