INTERACTION OF HUMAN NEUTROPHILS WITH OXIDIZED CHEMOTACTIC PEPTIDE

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A collaborative study was continued with Dr. Robert Aksamit in which we chemically prepared the oxidized derivatives of the chemotactic peptide, F-met-leu-phe: F-met-leu-phe sulfoxide and F-met-leu-phe sulfone. In previous studies we have shown that oxidized F-met-leu-phe derivatives bind to neutrophils and activate the oxidative metabolic burst of neutrophils without activating chemotaxis, indicating that these modified peptides may be useful probes for exploring the activation of neutrophil function. We have also used these oxidized derivatives in a series of enzyme release assays to determine whether the oxidized derivatives would activate neutrophil lysosomal enzyme release. We quantitated the release of lysozyme, elastase, myeloperoxidase, beta-glucuronidase, and lactoferrin, and observed that the oxidized derivatives stimulated the release of these enzymes from neutrophils. Their relative potency in activation of enzyme release correlated with their binding affinities: parent> sulfone> sulfoxide. Additional studies were performed to evaluate the effects of these peptides on neutrophil orientation, endocytosis, and activation of cytoskeletal F-actin polymerization. In each of these assays, the oxidized peptides-were potent stimuli for neutrophil activation. Studies are in progress with radiolabeled oxidized derivatives to determine whether the oxidized derivatives bind to the high or low affinity states of N-formyl peptide receptors on purified neutrophil plasma membranes. Other studies are also in progress to-determine whether the oxidized derivatives of F-met-leu-phe are processed or recycled differently than the parent form of the peptide by neutrophils. These studies should provide significant new information about the requirements for signal processing by activated neutrophils.