MYELOPEROXIDASE AND LEUKOCYTE GRANULE COMPONENTS

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Myeloperoxidase (MPO), hydrogen peroxide (H2O2), and chloride ion (C1-) form an antimicrobial system within phagolysosomes of neutrophils. In studies using purified MPO, antimicrobial activity was found to be modulated by certain nitrogen compounds (N-compounds). In studies on stimulated neutrophils, these N-compounds influenced the rate of neutrophil self-inactivation. The basis of these effects is MPO-catalyzed oxidation of C1- to hypochlorous acid (HOC1), which reacts with N-compounds to yield nitrogen-chlorine (N-C1) derivatives with differing antimicrobial and cytotoxic activities. The proposed studies will examine the interaction of isolated neutrophils with certain naturally occurring N-compounds that may mediate and regulate the oxidative toxicity of neutrophils in vivo. When stimulated neutrophils are studied in vitro, the major N-compounds available for reaction with HOC1 are ammonia (NH4+), taurine, and proteins that are secreted from the cytoplasmic granules. The reaction of HOC1 with NH4+ yields monochloramine (NH2C1), a lipophilic oxidizing agent with potent antimicrobial and cytotoxic activity. The role of NH2C1 in neutrophil oxidative toxicity will be studied with erythrocytes and bacteria as target cells. The reaction of HOC1 with taurine yields taurine-monochloramine (tauNHC1), a hydrophilic oxidizing agent with little or no toxicity. Formation and toxicity of tauNHC1 and related N-C1 derivatives will be studied under conditions that may promote toxicity: (a) when tauNHC1 is transported into the target-cell by a membrane transport system, and (b) when tauNHC1 reacts with NH4+ to yield NH2C1. NH4+-dependent toxicity will be studied with bacteria, erythrocytes and tumor cells as targets. Histamine is a naturally occurring N-compound that neutrophils encounter in high concentrations in vivo. The reaction of HOC1 with histamine yields histamine-monochloramine (hisNHC1), which has the unusual property of being either hydrophilic or lipophilic, depending on pH. Chlorination of histamine by stimulated neutrophils, the fate of hisNHC1, and the effect of hisNHC1 on neutrophil functions will be studied. The goal is to gain increased understanding of the regulation of neutrophil oxidative toxicity, so as to lead to new approaches to increasing resistance to infection while protecting normal tissues against oxidative attack.