Activation of the human neutrophil: the roles of lipid remodeling and intracellular calcium.

The stimulus-response coupling sequence of neutrophils has been partially elucidated, and a temporal order for some of the initial events in PMN activation has been established; membrane potential, Ca2+ motivation, Ca2+ influx, cAMP pulse, aggregation, O2- . generation and degranulation. Receptor-ligand interaction is followed by membrane hyperpolarization and the mobilization of Ca2+ from intracellular loci. In common with other secretory cells, neutrophils utilize Ca2+ as a second messenger to mediate cellular responses. For optimal activation, neutrophils require an influx of extracellular Ca2+. However, the mechanism by which Ca2+ enters neutrophils or other cells is not known. In view of our recent findings that phosphatidic acid and oxidized trienoic acids can translocate Ca2+ in lipid bilayers, it should be apparent that a study of phospholipid metabolism (particularly changes in phosphatidyl inositol and phosphatidic acid) in human neutrophil activation together with a temporal analysis of Ca2+ influx will contribute to an understanding of the mechanism of stimulus-secretion coupling. Since arachidonic acid metabolites play an important role in inflammation and have recently been suspected of modulating stimulus-secretion coupling, studies of the release of arachidonic acid from membrane phospholipids are important because all prostaglandins and hydroxy acids are derived from this initial step. Finally, the generation, by neutrophils, of free arachidonic acid and its oxygenation products might serve as a model system for other tissues in addition to their important role in inflammation.