N-乙酰半胱氨酸对稳定期慢性阻塞性肺疾病的治疗作用

目的：探讨N-乙酰半胱氨酸（NAC）对稳定期慢性阻塞性肺疾病（COPD）患者的治疗效果。方法：选取本院2012年8月-2013年2月确诊为COPD稳定期的60例患者,按照随机数字表法将其分为观察组和对照组各30例。对照组给予常规治疗,观察组在常规治疗基础上联合NAC治疗1年,观察比较两组FEV1%pred、SGRQ评分、急性加重次数及住院次数的差异。结果：两组治疗后与治疗前比较,FEV1%pred明显升高（P〈0.05）,SGRQ评分、急性加重次数、住院次数均明显降低（P〈0.05）;且两组治疗后比较差异均有统计学意义（P〈0.05）。结论：NAC可以显著改善稳定期COPD患者肺功能、生活质量,并降低急性加重次数、住院次数,值得临床推广。     

No Net Splanchnic Release of Glutathione in Man during N-Acetylcysteine Infusion

Glutathione and amino acid concentrations were measured in arterial and hepatic vein plasma in four healthy volunteers and two patients with cirrhosis. There was no significant splanchnic efflux of glutathione (95% confidence limits,-0.501 to 0.405 μmol/min). After infusion of N-acetylcysteine (NAC) in a high dose (150 mg/kg body weight primer plus 15 mg/(h × kg BW), corresponding to treatment of acetaminophen overdose, there was no change in the splanchnic glutathione efflux (95% confidence limits,-0.531 to 0.375 μmol/min). NAC increased hepatic plasma flow rate from 0.90 ± 0.531 min^-1 to 0.97 ± 0.11 (mean ± SEM; p < 0.05). The effects of NAC treatment on plasma amino acids corresponded to an increased load on hepatic metabolic N conversion and transamination among non-essential amino acids. Splanchnic uptake of serine, alanine, cystine, isoleucine, and phenylalanine increased after NAC compatible with stimulated hepatic glutathione synthesis. In contrast to the rat, plasma glutathione in man probably originates mainly from extrahepatic tissues.     

N-乙酰半胱氨酸对葡聚糖硫酸钠诱导的小鼠溃疡性结肠炎的保护作用

目的观察N-乙酰半胱氨酸(NAC)灌肠对小鼠急性溃疡性结肠炎的作用。方法5%葡聚糖硫酸钠(DSS)自由饮用7 d诱导小鼠急性溃疡性结肠炎,同时予以生理盐水(NS)、5-氨基水杨酸(5-ASA)、NAC保留灌肠,观察小鼠体重、粪便性状、隐血便血,计算疾病活动度(DAI)积分,检测结肠长度、结肠过氧化物酶(MPO)活性、血清过氧化物歧化酶(SOD)活力和丙二醛(MDA)含量及肠黏膜病理改变。结果NAC组小鼠隐血、便血、体重下降、DAI积分、病理改变等均好于模型组、NS组(P<0.05),与5-ASA组疗效相似。NAC组SOD活力高于模型组,MPO活性、MDA含量则低于模型组(P<0.05)。结论NAC对DSS诱导的小鼠急性溃疡性结肠炎黏膜损伤有保护作用,其机制可能与抗氧化应激有关。     

