MYLEOPEROXIDASE AND LEUKOCYTE GRANULE COMPONENTS

中性粒细胞的刺激导致有毒物质的分泌 胞质颗粒中的蛋白质和髓过氧化物酶(MPO) 激活中性粒细胞氧(O2)代谢，从而产生有毒的氧化剂。 中性粒细胞毒素通过杀死入侵的微生物来对抗感染，但 也会导致炎症组织的破坏。长期目标是 为了确定氧化剂的特性，确定它们在抗菌中的作用 对宿主细胞的活性和损伤，并阐明调节机制 它们的效力和选择性。工作假说是氢 过氧化氢(H202)和MPO/H202/氯(C1-)体系的产物是 主要的氧化毒素。超氧化物(02-)是白细胞的第一个产物 02代谢，但02-的主要作用不是作为一种毒素。相反， 02-是H202生产的中间体，也是胞外的氧化剂 还原剂，如抗坏血酸(维生素C)和巯基化合物。 这些还原剂被02-氧化增加了H202的产量和消耗 不能对H202和MPO产物解毒的还原剂 系统。MPO系统的毒性也受氨(NH4+)的调节， 以及来自细胞质颗粒的富含赖氨酸的多肽。MPO催化了 氯被H_202氧化生成次氯酸(HOC_1)，该反应 与NH4+反应生成杀菌剂一氯胺(NH2C1)。然而， NH_2C_1还可通过抑制中性粒细胞02代谢来抑制毒性。 NH4+或NH_2C_1对MPO分泌有抑制作用。HOCl2与环氧氯丙烷的反应 赖氨酸肽虽然寿命长，但相对无毒。 多肽-氯胺。拟议的研究将描述 02-、H202及MPO体系产物与抗坏血酸和维生素C的相互作用 其他胞外还原剂，并检测这些还原剂对 分离的中性粒细胞的抗菌活性和细胞毒活性。这个 锰(Mn2+)促进MPO氧化还原剂的能力 进行研究，以确定MPO是否可以作为一种氧化酶并产生 02代谢缺陷的中性粒细胞中的有毒氧化剂。的影响 NH4+对中性粒细胞02代谢、MPO分泌和抗菌活性的影响 将被测量，以及赖氨酸肽与MPO的相互作用 系统将使用纯化的多肽和 MPO。这些研究将提供对氧化剂和 中性粒细胞功能中的还原剂，并可能导致改进的方法 在对抗感染的同时抑制对宿主组织的破坏。

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 Cl- 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.