Nitric oxide and the immune response

During the past two decades, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system. It is involved in the pathogenesis and control of infectious diseases, tumors, autoimmune processes and chronic degenerative diseases. Because of its variety of reaction partners (DNA, proteins, low-molecular weight thiols, prosthetic groups, reactive oxygen intermediates), its widespread production (by three different NO synthases (NOS) and the fact that its activity is strongly influenced by its concentration, NO continues to surprise and perplex immunologists. Today, there is no simple, uniform picture of the function of NO in the immune system. Protective and toxic effects of NO are frequently seen in parallel. Its striking inter- and intracellular signaling capacity makes it extremely difficult to predict the effect of NOS inhibitors and NO donors, which still hampers therapeutic applications.     

Nitric oxide neurotoxicity

Derangements in glutamate neurotransmission have been implicated in several neurodegenerative disorders including, stroke, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Activation of the N-methyl- -aspartate (NMDA) receptor subtype of glutamate receptors results in the influx of calcium which binds calmodulin and activates neuronal nitric oxide synthase (nNOS), to convent -arginine to citrulline and nitric oxide (NO). NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO−), the reaction product from NO and superoxide anion. In pathologic conditions, peroxynitrite and oxygen free radicals can be generated in excess of a cell antioxidant capacity resulting in severe damage to cellular constitutents including proteins, DNA and lipids. The inherent biochemical and physiological characteristis of the brain, including high lipid concentrations and energy requirements, make it particularly susceptible to free radical and oxidant mediated insult. Increasing evidence indicates that many neurologic disorders may have components of free radical and oxidative stress induced injury.     

Nitric oxide in the endometrium

Nitric oxide (NO) is an important mediator of paracrine interactions, especially within the vascular system. It is a powerful inhibitor of platelet aggregation and a potent vasodilator. NO is also a neurotransmitter and it plays a role in cell-mediated cytotoxicity. NO-generating enzymes (nitric oxide synthases, NOS) have been described in the endometrium of a number of species, suggesting that NO might be involved in endometrial function. In human endometrium, endothelial NOS and inducible NOS have been localized to glandular epithelium in the non-pregnant uterus. Weak inducible NOS immunoreactivity has been observed in decidualized stromal cells. NO might participate in the initiation and control of menstrual bleeding. Furthermore, it may play a part in the inhibition of platelet aggregation within the endometrium, where menstrual haemostasis is thought to occur primarily by vasoconstriction rather than clot organization. Endometrially derived NO could also suppress myometrial contractility. Recent attention has focused on the part that NO might play in maintaining myometrial quiescence during pregnancy. NO also appears to relax the non-pregnant myometrium, an action which could be exploited for the medical treatment of primary dysmenorrhoea.     

一氧化氮与脓毒性休克的关系

在脓毒性休克中,巨噬细胞和血管平滑肌细胞等细胞的诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)表达上调,使血管内皮源性舒张因子即一氧化氮(nitric oxide,NO)生成增多,引起血管过度扩张、微循环淤血、血管平滑肌对缩血管物质的反应性降低、心肌功能抑制等,导致严重的...     

Nitric oxide neurons and neurotransmission

Nitric oxide was identified as a biological intercellular messenger just over 20 years ago, and its presence and potential importance in the nervous system was immediately noted. With the cloning of NO synthase and the physiological NO receptor soluble guanylyl cyclase, a variety of histochemical methods quickly led to a rather complete picture of where NO is produced and acts in the nervous system. However, the details regarding the subcellular localization of NO synthase and the identity of its molecular binding partners require further clarification. Although the hypothesis that calcium influx via activation of NMDA receptors is a key trigger for NO production has proven very popular and led to suggested roles for NO in synaptic plasticity, there is little direct evidence to support this notion. Instead, studies from the peripheral nervous system indicate a key role for voltage-sensitive calcium channels in regulating NO synthase activity. A similar mechanism may also be important in central neurons, and it remains an important task to identify the precise sources of calcium regulating NO production in specific NO neurons. Also, although cGMP production appears to mediate the physiological signaling by NO, the specific roles of cGMP-dependent ion channels, protein kinases and phosphodiesterases in mediating NO action remain to be determined.     

一氧化氮与肌腱愈合

背景：研究表明一氧化氮在肌腱损伤愈合中发挥了重要作用。 目的：综述一氧化氮与肌腱损伤愈合的相关研究进展。 方法：应用计算机检索1992年1月至2011年12月 PubMed数据库相关文章,检索词为“NO,tendon,healing”,并限定文章语言种类为English。同时计算机检索1995-01/2011-12中国期刊全文数据库相关文章,检索词为“一氧化氮,肌腱,愈合”,并限定文章语言种类为中文。共检索到文献115篇,最终纳入符合标准的文献37篇。 结果与结论：通常健康肌腱中不表达一氧化氮合酶,而损伤后一氧化氮合酶3种同功酶呈现高表达但表达时相不同,使用一氧化氮抑制剂会削弱肌腱的愈合,而适宜剂量的一氧化氮供体可促进肌腱愈合,其原因之一可能是一氧化氮降低了炎症反应并改善了细胞外基质代谢,从而减轻愈合期肌腱的症状和质量,提高了肌腱的功能。     

Nitric oxide and asthmatic inflammation

Asthmatic patients show an increased expression of inducible nitric oxide synthase (iNOS) in airway epithelial cells and an increased level of nitric oxide (NO) in exhaled air. The NO derived from airway epithelial cells may be a mechanism for amplifying and perpetuating asthmatic inflammation, through inhibition of T helper 1 (Th1) cells and their production of interferon γ (IFN-γ). This would result in an increase in the number of Th2 cells and the cytokines interleukin 4 (IL-4) (which is important for IgE expression) and IL-5 (which plays a critical role in the recruitment of eosinophils into the airways). Although this mechanism may be part of our nonspecific airway defence against parasite invasions, it appears to have been activated inappropriately is asthma. Here, Peter Barnes and Eddy Liew argue that the development of specific iNOS inhibitors may represent a novel therapeutic approach for asthma and other allergic diseases.     

Nitric oxide and bone.

Nitric oxide (NO) is a free radical which has important effects on bone cell function. The endothelial isoform of nitric oxide synthase (eNOS) is widely expressed in bone on a constitutive basis, whereas inducible NOS is only expressed in response to inflammatory stimuli. It is currently unclear whether neuronal NOS is expressed by bone cells. Pro-inflammatory cytokines such as IL-1 and TNF cause activation of the iNOS pathway in bone cells and NO derived from this pathway potentiates cytokine and inflammation induced bone loss. These actions of NO are relevant to the pathogenesis of osteoporosis in inflammatory diseases such as rheumatoid arthritis, which are characterized by increased NO production and cytokine activation. Interferon gamma is a particularly potent stimulator of NO production when combined with other cytokines, causing very high concentrations of NO to be produced. These high levels of NO inhibit bone resorption and formation and may act to suppress bone turnover in severe inflammation. The eNOS isoform seems to play a key role in regulating osteoblast activity and bone formation since eNOS knockout mice have osteoporosis due to defective bone formation. Other studies have indicated that the NO derived from the eNOS pathway acts as a mediator of the effects of oestrogen in bone. eNOS also mediates the effects of mechanical loading on the skeleton where it acts along with prostaglandins, to promote bone formation and suppress bone resorption. Pharmacological NO donors have been shown to increase bone mass in experimental animals and preliminary evidence suggests that these agents may also influence bone turnover in man. These data indicate that the L-arginine/NO pathway represents a novel target for therapeutic intervention in the prevention and treatment of bone diseases.