N-乙酰半胱氨酸对肝缺血再灌注损伤大鼠Toll样受体4表达的影响

目的：探讨N-乙酰半胱氨酸(N-acetylcysteine,NAC)对肝缺血再灌注(ischemic reperfusion,I/R)损伤大鼠Toll样受体4(Toll-like receptor 4,TLR4)表达的影响。方法：Wistar大鼠随机分为3组：假手术组(P)、I/R组、I/R+NAC组。P组只开腹不阻断肝血流,另2组阻断大部肝血流后再灌注,其中I/R+NAC组再灌注前5 min尾静脉给予300 mg/kg NAC。各组分别检测不同时间点的血丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、脂多糖(LPS)与肝组织TLR4 mRNA及其蛋白。结果：在各时间点,P组血ALT,AST,LPS和肝绍织TLR4表达无显著差异；另2组较P组均有显著升高,但I/R+NAC组各指标升高低于I/R组。肝组织TLR4 mRNA表达在I/R组从3 h起显著增强并维持高表达,而I/R+NAC组各时相无显著变化；但两者TLR4蛋白表达变化类似,都在6,24 h表达显著增强。结论：LPS及其TLR4参与了I/R肝损伤的病理过程；NAC减弱肠源性LPS及其启动的TLR4炎症信号通路而保护缺血再灌注肝损伤。     

Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury.

Mitochondrial dysfunction and internucleosomal DNA fragmentation are well-recognized features of acetaminophen (AAP)-induced hepatocyte cell death. However, the endonucleases responsible for this effect have not been identified. Apoptosis-inducing factor (AIF) and endonuclease G are nucleases located in the intermembrane space of mitochondria. AIF is thought to trigger chromatin condensation and induce cleavage of DNA into high molecular weight fragments (50-300 kb), and endonuclease G can produce oligonucleosomal DNA fragments. Therefore, the objective of this investigation was to test the hypothesis that endonuclease G and AIF could be involved in AAP-induced nuclear DNA fragmentation. Using immunofluorescence microscopy, it was shown that in primary cultured mouse hepatocytes, endonuclease G and AIF translocated to the nucleus between 3 and 6 h after exposure to 5 mM AAP. In contrast, other mitochondrial intermembrane proteins such as cytochrome c or the second mitochondria-derived activator of caspases (Smac) did not accumulate in the nucleus. The translocation of AIF and endonuclease G correlated with mitochondrial dysfunction as indicated by the progressive loss of the mitochondrial membrane potential (measured with the JC-1 assay) and the appearance of nuclear DNA fragments in the cytosol (determined by an anti-histone ELISA). Pretreatment with 20mM N-acetylcysteine prevented mitochondrial dysfunction, the nuclear translocation of endonuclease G and AIF, and the nuclear DNA fragmentation. The data support the conclusion that endonuclease G and AIF translocate to the nucleus in response to AAP-induced mitochondrial dysfunction and may be responsible, at least in part, for the initial DNA fragmentation during AAP hepatotoxicity.     

N-乙酰半胱氨酸对乙醇代谢的影响及机制研究

 目的研究N-乙酰半胱氨酸(NAC)是否能通过加速乙醇代谢而解酒以及是否能对抗乙醇对肝脏的损害及其作用机制。方法小鼠随机分组,分别灌胃给予蒸馏水和不同剂量的NAC,20 min后灌胃给予白酒,观察小鼠的翻正反射,攀网能力,用生化比色法测定肝脏中的乙醇脱氢酶(ADH)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、谷胱甘肽硫转移酶(GST)的活性及谷胱甘肽(GSH)和丙二醛(MDA)的含量。用气相色谱法测定血中乙醇的浓度。结果NAC可以减少小鼠灌胃给酒后的醉酒率,延长醉酒的潜伏时间,对抗乙醇引起的攀网能力下降,增加肝脏ADH的活性,从而增加乙醇代谢速度,降低血中乙醇的浓度;增加肝脏SOD,GSH-Px,GST的活性,提高肝脏GSH的含量,有利于清除自由基;减少肝脏中MDA的含量。而且均存在剂量依赖关系。结论NAC能加速乙醇代谢及对抗乙醇的肝脏损害,其作用机制可能与其提高ADH及抗氧化酶活性、加速清除乙醇代谢过程中产生的自由基、减少过氧化脂质的生成有关。     

Mechanism of the protective action of n-acetylcysteine and methionine against paracetamol toxicity in the hamster

