呼吸系统中的内源性硫化氢

20世纪90年代中期人们发现,哺乳动物的多种组织、器官中存在内源性硫化氢(hydrogen sulfide,H2s),并逐渐认识到H2S是继一氧化氮和一氧化碳后发现的第3个内源性气体信号分子.已有实验证明H2S在循环系统、神经系统、呼吸系统、消化系统、泌尿系统等均有重要病理生理意义.本文将着重讨论H2S在呼吸系统疾病中的作用.     

慢性肾脏疾病血清内源性硫化氢变化的研究

目的探讨慢性肾脏疾病患者血清中内源性硫化氢(H2S)的变化。方法选择2008年1月至12月重庆市第九人民医院肾内科慢性肾脏疾病患者186例为试验组(慢性肾炎108例,高血压肾脏疾病39例,糖尿病肾病30例,狼疮性肾脏疾病9例),健康对照组50例。测定并比较各组肾功能、内源性H2S、一氧化氮(NO),分析H2S与血压、NO、血肌酐变化是否相关。结果慢性肾脏疾病患者血清中内源性H2S明显下调,与对照组相比,差异有统计学意义(P<0.01)。慢性肾脏疾病患者H2S与血压及血肌酐呈负相关。在慢性肾炎、狼疮性肾脏疾病中H2S与NO呈负相关。结论 H2S在维持肾脏正常生理功能中起着重要作用,其下调可能与慢性肾脏疾病进展有关。     

门静脉高压大鼠内源性硫化氢体系的变化

在肝硬化门静脉高压形成中，门静脉系统的血流量增加是门静脉高压产生和加重的重要因素之一，近几年来人们发现气体信号分子NO、CO可以引起内脏血管扩张而使门静脉系统血流量增加。最近的研究发现H2S具有与NO、CO相似的生物学效应，如舒张血管、抑制平滑肌细胞增殖等。内源性H2S在诸多心血管疾病的发病过程中发挥着重要的病理生理学作用，广泛参与低氧性肺动脉高压、肺动脉高压、高血压、感染性休克等心肺疾病的发病过程。在门静脉高压的发病过程中是否也有H2S的参与，目前国内外鲜见报道。本研究以部分门静脉结扎大鼠为对象，观察门静脉高压大鼠门静脉压力的变化以及CSE基因表达的改变，以探讨H2S在门静脉高压中的作用。     

H2S调节心血管功能的研究进展

越来越多的证据支持H2S是第三种内源性气体信号分子。内源性H2S以半胱氨酸为底物在胱硫醚-β-合成酶或胱硫醚-γ-裂解酶催化下生成。在心血管系统中,H2S作用于血管平滑肌KATP通道和Cl-/HCO-3交换体舒张血管,并参与血压中枢调节。此外,H2S促进血管平滑肌的凋亡并抑制其增殖。H2S也作用于心肌KATP通道调节心肌收缩。病理状态下,H2S参与多种心血管疾病的发生,如高血压、心肌缺血/再灌注损伤,外源性的H2S可减轻疾病程度。     

硫化氢对大鼠实验性肝硬化门静脉压力的影响

目的应用内源性硫化氢（H2S）供体硫氢化钠（NaHS）探讨内源性H2S/胱硫醚-γ-裂解酶（CSE）体系对大鼠肝硬化门静脉压力的影响。方法将32只健康雌性SD大鼠随机分为4组：C组和C＋S组采用复合因素法复制肝硬化模型。模型制备52 d后,N＋S组和C＋S组大鼠腹腔注射NaHS 56μmol/（kg.d）,N组和C组腹腔注射同等剂量的生理盐水。1周后分别测定各组大鼠门静脉压力（PVP）及门静脉血浆中H2S含量;采用免疫组织化学方法检测大鼠肝门区门静脉平滑肌细胞中CSE蛋白表达。结果与N组和N＋S组相比,C组和C＋S组PVP均升高,H2S含量及CSE蛋白表达均降低;与C组相比,C＋S组PVP降低,H2S含量及CSE蛋白表达均升高。结论 NaHS作为H2S供体可能具有改善肝硬化大鼠门脉高压的作用,其机制可能与H2S含量及CSE蛋白表达升高有关。     

