一氧化氮与感染性休克

感染性休克是危重病症常见的并发症。感染性休克与ＮＯ的过量生成有关。过量的ＮＯ有抑制肝细胞及血管平滑肌细胞的细胞呼吸作用，通过产生血流的异常分布或对细胞呼吸的直接抑制作用而造成感染性休克中组织氧摄取能力的下降     

一氧化氮与败血症休克

败血症休克时体内ＮＯ生成过量，后者主要通过抑制血管反应性和心肌收缩性，以及直接细胞毒性效应促进败血症休克发生发展。抑制ＮＯ合成酶，减少ＮＯ的过量生成呈现了良好的抗休克作用。上述研究发现为进一步探明败血症休克的分子机制及其防治开拓了新视野。     

NO－样舒血管因子在大鼠腹膜炎败血症中的作用

为探讨ＮＯ样舒血管因子（ＮＯ－ＬＲＦ）在腹膜炎败血症中的作用及其病理生理意义，本工作在大鼠腹膜炎败血症模型上，发现早、晚期败血症大鼠的离体主动脉环对去甲肾上腺素的反应降低；血管组织ｃＧＭＰ含量增加，表明败血症动物Ｌ－Ａｒｇ／ＮＯ途经增强，用ＮＯ合成前体Ｌ－精氨酸（Ｌ－Ａｒｇ）或ＮＯ合成抑制剂ＮＧ－ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ（Ｌ－ＮＮＡ）、可溶性鸟苷酸环化酶抑制剂亚甲蓝灌流，分别增加或降低败血症动物主动脉的上述变化，但上述药物的作用不依赖于血管内皮的存在，提示败血症动物主要为非内皮源性ＮＯ－ＬＲＦ增强。整体实验发现：Ｌ－Ａｒｇ可明显改善而Ｌ－ＮＮＡ却恶化休克过程，提示ＮＯ－ＬＲＦ可能参与败血症休克时机体的适应性保护机制。     

NO与感染性休克

ＮＯ与感染性休克甘辉立＊综述感染性休克是在监护室中最常见的死亡原因，在美国也是位居第十三位的死亡原因，每年约有１０万人死于感染性休克［１］。感染性病灶中的细菌内毒素或外毒素释放入血常常诱发败血症级联反应，即诱发内皮细胞、巨噬细胞释放炎性介质如ＴＮＦ－...     

NO—样舒血管因子在大鼠腹膜炎败血症中的作用

为探讨ＮＯ样舒血管因子（ＮＯ－ＬＲＦ）在腹膜炎败血症中的作用及其病理生理意义，本工作在大鼠腹膜炎败血症模型上，发现早、晚期败血症大鼠的离体主动脉环对去甲肾上腺素的反应降低；血管组织ｃＧＭＰ含量增加，表明败血症动物Ｌ－Ａｒｇ／ＮＯ途经增强，用ＮＯ合成前体Ｌ－精氨酸（Ｌ－Ａｒｇ）或ＮＯ合成抑制剂ＮＧ－ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ（Ｌ－ＮＮＡ）、可溶性鸟苷酸环化酶抑制剂亚甲蓝灌流，分别增加或降低败血     

细菌内毒素及其诱导的细胞因子在革兰氏阴性菌败血症休克中的作用

细菌内毒素（ＬＰＳ）是引起革兰氏阴性菌（ＧＮＢ）败血症休克的重要始动因素，ＬＰＳ通过与宿主体内相应受体结合，诱导效应细胞释放多种炎性细胞因子，如ＴＮＦ－α、ＩＬ－１和ＩＬ－６等。动物模型和临床研究表明，ＬＰＳ攻击动物或ＧＮＢ感染患者的血循环中炎性细胞因子均可明显增加，且与预后的关系密切。因此，针对ＬＰＳ致病过程特点以及细胞因子在ＧＮＢ败血症休克中的作用，寻找有效降低败血症休克病死率的方法已成为当今抗感染免疫研究领域的重点。     

热休克反应对大鼠感染性脑水肿细胞因子和一氧化氮的 …

为研究ＩＬ－１β－、ＴＮＦ－α及ＮＯ在感染性脑水肿时的变化和热休克反应对它们的影响，探讨热休克反应对大鼠感染性脑水中的保护作用是否与其有关，本实验采用ＥＬＩＳＡ法和Ｇｒｉｅｓｓ法分别检测各组大鼠脑组织均浆中ＩＬ－１β－、ＴＮＦ－α及ＮＯ的含量，大鼠分３组：①正常对照组（ＮＳ）；②感染性脑水肿组（ＰＢ）；③热休克处理组（ＨＳ＋ＰＢ）。每组又分为４ｈ、８ｈ、２４ｈ三个时间点。结果显示：与ＮＳ组比较，４     

