MYELOPEROXIDASE AND LEUKOCYTE GRANULE COMPONENTS

刺激嗜中性白细胞导致分泌有毒的 蛋白质和酶髓过氧化物酶（MPO）从 细胞质颗粒和激活中性粒细胞氧（O2） 代谢，产生有毒的氧化剂。 神经毒素 通过杀死入侵的微生物来对抗感染， 导致炎症组织破坏。 远景目标纲要 是为了描述氧化剂，确定它们在 抗微生物活性和对宿主细胞的损伤，并阐明 调节其效力和选择性的机制。 的 工作假设是过氧化氢（H2 O2）和产物 MPO/H_2O_2/Cl ~-体系的主要氧化产物是MPO/H_2O_2/Cl ~- 毒素 超氧化物（02-）是白细胞02的第一个产物 02-的主要作用不是作为毒素。 相反，O2-是H2 O2生产中的中间体和氧化剂 对于细胞外还原剂如抗坏血酸盐（维生素C）和 巯基化合物。 这些还原剂被02- 增加H2 O2产量并消耗还原剂， 它们不能解毒H2 O2和MPO系统的产物。 MPO系统的毒性也受氨（NH 4+）调节， 和来自细胞质颗粒的富含赖氨酸的肽。 MPO 催化H2 O2氧化C1-生成次氯酸 （HOC 1），其与NH 4+反应以产生杀菌剂 一氯胺（NH 2Cl）。 然而，NH 2C 1也可以抑制 通过抑制中性粒细胞O2代谢和NH 4+或 NH_2C_1可抑制MPO的分泌。 HOC 1与 赖氨酸-肽产生相对无毒但寿命长的 肽-氯胺。 拟议的研究将描述 O2-、H2 O2和MPO系统的产物与 抗坏血酸和其他细胞外还原剂，并检查影响 还原剂的抗菌和细胞毒活性 孤立的中性粒细胞 锰（Mn 2+）促进 将研究MPO对还原剂的氧化，以确定 MPO是否可以作为氧化酶并产生毒性氧化剂 在具有缺陷O2代谢的嗜中性粒细胞中。 NH 4+的影响 对中性粒细胞O2代谢、MPO分泌和抗菌 活性将被测量，并且赖氨酸-肽的相互作用 将使用纯化的肽研究MPO系统， MPO。 这些研究将提供新的见解， 中性粒细胞功能中的氧化剂和还原剂， 用于在抑制感染的同时对抗感染的改进方法 对宿主组织的损害。

Stimulation of neutrophilic leukocytes results in secretion of toxic proteins and the enzyme myeloperoxidase (MPO) from cytoplasmic granules and activates neutrophil oxygen (O2) metabolism, which produces toxic oxidants. Neutrophil toxins combat infection by killing invading microorganisms but also contribute to inflammatory tissue destruction. Long-range goals are to characterize the oxidants, determine their role in antimicrobial activity and damage to host cells, and elucidate mechanisms that regulate their potency and selectivity. The working hypothesis is that hydrogen peroxide (H202) and products of the MPO/H202/chloride (C1-) system are the major oxidative toxins. Superoxide (02-) is the first product of leukocyte 02 metabolism, but the principal role of 02- is not as a toxin. Instead, 02- is an intermediate in H202 production and an oxidant for extracellular reductants such as ascorbate (vitamin C) and sulfhydryl compounds. Oxidation of these reductants by 02- increases H202 production and consumes the reductants so that they can't detoxify H202 and products of the MPO system. Toxicity of the MPO system is also regulated by ammonia (NH4+), and lysine-rich peptides from the cytoplasmic granules. MPO catalyzed the oxidation of C1- by H202 to yield hypochlorous acid (HOC1), which reacts with NH4+ to yield the bactericidal agent monochloramine (NH2C1). However, NH2C1 can also suppress toxicity by inhibiting neutrophil 02 metabolism, and NH4+ or NH2C1 may inhibit MPO secretion. The reaction of HOC1 with the lysine-peptides yields relatively non-toxic though long-lived peptide-chloramines. The proposed studies will characterize the interaction of 02-, H202, and products of the MPO system with ascorbate and other extracellular reductants, and examine effects of the reductants on antibacterial and cytotoxic activities of isolated neutrophils. The ability of manganese (Mn2+) to promote oxidation of reductants by MPO will be studied, to determine whether MPO could act as an oxidase and produce toxic oxidants in neutrophils with defective 02 metabolism. The effect of NH4+ on neutrophil 02 metabolism, MPO secretion, and antibacterial activity will be measured, and the interaction of lysine-peptides with the MPO system will be studied using purified peptides and MPO. These studies will provide new insights into the role of oxidants and reductants in neutrophil function and may lead to improved methods for combating infection while suppressing damage to host tissues.