Guzik T J, Korbut R, Adamek-Guzik T
Chair of Pharmacology, Jagiellonian University School of Medicine, Poland.
J Physiol Pharmacol. 2003 Dec;54(4):469-87.
Nitric oxide (NO) and reactive oxygen species exert multiple modulating effects on inflammation and play a key role in the regulation of immune responses. They affect virtually every step of the development of inflammation. Low concentrations of nitric oxide produced by constitutive and neuronal nitric oxide synthases inhibit adhesion molecule expression, cytokine and chemokine synthesis and leukocyte adhesion and transmigration. Large amounts of NO, generated primarily by iNOS can be toxic and pro-inflammatory. Actions of nitric oxide are however not dependent primarily on the enzymatic source, but rather on the cellular context, NO concentration (dependent on the distance from NO source) and initial priming of immune cells. These observations may explain difficulties in determining the exact role of NO in Th1 and Th2 lymphocyte balance in normal immune responses and in allergic disease. Similarly superoxide anion produced by NAD(P)H oxidases present in all cell types participating in inflammation (leukocytes, endothelial and other vascular cells etc) may lead to toxic effects, when produced at high levels during oxidative burst, but may also modulate inflammation in a far more discrete way, when continuously produced at low levels by NOXs (non-phagocytic oxidases). The effects of both nitric oxide and superoxide in immune regulation are exerted through multiple mechanisms, which include interaction with cell signalling systems like cGMP, cAMP, G-protein, JAK/STAT or MAPK dependent signal transduction pathways. They may also lead to modification of transcription factors activity and in this way modulate the expression of multiple other mediators of inflammation. Moreover genetic polymorphisms exist within genes encoding enzymes producing both NO and superoxide. The potential role of these polymorphisms in inflammation and susceptibility to infection is discussed. Along with studies showing increasing role of NO and free radicals in mediating inflammatory responses drugs which interfere with these systems are being introduced in the treatment of inflammation. These include statins, angiotensin receptor blockers, NAD(P)H oxidase inhibitors, NO-aspirin and others. In conclusion in this mini-review we discuss the mechanisms of nitric oxide and superoxide dependent modulation of inflammatory reactions in experimental animals and humans. We also discuss potential roles of nitric oxide as a mediator of allergic inflammation.
一氧化氮（NO）和活性氧对炎症具有多种调节作用，并在免疫反应的调节中发挥关键作用。它们几乎影响炎症发展的每一个步骤。组成型和神经元型一氧化氮合酶产生的低浓度一氧化氮可抑制黏附分子表达、细胞因子和趋化因子合成以及白细胞黏附和迁移。主要由诱导型一氧化氮合酶产生的大量NO可能具有毒性且促炎。然而，一氧化氮的作用并不主要取决于酶的来源，而是取决于细胞环境、NO浓度（取决于与NO源的距离）以及免疫细胞的初始激活状态。这些观察结果可能解释了在确定NO在正常免疫反应和过敏性疾病中Th1和Th2淋巴细胞平衡的确切作用时所遇到的困难。同样，参与炎症的所有细胞类型（白细胞、内皮细胞和其他血管细胞等）中存在的NAD(P)H氧化酶产生的超氧阴离子，在氧化爆发期间大量产生时可能导致毒性作用，但当由NOXs（非吞噬性氧化酶）持续低水平产生时，也可能以一种更为离散的方式调节炎症。一氧化氮和超氧阴离子在免疫调节中的作用都是通过多种机制发挥的，这些机制包括与细胞信号系统如cGMP、cAMP、G蛋白、JAK/STAT或MAPK依赖性信号转导途径相互作用。它们还可能导致转录因子活性的改变，从而调节多种其他炎症介质的表达。此外，编码产生NO和超氧阴离子的酶的基因中存在基因多态性。本文讨论了这些多态性在炎症和感染易感性中的潜在作用。随着研究表明NO和自由基在介导炎症反应中的作用日益增加，干扰这些系统的药物正被引入炎症治疗中。这些药物包括他汀类药物、血管紧张素受体阻滞剂、NAD(P)H氧化酶抑制剂、NO-阿司匹林等。总之，在本综述中，我们讨论了实验动物和人类中一氧化氮和超氧阴离子依赖性调节炎症反应的机制。我们还讨论了一氧化氮作为过敏性炎症介质的潜在作用。
