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Free radical producing activity and intracellular signal transduction mechanisms of phagocytes by heavy metals

重金属吞噬细胞自由基产生活性及细胞内信号转导机制

基本信息

批准号：
08457114
负责人：
OGINO Keiki
金额：
$ 0.7万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457114/
关键词：
Free radicals Zinc oxide Phagocytes Intracelluar signal transduction pathway Monoamine oxidase Glutathione Nitric oxide synthase peroxynitrite 貧食細胞化学発光好中球 TNFα 一酸化窒素カルシウム

项目摘要

The activation mechanisms of intraperitoneal-eluted rat neutrophils and mouse macrophage -like cell line Raw 264.7 by zinc oxide (ZnO) was investigated to explore the etiological mechanisms of metal fume fever induced by ZnO.The activation of phagocytes by ZnO was enhanced by the addition of glutathione (GSH) and thiol compounds. Superoxide (O2^-) and hydrogen peroxide (H2O2) may be produced by NADPH oxidase via the intracellular signal transduction pathway such as GTP-binding protein, protein kinase C, tyrosine kinase, and intracellar calcium and membraneous CR3 if ZnO was added as a stimulant to neutrophils. If GSH was added to ZnO, the production of acitive oxygen species was dependent on FcgammaR in addition to CR3. The differnce in the activation of neutrophils by ZnO and ZnO plus GSH was investigated. The activation of neutrophils by ZnO may be dependent on the production of O2^- and peoxynitrite (ONOO^-) via NADPH oxidase and nitric oxide synthase (NOS). The activation of neutrophils by ZnO plus GSH may participated in the elevated H2O2 via the activation of monoamine oxidase (MAO) mainly localized in mitochodrium. These results suggest pot only the new evidence of the origin of H2O2 associated with the activation of nuclear transcription factor and the etiology of apoptosis but also the discovery of the relationship between MAO and intracellar signal transduction mechanisms. Moreover, from the results of Raw 246.7, GSH promoted the cleaning of ZnO particles by phagocytosis.From this research project, it is speculated that zinc fume fever may be caused by the intrinsic factor GSH in addition to ZnO particles.

为探讨氧化锌（ZnO）诱发金属烟尘热的发病机制，研究了氧化锌（ZnO）对腹腔洗脱的大鼠中性粒细胞和小鼠巨噬细胞样细胞系Raw 264.7的激活机制。当加入ZnO刺激中性粒细胞时，NADPH氧化酶可通过GTP结合蛋白、蛋白激酶C、酪氨酸激酶、细胞内钙离子和膜CR 3等细胞内信号转导途径产生超氧化物（O2^-）和过氧化氢（H2 O2）。如果GSH被添加到ZnO中，则活性氧物种的产生除了依赖于CR 3之外还依赖于Fc γ R。本文研究了ZnO和ZnO + GSH对中性粒细胞活化的差异。ZnO对中性粒细胞的激活可能依赖于通过NADPH氧化酶和一氧化氮合酶（NOS）产生O2^-和过氧亚硝酸盐（ONOO^-）。ZnO + GSH对中性粒细胞的激活可能通过激活主要位于线粒体的单胺氧化酶（MAO）参与了H2 O2的升高。这些结果不仅为H_2O_2的来源与核转录因子的激活及细胞凋亡的病因学提供了新的证据，而且为发现MAO与细胞内信号转导机制的关系提供了新的线索。而且，从Raw 246.7的结果看，GSH通过吞噬作用促进了ZnO颗粒的清洁，从本研究项目推测锌烟热可能是由ZnO颗粒以外的内在因素GSH引起的。