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Research on the role of NO in microbial pathogenesis

NO在微生物发病机制中的作用研究

基本信息

批准号：
12470065
负责人：
MAEDA Hiroshi
金额：
$ 7.94万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

The importance of free radical molecular species in the pathogenesis of various viral diseases has been increasingly recognized in recent years. Oxygen radicals such as superoxide and hydroxyl radical have been implicated as possible pathogenic molecules in viral disease pathogenesis. Much attention has been given to another simple inorganic radical [nitric oxide (NO)] in me host's defense mechanism and pathogenesis of virus infection. The NO synthesis pathway, in particular the inducible isoform of NO synthase (iNOS), is expressed in different viral diseases via induction of proinflammatory cytokines such as interferon-α and interleukin-1β. iNOS produces an excessive amount of NO for a long time compared with other constitutive isoforms of NOS, i.e., neuronal NOS and endothelial NOS. NO biosynthesis, particularly through expression of an inducible NO synthase (iNOS), occurs in a variety of microbial infections. Our work on murine salmonellosis in iNOS-deficient mice indicated that NO has significant host defense functions in Salmonella infections not only because of its direct antimicrobial effect but also via cytoprotective actions for infected host cells, possibly through its antiapoptotic effect. Reactive nitrogen oxide species such as peroxynitrite are produced in biological systems through the reaction of NO with superoxide. Among these reactive nitrogen species, peroxynitrite and its biological actions are of considerable interest in that peroxynitrite causes oxidation and nitration of amino acid residues of proteins and guanine of DNA, lipid peroxidation, and DNA cleavage. Peroxynitrite thus formed in infectious foci may be a dominant nitrogen oxide species during the host's defense reactions. Thus, understanding of the role of NO and oxygen radical generation in infections will provide insight into not only viral pathogenesis but also the host-pathogen interaction in microbial infections at a molecular level.

近年来，自由基分子种类在各种病毒性疾病发病机制中的重要性已被越来越多地认识到。氧自由基如超氧化物和羟基自由基是病毒性疾病发病机制中可能的致病分子。另一种简单的无机自由基一氧化氮（NO）在病毒感染的机体防御机制和致病机制中的作用已引起人们的广泛关注。NO合成途径，特别是NO合酶的诱导型同种型（iNOS），通过诱导促炎细胞因子如干扰素-α和白细胞介素-1 β在不同的病毒性疾病中表达。与NOS的其它组成型同种型相比，iNOS长时间产生过量的NO，即，神经元NOS和内皮NOS。NO生物合成，特别是通过诱导型NO合酶（iNOS）的表达，发生在多种微生物感染中。我们的工作鼠沙门氏菌感染iNOS缺陷小鼠表明，NO具有显着的宿主防御功能，沙门氏菌感染不仅因为其直接的抗菌作用，但也通过感染的宿主细胞的细胞保护作用，可能通过其抗凋亡作用。在生物系统中，通过NO与超氧化物的反应产生活性氮氧化物物质，例如过氧亚硝酸盐。在这些活性氮物种中，过氧亚硝酸盐及其生物学作用是相当感兴趣的，过氧亚硝酸盐引起蛋白质的氨基酸残基和DNA的鸟嘌呤的氧化和硝化，脂质过氧化和DNA切割。因此，在感染灶中形成的过氧亚硝酸盐可能是宿主防御反应过程中的主要氮氧化物种类。因此，了解NO和氧自由基的产生在感染中的作用，将提供洞察不仅病毒的发病机制，而且在分子水平上的微生物感染的宿主-病原体相互作用。