NO与细胞凋亡

自由基ＮＯ是体内ＮＯＳ催化Ｌ－精氨酸氧化生成的一种具有多种生物学效应的特殊介质，通过和细胞内的酶作用，形成ＯＨ－，直接损伤ＤＮＡ等方式发挥其影响。除在转录及表达水平经防止凋亡抑制基因ｂｃ１－２表达减少而阻止Ｂ细胞凋亡外，ＮＯ经损伤ＤＮＡ、抑制核酸和蛋白质合成、减少ＡＴＰ产生、降低ｐＨ和改变Ｃａ２＋分布、增强ｐ５３表达等途径介导其他多种细胞凋亡。     

家兔内毒素休克时乐及主动脉一氧化碳水平的变化

目的：探讨一氧化碳（ＣＯ）是否作为一种新的内源性介质参与内毒素休克发病机制。结果：血浆以及主动脉ＣＯ和一氧化氮（ＮＯ）水平在内毒素休克时均显著增高，使用血红素氧合酶抑制剂锌原卟咻和恰酶抑制剂糖皮质激素地塞米松均可显著减轻内毒素休克中的血压下降和代谢性酸中毒程度，但是锌原卟咻仅能显著抑制血浆以及主动脉ＣＯ水平的增高，但对ＮＯ２／ＮＯ３水平无显著影响；而使用地塞米松则可显著抑制血浆以及主动脉ＮＯ２／Ｎ     

选择性抑制诱导型一氧化氮合成酶对内毒素性休克的影响

选择性抑制诱导型一氧化氮合成酶对内毒素性休克的影响目的：了解一氧化氮（ＮＯ）在内毒素致感染性休克时所起的作用，及选择性抑制诱导型一氧化氮合成酶（ｉＮＯＳ）对感染性休克的治疗效果。方法：将公羊１６只，随机分为２组，用内毒素持续静脉注射诱发内毒素性休克。...     

败血症休克大鼠血管L-精氨酸/一氧化氮途径的变化

目的:观察败血症休克大鼠主动脉内膜、中膜和外膜一氧化氮合成途径的改变。方法:雄性Wistar大鼠盲肠结扎并穿孔复制败血症休克模型,分别测定假手术组、早期休克组和晚期休克组大鼠主动脉内膜、中膜和外膜的亚硝酸盐(NO^-₂)含量、一氧化氮合酶(NOS)活性及L-精氨酸(L-Arg)转运;免疫组化染色检测诱导型一氧化氮合酶(iNOS)在主动脉各层的分布。结果:早期及晚期败血症休克大鼠主动脉内膜产生的NO^-₂含量、NOS活性及L-Arg转运速率均低于假手术组,而中膜和外膜的NO^-₂、NOS活性及L-Arg转运速率则显著高于假手术组,外膜增加的程度尤为显著。免疫组织化学染色显示,败血症休克时血管中膜和外膜尤其是外膜iNOS阳性染色明显较强。结论:败血症休克时血管内膜NO合成受到抑制,而中膜和外膜NO合成显著增强,这一改变与休克状态下血管中L-Arg转运、iNOS表达及其活性的变化有关。     

Induction of nitric oxide production by polyosides from the cell walls of Streptococcus mutans OMZ 175, a gram-positive bacterium, in the rat aorta.

The cardiovascular dysfunctions associated with septic shock induced by gram-negative or gram-positive bacteria (gram-positive or gram-negative septic shock) are comparable. In gram-negative septic shock, lipopolysaccharide (LPS) induces nitric oxide (NO) synthase, which contributes to the vascular hypotension and hyporeactivity to vasoconstrictors. The role of NO in gram-positive septic shock and the nature of the bacterial wall components responsible for the vascular effects of gram-positive bacteria are not well known. This study investigated the vascular effects of cell wall serotype polyosides, rhamnose glucose polymers (RGPs), from Streptococcus mutans, in comparison with lipoteichoic acid (LTA) from Staphylococcus aureus, on the induction of NO synthase activity in the rat aorta. We show that 10 microg of both RGPs and LTA per ml induced hyporeactivity to noradrenaline, L-arginine-induced relaxation, increases of 2.2- and 7.8-fold, respectively, of cyclic GMP production, and increases of 7- and 12-fold in nitrite release. All of these effects appeared after several hours of incubation and were inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. Electron paramagnetic resonance spin trapping experiments demonstrated directly that RGPs and LTA induced NO overproduction (four- to eightfold, respectively) in rat aortic rings; this production was inhibited by L-NAME and prevented by dexamethasone. These results demonstrate directly the induction of NO production in vascular tissue by LTA and show that another, chemically different component of gram-positive bacteria can also have these properties. This result suggests that different components of the gram-positive bacterial wall could be implicated in the genesis of cardiovascular dysfunctions observed in gram-positive septic shock.     

