MYELOPEROXIDASE AND LEUKOCYTE GRANULE COMPONENTS

中性粒细胞的刺激导致有毒物质的分泌 蛋白质和髓过氧化物酶(MPO) 胞质颗粒和激活中性粒细胞氧(O2) 新陈代谢，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 有助于炎症组织的破坏。远景目标 是为了表征氧化剂，确定它们在 抗菌活性和对宿主细胞的损害，并阐明 调节其效力和选择性的机制。这个 工作假设是过氧化氢(H202)及其产物 是MPO/H_202/氯(C_1-)体系的主要氧化产物 毒素。超氧化物(02-)是白细胞02的第一个产物 新陈代谢，但02-的主要作用不是作为毒素。 相反，02-是生产H202的中间体和氧化剂 对于细胞外还原剂，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H202的产量和消耗还原剂，以便 它们不能为H202和MPO系统的产品解毒。 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 H_2O_2催化C_1-氧化生成次氯酸 (HOc1)，它与NH4+反应生成杀菌剂 一氯胺(NH2C1)。然而，NH2C1也可以抑制 通过抑制中性粒细胞02代谢和NH4+或 NH_2C_1可抑制MPO的分泌。HOCl2与环氧氯丙烷的反应 赖氨酸多肽虽然寿命长，但相对无毒。 多肽-氯胺。拟议的研究将描述 02-、H202和MPO系统的产物与 抗坏血酸和其他细胞外还原剂，并检查效果 还原剂对沙门氏菌抗菌活性和细胞毒活性的影响 孤立的中性粒细胞。锰(Mn2+)的促进性 将研究MPO对还原剂的氧化，以确定 MPO是否可以作为一种氧化剂产生有毒的氧化剂 在中性粒细胞中存在O2代谢缺陷。NH4+的影响 中性粒细胞02代谢、MPO分泌和抗菌作用 将测量活性，以及赖氨酸-多肽的相互作用 与MPO系统将研究使用纯化的多肽和 MPO。这些研究将为我们提供新的洞察 氧化剂和还原剂在中性粒细胞中的作用并可能导致 改进了在抑制感染的同时对抗感染的方法 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.