硫化氢在心肌缺血再灌注损伤中的作用机制

硫化氢(H2S)是一种气体信号分子,在哺乳动物体内广泛存在.内源性H2S主要在线粒体中代谢.外源性或内源性H2S对心肌缺血再灌注损伤均具有保护作用,主要作用机制包括抗炎、抗氧化、抗凋亡和促进血管新生等.该文介绍H2S在心肌缺血再灌注损伤中的作用和机制及H2S供体相关药物,以期对缺血性心脏病的干预提供新思路.     

硫化氢对常见心血管疾病的保护作用及其机制

硫化氢(H2S)作为一种内源性气体信号分子,是维持心血管系统稳态的关键因素之一。体内H2S的生成与分解具有多种途径。生理情况下,内源性H2S具有抑制炎症反应,调节血管张力以及促进血管新生的作用。近年来,越来越多的研究证实,H2S在高血压、心力衰竭、动脉粥样硬化以及心肌梗死后心肌缺血再灌注损伤中发挥重要的病理生理学效应。具有缓释作用、半衰期长、组织特异性高和低毒性的H2S供体,可能成为心血管疾病治疗潜在药物,具有重大临床意义。     

内源性硫化氢在不同时期大鼠肝硬化中的作用

目的: 观察内源性胱硫醚- γ - 裂解酶(cystathionine gamma-lyase, CSE)/硫化氢(hydrogen sulfide, H2S)(CSE/H2S)体系在不同时期肝硬化大鼠模型上的变化, 以探讨内源性H2S在肝硬化发生发展过程中的作用.方法: 制备四氯化碳诱导的肝硬化大鼠模型,在第15、30、52天取大鼠门静脉血检测H2S浓度, 用免疫组化和RT-PCR方法观察肝组织CSE mRNA的表达.结果: 肝硬化早、中、晚期大鼠门静脉血中H2S的含量均显著低于正常对照组( F =126.208, P = 0.000), 且H2S浓度随着肝脏病变的加重而逐渐降低( r = -0.777, P<0.05). 肝硬化不同时期肝组织CSE蛋白的灰阶值均低于正常对照组( F = 156.04, P = 0.000), 表明CSE表达增强. 各组CSE mRNA的表达均分别显著高于正常对照组( F = 23.927, P = 0.000), 且随着肝脏病变的加重表达逐渐增加.结论: H2S体系在肝硬化发生发展中起着保持血管舒张状态的重要作用.     

气体信号分子家族的新成员——H2S

硫化氢(hydrogen sulfide，H2S)是一种带有臭鸡蛋味的有毒气体，过量吸入可以影响肺、脑、肾等多种脏器的正常功能。以往对于H2S的研究偏重于其毒性作用，直至90年代中期才发现，内源性H2S具有多种生理功能，如促进海马长时程增强(LTP，认为与学习、记忆有关)的诱导，调节消化道和血管平滑肌张力，抑制血管平滑肌增殖，调节下丘脑-垂体-肾上腺轴的功能等。由于H2S具有：①属于小分子量气体，例如NO和CO2②可以自由穿过膜结构，发挥作用不依赖于膜受体；③在某些酶的催化下可以内源性生成，并接受调节；④生理浓度下即有特定生理功能；     

人食管H_2S合成酶的免疫组化研究

目的探讨H2S合成酶:胱硫醚-β-合酶(CBS)、胱硫醚-γ-裂解酶(CSE)在人食管平滑肌中的分布。方法取正常人食管平滑肌组织,应用免疫组化方法检测CBS、CSE在其中的分布。结果人食管平滑肌组织可见CBS阳性神经元及CSE阳性神经元。结论内源性H2S可能影响食管功能。     

Hydrogen sulfide (H2S), an endogenous gas with odor of rotten eggs might be a cardiovascular function regulator

A novel concept of "gasotransmitter" arrived recently. They are small molecules of endogenous gases. Hydrogene sulfide (H2S) is qualified as the third gasotransmitter beside nitric oxide (NO) and carbon monoxide (CO). The physiological functions of endogenous H2S are not well-known. The location of the H2S synthetizing enzymes as well as the detector of endogenous levels of H2S in the tissues suggests that the cardiovascular system is a source of H2S generation. This gas relaxes vascular smooth muscle both in vitro and in vivo probably by opening smooth K+ATP channels. Being a reducing agent, H2S may alter cellular redox status. It is able to produce thiyls free radicals: SH degrees and S degrees . The advances in H2S researchs may revolutionize many conventional doctrines in the cardiovascular area.     

