ACTIVATION OF THE HUMAN NEUTROPHIL

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These studies are designed to study the activation of human neutrophils by phagocytic and non-phagocytic stimuli, with particular reference to the role of membrane lipids as transducers or modulators of stimulus-response coupling. Calcium acts as a "second messenger" in the activation of the neutrophil. A rise in cytosolic Ca is the first measurable event following activation by a variety of stimuli. Ca is mobilized principally from intracellular stores. A role for the breakdown of phosphatidyl inositols, in particular phosphatidyl inositol 4,5 bisphosphate with the generation of diacyl glycerol and inositol 1,4,5 trisphosphate has been implicated in the Ca movements accompanying neutrophil activation. The role of these lipids and their derivatives during neutrophil activation will be critically evaluated. The tumor promoter PMA can bypass this Ca requirement, possibly by activating a protein kinase C; this protein kinase C is activated by diacyl glycerol and serves to modify the Ca requirements as a variety of Ca requiring enzyme reactions. The role of protein kinases in mediating and modulating the neutrophil responses will be investigated. Further investigation into the inter-relation of Ca movements, phospholipid remodeling and protein kinase activity should yield crucial information on the activation and modulation of neutrophil responses. Since the appropriate functioning of the neutrophil is important in host defenses, as well as in inflammatory disorders, a more fundamental understanding of the activation sequence of the neutrophil is of obvious clinical importance.