一氧化氮合酶与主动脉瘤

一氧化氮合酶(NOS)通过催化L-Arg生成NO参与动脉瘤的变化。本文通过一氧化氮合酶在调节基质金属蛋白酶(MMPs)活性、调节平滑肌细胞凋亡以及动脉壁的氧化损伤中的作用对其与主动脉瘤形成的关系作一综述,若针对一氧化氮合酶在主动脉瘤形成中的关键环节进行干预,有可能为主动脉瘤的治疗提供新的途径。     

巨噬细胞诱导型一氧化氮合酶的表达调节机制

一氧化氮是一种重要的巨噬细胞免疫效应分子,它参与免疫调节和宿主防御反应.一氧化氮的生成主要由诱导型一氧化氮合酶调节,然而诱导型一氧化氮合酶表达的调节机制及信号通路尚不完全清楚.     

一氧化氮及一氧化氮合酶在心血管系统中的研究进展

自1987年证实内皮细胞(endo thelial cell,EC)合成并释放一氧化氮(Nitric oxide,NO)以来,NO在心血管系统中的作用即倍受重视。目前的研究表明,一氧化氮及一氧化氮合酶(NO/nitric oxide sgnghase,NOS)不仅在心血管、免疫、神经系统中有着广泛的生理功能,而且参与多种疾病的发生和发展。     

一氧化氮与缺血性脑血管疾病

在脑缺血性损伤过程中,一氧化氮(n itric oxide,NO)发挥着复杂的作用,多途径参与生理和其病理过程。NO在脑缺血过程中起着保护与损伤双重作用,其对脑组织的损伤或保护取决于脑缺血的不同时期和一氧化氮合酶(n itric oxide synthase,NOS)的同工酶类型等因素。脑缺血早期内皮细胞型一氧化氮合酶(endothelial NOS,eNOS)催化生成的NO对脑缺血有防护作用,而在脑缺血缺氧的大部分时期由诱生型一氧化氮合酶(induc ib leNOS,iNOS)和神经元型一氧化氮合酶(neuronal NOS,nNOS)催化生成的一氧化氮对脑缺血则具有损伤作用。     

核因子—kB及诱生型一氧化氮酶催化合成的一氧化氮与肺部疾病

ＮＫ－ｋＢ是一种多向性转录调节蛋白，参与众多细胞因子和炎症介质表达的转录调控，与多各炎症疾病有着密切的关系。近年来，也发现在哺乳动物细胞的一氧化氮合酶家族中的诱生型一氧化氮合酶在致炎细胞因子或脂多糖作用下，其催化合成的一氧化氮在许多炎症疾病中发挥着重要的作用，因此，阐述ＮＦ－ｋＢ及诱生型一氧化氮合酶基因在ＮＦ－ｋＢ参与诱导活化下催化合成的的一氧化氮在肺部疾病中的作用，有着重要的理论意义和潜在的临床     

核因子-κB及诱生型一氧化氮酶催化合成的一氧化氮与肺部疾病

ＮＦ－κＢ是一种多向性转录调节蛋白,参与众多细胞因子和炎症介质表达的转录调控,与多种炎症疾病有着密切的关系．近年来,也发现在哺乳动物细胞的一氧化氮合酶家族中的诱生型一氧化氮合酶在致炎细胞因子或脂多糖作用下,其催化合成的一氧化氮在许多炎症疾病中发挥着重要的作用．因此,阐述ＮＦ－κＢ及诱生型一氧化氮合酶基因在ＮＦ－κＢ参与诱导活化下催化合成的一氧化氮在肺部疾病中的作用,有着重要的理论意义和潜在的临床应用价值．     

一氧化氮、一氧化氮合酶和心脏功能

一氧化氮合酶(nitric　oxide synthase,NOS)催化L-精氨酸的氧化反应生成L-胍氨酸和一氧化氮(nitric oxide,NO)。其产物NO可通过依赖cGMP(环磷酸鸟苷)途径与非依赖cGMP途径发挥其复杂的生理学功能,如在心血管系统具有维持血管张力、调节血压,抑制血管平滑肌细胞迁移、增生,抑制血小板聚集与白细胞对血管壁的粘附以及调节影响心肌收缩与舒张功能的作用,并参与心率变异调节功能。本文就3种NOS同工酶的基因及其基因表达调节及影响因素进行简要综述。着重介绍nNOS1的心脏自主神经调节机制,iNOS对心脏收缩抑制以及心脏保护与损伤的双重作用,并对eNOS参与心功能调节的机制及其它生理、病理学等方面研究进展进行综述。     