NO及NO合成酶与感染性休克

感染性休克病理生理学过程十分复杂。NO在其中的作用既具有有害的一面，同时也存在有利的一面。受内毒素、细胞因子等诱导，iNOS表达上调并产生大量NO，引起循环衰竭、组织细胞损伤以及通过调节炎症介质基因表达扩大全身炎症反应。另一方面，eNOS所产生的NO对机体具有保护作用。然而，感染性休克时，eNOS蛋白质合成及其功能受到损害，反而成为血管内皮功能失常、诱发多器官功能障碍的重要原因。     

感染性休克下调大鼠血管内皮和血小板L-精氨酸/一氧化氮通路

目的：观察感染性休克对大鼠血小板及血管L-精氨酸(L-Arg)/一氧化氮合酶(NOS) /一氧化氮(NO)通路的影响及其相互联系,探讨感染性休克损伤的机制。方法:利用盲肠结扎并穿孔复制早期和晚期感染性休克大鼠模型,采用Greiss法测定血管各层及血小板孵育液亚硝酸盐(NO^-₂/NO^-₃)含量;以同位素示踪法检测其NOS活性及L -Arg转运。结果:早、晚期感染性休克大鼠血小板和主动脉内膜NO-2/NO-3水平、NOS 活性及低亲合L-Arg 转运量均显著低于假手术组(高亲合L- Arg 转运量在早期休克增加、晚期休克降低);而中膜和外膜的NO^-₂/NO^-₃水平、NOS 活性及L-Arg 转运量则显著高于假手术组,均以休克晚期改变为显著。血小板和主动脉内膜NO^-₂/NO^-₃生成、NOS 活性及高、低亲合L-Arg 转运的改变均呈正相关(均P< 0. 01)。结论:感染性休克下调血管内膜和血小板的L-Arg/NO通路,上调血管中膜和外膜L-Arg/ NO通路。提示检测血小板L-Arg/NO通路的变化可能反映休克时血管内皮功能的损伤。     

感染性和内毒素性休克大鼠动脉组织中硫化氢的变化

探讨内源性硫化氢 (H2 S)在感染性和内毒素性休克大鼠血管组织中的含量变化及意义。用盲肠结扎穿孔法制备大鼠感染性休克模型和静脉注射内毒素法制备内毒素休克大鼠模型 ,观察大鼠血液动力学、代谢变化及测定内源性硫化氢含量和一氧化氮含量 ,并计算其相关性。感染性及内毒素性休克大鼠的血液动力学参数均明显低于对照组 ,而左室舒张末压明显高于对照组 (P <0 0 1) ,血糖明显低于对照组 (P <0 0 1) ,血乳酸水平明显高于对照组(P <0 0 1)。感染性和内毒素性休克大鼠动脉组织中H2 S含量明显高于对照组 ,(均P <0 0 1)。休克大鼠血管H2 S含量与血压、心功能及低血糖的程度呈高度负相关 (均P <0 0 1)。以上结果说明内源性H2 S可能参与休克过程中的病理生理调节     

川芎嗪对内毒素性休克大鼠脑损伤的作用

目的:研究川芎嗪(ligustrazine,Lig)对内毒素性休克大鼠脑损伤的作用并探讨其作用机制。方法:将48只健康Wistar大鼠随机分为正常组、LPS组和LPS+Lig组,每组16只,上述每组再分为2个亚组:6 h组和12 h组,各8只大鼠。以尾静脉注射5 mg/kg脂多糖(LPS)建立内毒素性休克大鼠模型,腹腔注射盐酸川芎嗪注射液200 mg/kg,分别在相应时点进行眼球摘除采血并断头取脑组织,ELISA法检测血清中神经元特异性烯醇化酶(neuron-specific enolase,NSE)含量,脑组织匀浆检测一氧化氮(nitric oxide,NO)含量,TUNEL染色法检测脑组织中海马区细胞凋亡情况,Western blot法检测Bax和Bcl-2蛋白的表达。结果:与LPS组相比,川芎嗪能降低内毒素性休克所致大鼠NSE和NO含量的上升,同时抑制海马区细胞的凋亡,增加Bax的蛋白表达并降低Bcl-2的蛋白表达。结论:川芎嗪通过降低NSE和NO含量,减轻内毒素性休克大鼠的脑损伤程度,可能与其调节Bax和Bcl-2蛋白的表达有关。     