Effect of theophylline on endogenous hydrogen sulfide production in patients with COPD

BACKGROUND: Airway inflammation plays a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Endogenous hydrogen sulfide (H2S) is involved in the physiological and pathophysiological process in systemic inflammation and may be involved in the pathogenesis of airway inflammation and airflow obstruction in COPD. The non-selective phosphodiesterase inhibitor theophylline has bronchodilator/anti-inflammatory properties and is widely used in the treatment of airways diseases. It is not fully understood whether endogenous H2S mediates the mechanism of theophylline anti-inflammatory effect. METHODS: The effect of short-term theophylline treatment on airway inflammation and endogenous H2S production was prospectively studied in thirty-seven patients with stable COPD. Patients were randomly divided into theophylline-treatment group (nineteen patients, orally given sustained theophylline tablets for 1 month, 0.2g, q 12h) and control group (eighteen patients, not given any theophylline). Symptom score, lung function, total and differential cell counts in sputum, serum H2S and nitric oxide (NOx) levels, sputum and serum IL-8 levels were measured at baseline and 1 month later. RESULTS: No significant difference was found in symptom scores, lung function and other investigated experimental parameters at baseline between treatment and control groups, and between baseline and a month follow-up in control patients. Symptom scores were significantly lowered only in the treated patients after treatment, compared with those before (P<0.01). The proportion of neutrophils in sputum was significantly decreased (P<0.05) while that of macrophages was markedly increased (P<0.01) in the treated patients after treatment, compared with that before. No significant change was found in serum H2S and NOx levels, serum and sputum IL-8 levels before and after experiment in treatment group. Serum H2S level correlated positively with percentage of predicted FEV1 (r=0.465, P=0.005), and with proportion of sputum macrophages (r=0.349, P=0.05), but negatively with proportion of sputum neutrophils (r=-0.351, P=0.049) in all patients at baseline. CONCLUSIONS: Short-term theophylline treatment improved symptoms and decreased sputum neutrophils in COPD, while serum H2S levels were not affected in our study population. Large samples will be needed to illustrate the effect of long-term theophylline treatment on inflammatory mediators and H2S generation in COPD.     

Endogenous hydrogen sulfide contributes to the cardioprotection by metabolic inhibition preconditioning in the rat ventricular myocytes

The possible role of hydrogen sulfide (H2S) in cardioprotection was investigated in isolated rat ventricular myocytes exposed to severe metabolic inhibition (MI) in glucose-free buffer containing 2-deoxy-D-glucose (2-DOG), an inhibitor of glycolysis. Pretreatment (30 min) with NaHS (a H2S donor) at concentrations of 10(-5) to 10(-4) mol/L caused a concentration related increase in cell viability and the ratio of rod-shaped cells. A time course study showed that NaHS-induced cardioprotection occurred in 2 time windows (approximately 1 h and 16-28 h). To observe whether endogenous H2S may be involved in the delayed cardioprotection response of IP, DL-propargylglycine (PAG) and beta-cyano-L-alanine (BCA; two inhibitors of H2S biosynthesis) were used. Both drugs significantly attenuated the cardioprotection produced by MI using cell viability, cellular injury index, and electrically-induced [Ca2+]i transients as end-points. These data suggest that endogenous H2S plays an important role in the cardioprotection following MI preconditioning. In an attempt to determine the mechanism of the cardioprotective effect of H2S, we examined the effect of blocking KATP channels with glibenclamide (a non-selective KATP channel blocker), 5-hydroxydecanoic acid (5-HD, a mitochondrial KATP blocker), and HMR-1098 (a sarcolemmal KATP blocker). The cardioprotective effects of NaHS were significantly attenuated by glibenclamide and HMR-1098 treatment but not by 5-HD. Inhibition of NO production with L-NG nitroarginine methyl ester (L-NAME) also attenuated the cardioprotection of NaHS. In conclusion, our findings provide the first evidence that H2S may protect the heart most probably by activating sarcolemmal KATP channels and/or provoking NO release and the cardioprotective effects of metabolic ischemic preconditioning is, at least partially, mediated by endogenous H2S.     

