Cuzzocrea Salvatore
Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy.
Curr Pharm Des. 2006;12(27):3551-70. doi: 10.2174/138161206778343082.
A vast amount of circumstantial evidence implicates oxygen-derived free radicals, especially reactive oxygen species and nitric oxide as mediators of inflammation and/or tissue destruction in inflammatory and arthritic disorders. The aim of the current article is to overview the recent developments in this field, as it relates to the roles of nitric oxide (NO) and reactive oxygen species in the pathogenesis of this condition. The first part of the review focuses on the biochemical impact of NO and reactive oxygen species. The second part of the review deals with the novel findings related to the recently identified regulatory roles of the inducible isoform of nitric oxide synthase (iNOS) in the expression of pro-inflammatory mediators in inflammation. Reactive oxygen species can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3phosphate dehydrogenase, inhibition of membrane sodium/potassium ATP-ase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of inflammation. Reactive oxygen species are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Recently it has been demonstrated that iNOS inhibitor prevents the activation of poly (ADP ribose) synthetase, and prevents the organ injury associated with inflammation. Although the severity and duration of inflammation may dictate the timing and extent of NOS expression, it is now evident that the up-regulation of NOS can take place during sustained inflammation. Thus, induced nitric oxide, in addition to being a "final common mediator" of inflammation, is essential for the up-regulation of the inflammatory response. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of reactive oxygen species, with them associated toxicities, and indirectly through the amplification of the inflammatory response.
大量的间接证据表明，氧衍生的自由基，特别是活性氧和一氧化氮，是炎症和关节炎性疾病中炎症和/或组织破坏的介质。本文的目的是概述该领域的最新进展，因为它涉及一氧化氮（NO）和活性氧在这种疾病发病机制中的作用。综述的第一部分重点关注NO和活性氧的生化影响。综述的第二部分涉及与最近发现的诱导型一氧化氮合酶（iNOS）在炎症中促炎介质表达的调节作用相关的新发现。活性氧可以引发广泛的毒性氧化反应。这些反应包括引发脂质过氧化、直接抑制线粒体呼吸链酶、使甘油醛-3-磷酸脱氢酶失活、抑制膜钠/钾ATP酶活性、使膜钠通道失活以及蛋白质的其他氧化修饰。所有这些毒性可能在炎症的病理生理学中起作用。活性氧都是能够引发DNA单链断裂的潜在反应物，随后激活核酶聚（ADP核糖）合成酶（PARS），导致细胞最终严重能量耗竭和坏死型细胞死亡。最近已证明，iNOS抑制剂可防止聚（ADP核糖）合成酶的激活，并防止与炎症相关的器官损伤。尽管炎症的严重程度和持续时间可能决定NOS表达的时间和程度，但现在很明显，在持续炎症期间NOS可以上调。因此，诱导型一氧化氮除了是炎症的“最终共同介质”外，对于炎症反应的上调也是必不可少的。此外，一个通路的图景正在形成，它通过活性氧的形成及其相关毒性直接导致组织损伤，并通过炎症反应的放大间接导致组织损伤。