Time-Dependent Production of Endothelium-Related Biomarkers is Affected Differently in Hemorrhagic and Septic Shocks

Shock is associated with inflammation-induced endothelial dysfunction. The aim of this study was to determine time-dependent alteration of blood biomarkers related to endothelial function in hemorrhagic and septic shocks. Hemorrhagic shock was induced by bleeding the animals. A cecal ligation and incision model was used to induce septicemia. Resuscitation was carried out by infusion of lactated Ringer’s solution. Resuscitation extended survival time in both shock groups. Blood pressure increased by resuscitation in the hemorrhagic shock but not in the septic shock. While hemorrhage caused a decrease in plasma levels of nitric oxide (NO) and hydrogen sulfide (H₂S), asymmetric dimethylarginine (ADMA) and total antioxidant capacity (TAC) levels were increased. Only NO and TAC levels at the late phase were reversed by resuscitation. On the other hand, plasma levels of NO, ADMA, and TAC were increased by septicemia and resuscitation did not alter the septicemia-induced increase. These results indicate that blood biomarkers related to endothelial function were differentially affected by hemorrhage and septicemia. The time scale of biomarker production should be taken into consideration for the diagnostic and therapeutic approaches to these life-threatening diseases.     

Nitric oxide scavenging modulates an experimental vasoplesia in-vitro

Endogenous overproduction of nitric oxide (NO) is believed to be a primary cause of refractory hypotension in septic shock. Under this condition, effectiveness of vasopressors is diminished due to hyporeactivity of blood vessels, a condition termed as vasoplesia. Effective reduction of NO levels should alleviate the condition. In this study, we investigated whether NO scavenging could modulate the endotoxin mediated vasoplesia in-vitro. Further, we explored whether NO scavenging in combination with a moderate NO synthase (NOS) inhibition would also be effective in modulating NO mediated vasoplesia. Experimental vasoplesia was produced in-vitro by incubating isolated rat thoracic aortic rings with lipopolysaccharide (LPS). Vessel rings were then treated with N(omega)-nitro-L-arginine methyl ester (L-NAME; a NOS inhibitor), human hemoglobin (Hb; a NO scavenger), or both L-NAME and Hb. Vascular reactivity was assessed by measuring vessel ring isometric tension changes to norepinephrine (NE) doses; the median effective doses (logEC50) of NE before and after each experimental treatment were compared. Following a 6-hour LPS treatment, vascular reactivity logEC50 values for NE were significantly increased compared with control vessel rings incubated without LPS. Treatment with either L-NAME alone or Hb alone significantly improved the vessel ring reactivity to NE. When both L-NAME and Hb were used concomitantly, vascular reactivity was also significantly improved. These results indicate that NO scavenging with Hb is as effective as NO synthesis inhibition with NAME in modulating the endotoxin induced vasoplesia. In conclusion, NO scavenging, alone or in combination with a moderate NOS inhibition, may render an alternative therapeutic approach to NOS synthesis inhibition in modulating the vasoplesia in septic shock.     

Is macrophage migration inhibitory factor (MIF) the “control point” of vascular hypo-responsiveness in septic shock?

Macrophage migration inhibitory factor (MIF), a member of the cytokine family, is beginning to be recognized as a pleiotropic proinflammatory molecule. MIF exerts function via antagonistic regulation of glucocorticoids, inhibition to apoptosis-mediated p53, influence on vasodilator gas NO and inducible nitric oxide synthase (iNOS), feedback counter-regulation of complement C5a controlling MIF release, and interaction with major cations as well. Interestingly, aforementioned glucocorticoids, apoptosis, NO, iNOS, C5a, Ca2+, Mg2+, Na+, K+, and H+ that are greatly associated with vascular tone or vasomotion. Nevertheless, the elevated serum and cytosolic concentrations of MIF exactly affect all above facets in septic shock models and patients, during which vasodilation of the peripheral resistance vessels occurs, and accompanied with decreased responsiveness to vascular pressors. Thus MIF may bring into play as one of point-controlling proteins in the onset of sustained vascular hypo-reactivity during the process of septic shock.