Research on the role of NO in microbial pathogenesis

近年来，自由基分子在各种病毒性疾病发病机制中的重要性日益被人们所认识。超氧阴离子自由基和羟基自由基等氧自由基被认为是病毒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)]在宿主的防御机制和病毒感染的发病机制中受到了极大的关注。NO合成途径，尤其是诱导型一氧化氮合酶(INOS)，在不同的病毒疾病中通过诱导炎性细胞因子如干扰素-α和白介素1-β表达。与一氧化氮合酶的其他组成亚型，即神经型一氧化氮合酶和内皮型一氧化氮合酶相比，一氧化氮合酶长期产生过量的一氧化氮。NO的生物合成，特别是通过表达诱导型一氧化氮合酶(INOS)，在各种微生物感染中都会发生。我们对iNOS缺陷小鼠沙门氏菌病的研究表明，在沙门氏菌感染中，NO具有显著的宿主防御功能，不仅因为它的直接抗菌作用，而且还通过对感染的宿主细胞的细胞保护作用，可能是通过其抗凋亡作用。在生物系统中，过氧亚硝酸盐等活性氮氧化物物种是通过NO与超氧化物反应而产生的。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有意义的，因为过氧亚硝酸盐引起蛋白质和DNA的氨基酸残基的氧化和硝化、脂质过氧化和DNA裂解。由此在疫区形成的过氧亚硝酸盐可能是宿主防御反应中的主要氮氧化物物种。因此，了解NO和氧自由基在感染中的作用，不仅有助于在分子水平上深入了解病毒的发病机制，而且有助于从分子水平上了解微生物感染中宿主与病原体的相互作用。

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.