衰老时大鼠大脑皮质枕叶一氧化氮合酶阳性神经元的变化

本实验采用免疫组化 SABC法结合计算机图像分析技术 ,研究了衰老时大鼠大脑皮质枕叶一氧化氮合酶阳性神经元的分布及形态特征变化。结果发现 :一氧化氮合酶阳性细胞在枕叶皮质 ～ 层均有分布 ,属于非锥体形神经元 ;比较三个年龄组阳性细胞的数量和平均截面积的变化 ,发现老年组与幼年组及中年组相比 ,两项指标都显著减小 (P<0 .0 1)。而幼年组和中年组相比两项指标没有明显差别 (P>0 .0 5 )。提示 ,一氧化氮作为神经递质 ,可能与大脑皮质枕叶功能的调节有关 ;随着衰老 ,其阳性神经元的变化可能影响其发挥正常的生理功能     

原发性高血压患者血清NO、NOS及其亚型水平的分析

目的:测定原发性高血压患者外周血中血清一氧化氮(NO)、一氧化氮合酶(NOS)及其亚型水平,探讨NO/NOS系统参与血压调节的可能机制.方法:原发性高血压患者135例,正常对照组35例.采用化学法检测所有病例外周血的一氧化氮(NO)、总NOS、诱导型一氧化氮合酶(iNOS)和结构型一氧化氮合酶(cNOS)水平并作统计学分析.结果:高血压组NO、NOS、iNOS和cNOS水平均低于正常对照组,且差异具有显著性意义(分别为:P＜0.05,P＜0.01,P＜0.01,P＜0.01);iNOS/cNOS比值与正常对照组相比无显著差异(P＞0.05);对照组和高血压组的NOS浓度与iNOS和cNOS浓度均呈显著正相关;高血压组的cNOS水平与iNOS水平呈显著负相关.结论:高血压患者NO、NOS及其亚型浓度值可以作为临床评估高血压的参考指标;iNOS在正常人体内有表达;在高血压情况下,机体有通过增加iNOS的表达来弥补cNOS水平的病理性降低、调控NOS总体水平从而调节和平衡血压的趋势.     

一氧化氮在中枢神经系统中的作用

一氧化氮对中枢神经系统的作用具有两重性:低水平时保护神经元的活性,参与脑血管基本张力的调节;高水平时具有神经毒性作用,破坏神经细胞,加重缺血性脑组织的损害。对一氧化氮合酶调控的研究和应用选择性该酶抑制剂显得非常重要。     

Different effects of constitutive nitric oxide synthase and heme oxygenase on pulmonary or liver metastasis of colon cancer in mice

It has recently been reported that not only endogenous nitric oxide (NO) but also carbon monoxide (CO) produced by heme oxygenase (HO) have many physiological functions. The objective of the present study was to determine whether endogenous NO or CO is involved in the experimental pulmonary or liver metastasis of colon cancer in mice. Intravenous or intrasplenic injection of colon 26 cells from a mouse colon adenocarcinoma cell line resulted in multiple pulmonary or liver metastases. NG-nitro-l-arginine methyl ester (l-NAME), a competitive inhibitor of NO synthase (NOS), or zinc deuteroporphyrin 2, 4-bis glycol (ZnDPBG), a competitive inhibitor of HO, was administered to the mice only on the day of tumor inoculation. We assessed the number of tumor cells 24 h later and the outcome of metastases of the target organ. In the pulmonary metastasis model, l-NAME increased both the number of tumor cells 24 h later and outcome of metastases 18 days later, but did not have a significant effect on liver metastasis. On the other hand, metastasis to the liver, but not that to the lung, increased following administration of ZnDPBG. These results suggest that the activities of NOS and HO could influence experimental metastasis in an organ-specific manner. This revised version was published online in July 2006 with corrections to the Cover Date.     

Nitric oxide protects the ultrastructure of pancreatic acinar cells in the course of caerulein-induced acute pancreatitis

Nitric oxide (NO) as a unique biological mediator that has been implicated in many physiological and pathophysiological processes may have a significant influence on the course of acute pancreatitis and the recovery process. The aim of the study was to evaluate the effect of a NO synthase inhibitor or a substrate for NO endogenous production on the ultrastructural features of the acinar cells in the course of caerulein-induced acute pancreatitis. Acute pancreatitis was induced in the rats by a supramaximal dose of caerulein. During acute pancreatitis induction, the rats were treated with L-arginine (the substrate for NO synthesis), NG-nitro-L-arginine (L-NNA, NO synthase inhibitor), L-arginine + L-NNA or saline. Light and electron microscopy examinations were performed in all groups after pancreatitis induction and additionally after 7 and 14 days of recovery. The study demonstrated that the NO synthase inhibitor given during pancreatitis induction in rats enhances the damage to the acinar cells, detected ultrastructurally, and increases the cellular inflammatory infiltration. In the later period, the considerable damage to the mitochondria and the changes in secretory compartment were observed, including dilated cisternae of Golgi apparatus, focal degranulation of rough endoplasmic reticulum, and reduced number of zymogen granules and condensing vacuoles. L-arginine reversed to some extent the deleterious effect of L-NNA, although when administered alone it had no apparent effect on the ultrastructure of pancreatic acinar cells compared with untreated animals. The obtained results indicate that the NO synthase inhibitor enhances the ultrastructural degenerative alterations in the pancreatic acinar cells in the course of caerulein-induced acute pancreatitis and confirm the protective role of endogenous nitric oxide in this disease.     