The mechanism of the protective action of methionine and N-acetylcysteine against the toxicity of paracetamol was investigated in vivo. N-acetylcysteine inhibited the O-deethylation of ethoxyresorufin (cytochrome P-448) while methionine enhanced the N-demethylation of benzphetamine (cytochrome P-450) and increased hepatic microsomal levels of cytochrome P-450. These observations indicate that N-acetylcysteine, but not methionine, could afford protection against paracetamol hepatotoxicity, at least partly, by inhibiting cytochrome P-448 activity and thus the generation of the reactive intermediate. However, previous studies demonstrating no decrease in the urinary excretion of glutathione conjugates of paracetamol (derived from the reactive intermediate) in animals treated with N-acetylcysteine suggest that this is unlikely to be the prevailing mechanism of action.Administration of a large dose of paracetamol, as expected, depleted glutathione levels and inhibited cytosolic glutathione transferase activity. Administration of either N-acetylcysteine or methionine 1 h after paracetamol prevented both effects. On the basis of the present work and previously published observations, it is concluded that the major mechanism of action of N-acetylcysteine and methionine in vivo is by acting as precursors of intracellular glutathione.     

Mechanisms of matrix metalloproteinase-9 and matrix metalloproteinase-2 inhibition by N-acetylcysteine in the human term decidua and fetal membranes

OBJECTIVE: The purpose of this study was to evaluate the effect of N-acetylcysteine on the activity and secretion of the matrix metalloproteinases in the decidua, amnion, and chorion and the secretion of the tissue inhibitor of matrix metalloproteinase-1. STUDY DESIGN: Samples from eight nonlaboring women were taken at elective cesarean section and incubated in an in vitro organ culture in the absence or presence of N-acetylcysteine. Matrix metalloproteinase-2 and matrix metalloproteinase-9 activity was measured with the use of gel zymography. Western blot analysis was used to measure matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase-1 secretion. Data were analyzed with the paired Student t test. RESULTS: N-acetylcysteine had a direct inhibitory effect on matrix metalloproteinase-2 and matrix metalloproteinase-9 activity, regardless of tissue origin, starting at 1.0 mmol/L. In cultured media, 20 mmol/L N-acetylcysteine inhibited matrix metalloproteinase-2 and matrix metalloproteinase-9 activity in all three tissues. A differential response was demonstrated for matrix metalloproteinase-2 secretion, depending on the tissue that was studied. Its secretion was decreased in decidua at 10 mmol/L and 20 mmol/L; in amnion, the secretion was inhibited at 0.1 mmol/L and not affected at all in chorion. Matrix metalloproteinase-9 secretion was not affected in a statistically significant manner in any tissue. In the chorion, matrix metalloproteinase-9 showed a trend toward increased secretion. Tissue inhibitor of matrix metalloproteinase-1 secretion significantly decreased in the decidua at 20 mmol/L. CONCLUSION: N-acetylcysteine, at higher concentrations, has an inhibitory effect on matrix metalloproteinase-2 and matrix metalloproteinase-9 activity, regardless of the tissue origin and the differential effect on secretion depending on the tissue and N-acetylcysteine concentration.     

Fenoldopam and N-acetylcysteine for the prevention of radiographic contrast material-induced nephropathy: a review

Radiographic contrast material-induced nephropathy (RCIN) is the third most common cause of hospital-acquired renal insufficiency and has been associated with an increase in patient mortality. Many strategies to prevent RCIN have been explored unsuccessfully. The standard of care remains hydration with 0.45% sodium chloride before and after administration of contrast material. Recently, N-acetylcysteine and fenoldopam have been studied to determine their efficacy in preventing RCIN. Of seven prospective studies using various dosing regimens of N-acetylcysteine, four revealed beneficial results. Although some discrepancies exist, the data strongly suggest that N-acetylcysteine has a role in patients at risk for the development of RCIN. The data for fenoldopam are more limited, with only one retrospective study showing benefit. Additional prospective data are required to determine if fenoldopam has a role in the prevention of RCIN.