Transcellular sulfidopeptide leukotriene biosynthetic capacity of vascular cells

Abstract

Cells in the vasculature, including polymorphonuclear leukocytes, platelets, and endothelial cells, have been shown to be jointly involved in the biosynthesis of active lipid mediators derived from arachidonic acid. Stimulation of neutrophils with the calcium ionophore A23187 as a model for cell activation results in production of leukotriene (LT)A4 with subsequent intracellular conversion into LTB4. When platelets or endothelial cells were present in the incubation system, LTC4 was produced from the neutrophil-derived LTA4. Whereas production and release of LTA4 under resting conditions in vivo might be expected to be quite low, under pathologic conditions, LTA4 production could be markedly increased. Therefore, the metabolism of exogenous LTA4 by platelets and endothelial cells was studied at a wide range of LTA4 concentrations. The production of LTC4 during coincubation of neutrophils with platelets was found to be dependent on neutrophil number ranging from 2 x 10(5) to 2 x 10(7) cells/mL. When a fixed number of neutrophils were stimulated with platelets alone or with mixtures of platelets and endothelial cells, LTC4 production was observed to be dependent on both acceptor cell types. These results suggest that mixed cell populations, which are likely to occur in vivo, may be critical determinants of the profile of eicosanoids produced in pathophysiologic circumstances. We suggest that both endothelial cells and platelets, in the presence of neutrophils, contribute large quantities of sulfidopeptide leukotrienes to inflammatory and thrombotic situations. Furthermore, platelets, because of their quantity and reactivity, may play a pivotal role in transcellular biosynthesis of eicosanoids.