Constitutively synthesized nitric oxide is a physiological negative regulator of mammalian angiogenesis mediated by basic fibroblast growth factor

We recently reported that the systemically administered nitric oxide synthase (NOS) inhibitor Nw-nitro-L-arginine methyl ester, L-NAME, administered before, during and after the angiogenic treatment stimulated angiogenesis induced by basic fibroblast growth factor, bFGF, in the rat. This suggests that suppression of constitutively expressed NOS, cNOS, plus inducible NOS, iNOS, and thus reduced production of nitric oxide, NO, was the stimulating factor. In those studies, the rat mesenteric-window angiogenesis assay was used. Moreover, the systemic administration of a NO releaser inhibited bFGF-mediated angiogenesis. Using the same experimental system, we have now studied whether the inhibition of cNOS alone in adult animals under physiological conditions, i.e. prior to the administration of the angiogenic stimulation with bFGF, affected the subsequent angiogenic response. cNOS constitute endothelial cell NOS (ecNOS) and neuronal NOS (nNOS). L-NAME or its inactive enantiomer Nw-nitro-D-arginine methyl ester, D-NAME, were given continuously in the drinking water (1.0 g/L) during 14 days prior to the start of the treatment with bFGF. The treatment with L-NAME significantly enhanced the subsequent angiogenic response. NO synthesized under physiological conditions by ecNOS in endothelial cells and platelets or nNOS in platelets may thus act as a first constitutional angiostatic factor in bFGF-mediated mammalian angiogenesis.     

Expression of nitric oxide synthase isoforms in human liver cirrhosis

Several mediators of systemic vasodilatation in liver cirrhosis have been reported. Among these is nitric oxide (NO), which has been proposed as one of the main mediators. In this study, sera and liver biopsies were analysed from 15 patients with clinically and pathologically diagnosed liver cirrhosis. In addition, sera from seven and liver biopsies from three healthy controls were used. Serum levels of nitrite (the end product of NO) were measured using the Griess reaction and the expression of the inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (ecNOS) proteins was investigated using immunohistochemistry. This study shows that serum nitrite levels (94 +/- 9.8 micro mol/l) in cirrhotic patients were significantly (p < 0.05) increased in comparison with the controls (36.6 +/- 11.03 micro mol/l). iNOS was completely absent from the control group but was highly expressed in the livers from the cirrhotic group. iNOS was seen mainly in the inflammatory cells infiltrating the portal tracts, blood monocyte-like cells, hepatocytes, sinusoidal cells, and endothelial cells. However, expression of ecNOS was only seen in the vascular endothelial cells of both the control and the cirrhotic groups, but was much higher in the latter. It is therefore clear that NO is augmented in cirrhotic patients and it is mainly produced by induction of iNOS. Moreover, NO up-regulation is dependent on the inflammatory stage of liver cirrhosis. ecNOS production could be a normal chronic adaptation mechanism of the endothelium to the chronically increased splanchnic blood flow secondary to portal hypertension. In the near future, the appropriate inhibition of NO activity by using NOS-active agents may provide a novel strategy for the treatment of patients with liver cirrhosis.     

Expression of inducible nitric oxide synthase and nitrotyrosineduring the evolution of experimental pulmonary tuberculosis

Nitric oxide (NO) is a relevant antimycobacterial factor in mouse macrophages. NO is a product of inducible nitric oxide synthase (iNOS). NO toxicity is greatly enhanced by reacting with superoxide to form peroxynitrite that reacts with many biological molecules. Tyrosine is one of the molecules with which NO reacts and the product is nitrotyrosine (NT). The production of peroxynitrite and the nitrosylation of proteins might play a role in bacterial killing and also in mediating host injury. In this study, we used a well-characterized mouse model of pulmonary tuberculosis to examine the local kinetics of expression and cellular distribution of iNOS and NT at the cellular and subcellular level. The histopathological study showed two phases of the disease: early and late. The early phase was characterized by mononuclear inflammation and granuloma formation. During this phase, high percentages of activated macrophages were observed that were immunostained for iNOS and NT. Immuno-electronmicroscopy showed NT immunoreactivity in lysosomes and mycobacterial wall and cytoplasm. The concentration of iNOS mRNA and NO metabolites were also elevated. The late phase was characterized by progressive pneumonia with focal necrosis and a decrease of iNOS mRNA and NO metabolites. The strongest NT immunostained areas were the necrotic tissue. Macrophages became foamy cells with scarce iNOS immunostaining but strong NT immunoreactivity. At the ultrastructural level, these cells showed NT immunolabeling in cytoskeleton, mitochondria, lysosomes and cell membrane. NT was also located in bronchial epithelial cell mitochondria, in cell membranes and cytoplasm of endothelial cells and in actin bundles within smooth muscle cells. These results suggest an important role of NO in mycobacterial killing, particularly during the early phase of the infection. They also suggest an important participation by NO in tissue damage during the late phase of the disease.     

旋磁场对大鼠脏器SOD活力和NO含量的影响

目的:探讨旋磁场对大鼠肝组织、肾组织、心组织和脑组织中超氧化物歧化酶(SOD)活力和一氧化氮(NO)含量的影响.方法:用邻苯三酚法测定SOD活力;NO含量的测定采用改良的Griess法.结果:在30mT磁场中曝磁30min,大鼠肝、肾、心和脑组织中SOD活力显著高于对照组(P＜0.01或P＜0.05);大鼠肝组织和肾组织中NO含量显著高于对照组(P＜0.01);心组织NO含量高于对照组(P＜0.05);脑组织NO含量无明显变化.结论:旋磁场对大鼠脏器组织SOD活力和NO含量有一定影响.     

Nitric oxide in inflammatory bowel disease: a universal messenger in an unsolved puzzle

In recent years, nitric oxide (NO), a gas previously considered to be a potentially toxic chemical, has been established as a diffusible universal messenger that mediates cell-cell communication throughout the body. Constitutive and inducible NO production regulate numerous essential functions of the gastrointestinal mucosa, such as maintenance of adequate perfusion, regulation of microvascular and epithelial permeability, and regulation of the immune response. Up-regulation of the production of NO via expression of inducible nitric oxide synthase (iNOS) represents part of a prompt intestinal antibacterial response; however, NO has also been associated with the initiation and maintenance of inflammation in human inflammatory bowel disease (IBD). Recent studies on animal models of experimental IBD have shown that constitutive and inducible NO production seems to be beneficial during acute colitis, but sustained up-regulation of NO is detrimental. This fact is also supported by studies on mice genetically deficient in various NOS isoforms. However, the mechanism by which NO proceeds from being an indispensable homeostatic regulator to a harmful destructor remains unknown. Furthermore, extrapolation of data from animal colitis models to human IBD is questionable. The purpose of this review is to update our knowledge about the role of this universal mediator and the enzymes that generate it in the pathogenesis of IBD.     

RHODIOLA SACHALINESIS INDUCES THE EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE GENE BY MURINE FETAL HEPATOCYTES (BNL CL.2)

We have examined the effect of the aqueous extract of Rhodiola sachalinensis root (RSE), a traditional herbal medicine, on nitric oxide (NO) synthesis in murine fetal hepatocytes (BNL CL.2) by measuring the stable end-product nitrite and the mRNA of inducible NO synthase (iNOS). Interferon-gamma (IFN-γ) by itself failed to induce NO synthesis in BNL CL.2 cells. RSE also did not elicit NO synthesis at concentrations up to 1000 μg/ml, but dose- and time-dependently induced NO synthesis in the presence of IFN-γ in BNL CL.2 cells. Whereas RSE or IFN-γ failed to induce detectable levels of iNOS mRNA, a combination of RSE and IFN-γ markedly induced iNOS mRNA in BNL CL.2 cells. Thus, we found that RSE triggered IFN-γ-primed BNL CL.2 cells to synthesize NO by inducing iNOS gene expression. The capability of RSE to induce NO synthesis might be related to the therapeutic efficacy of RSE on the liver diseases.     

Rhodiola sachalinesis induces the expression of inducible nitric oxide synthase gene by murine fetal hepatocytes (BNL CL.2)

We have examined the effect of the aqueous extract of Rhodiola sachalinensis root (RSE), a traditional herbal medicine, on nitric oxide (NO) synthesis in murine fetal hepatocytes (BNL CL.2) by measuring the stable end-product nitrite and the mRNA of inducible NO synthase (iNOS). Interferon-gamma (IFN-γ) by itself failed to induce NO synthesis in BNL CL.2 cells. RSE also did not elicit NO synthesis at concentrations up to 1000 μg/ml, but dose- and time-dependently induced NO synthesis in the presence of IFN-γ in BNL CL.2 cells. Whereas RSE or IFN-γ failed to induce detectable levels of iNOS mRNA, a combination of RSE and IFN-γ markedly induced iNOS mRNA in BNL CL.2 cells. Thus, we found that RSE triggered IFN-γ-primed BNL CL.2 cells to synthesize NO by inducing iNOS gene expression. The capability of RSE to induce NO synthesis might be related to the therapeutic efficacy of RSE on the liver diseases.