硫化氢及其外源性供体对心血管疾病治疗潜力的研究进展

硫化氢(H2S)被认为是继一氧化碳、一氧化氮后的第3大内源性气体信号分子,可在哺乳动物组织中合成,并能自由地穿过细胞膜,在包括心血管系统在内的多系统中发挥多种生物作用。心血管疾病是世界范围内死亡的主要原因,其具体发病机制尚未完全明确。近年来,越来越多的研究支持内源性H2S和外源性H2S供体化合物对动脉粥样硬化、心肌肥厚、心力衰竭和缺血/再灌注损伤等心血管疾病发挥保护作用,本文综述了此方面的研究进展,重点介绍了H2S以及各种外源性H2S供体在治疗心血管疾病中的潜力。     

硫化氢对动脉粥样硬化的影响及其与 CX3CR1 的关系

目的在高脂饮食ApoE基因敲除小鼠动脉粥样硬化模型中,探讨硫化氢对动脉粥样硬化斑块的影响及其与斑块内趋化因子受体CX3CR1的关系。方法10周龄、雄性纯合子ApoE基因敲除小鼠予以高脂饮食喂养,在高脂饮食喂养第4、8、12、24周时处死小鼠并留取血浆和主动脉,通过化学比色法和Western Blot技术检测血浆硫化氢水平和主动脉胱硫醚-γ-裂解酶（CSE）表达情况。一部分小鼠在高脂饮食4或12周后开始每天予以硫化氢供体药物NaHS（1mg-kg^-1,i．P．）或生理盐水。高脂饮食24周后,通过超声生物显微镜成像技术评估小鼠主动脉及其主要分支内的动脉粥样硬化情况,随后处死小鼠并留取主动脉,通过H＆E染色和免疫组化技术进一步观察小鼠头臂干动脉粥样斑块的病变情况及CX3CR1的表达水平。结果在动脉粥样硬化斑块形成早期,即出现了CSE表达水平的显著降低,随着斑块的进展,CSE的表达水平进一步下调和CSE活性明显下降,最终导致血浆硫化氢水平的显著降低。动脉粥样硬化早期或中晚期予以NariS均可显著延缓动脉粥样硬化斑块的形成和进展,但是NaHS早期干预,其抗动脉粥样化的益处显著优于中晚期干预。NariS的抗动脉粥样硬化益处可能与其抑制斑块内CX3CR1的表达有关。结论动脉粥样硬化过程中存在着内源性硫化氢代谢紊乱,予以NaHS干预可抑制斑块内CX3CR1的表达和延缓动脉粥样硬化的进展,早期NaHS干预的疗效显著优于中晚期干预。     

Changes in arterial hydrogen sulfide (H(2)S) content during septic shock and endotoxin shock in rats

OBJECTIVES: To explore the changes of hydrogen sulfide (H(2)S) in vascular tissues of rats with septic shock and endotoxin shock and its possible pathophysiological implication. METHODS: Rat models of septic shock induced by cecal ligation and puncture and of endotoxic shock induced by injection of endotoxin were used in this study. The authors measured hymodynamic variations, metabolic data, H(2)S and nitric oxide (NO) contents of different arteries in rats with septic shock and endotoxic shock. RESULTS: The results showed that hemodynamic parameters including the heart rate (HR), the mean arterial pressure (BP), and the +dP/dt max decreased markedly, while the left ventricular end-diastolic pressure (LVEDP) increased significantly and the rats developed hypoglycemia and lactic acidosis. Arterial H(2)S contents were significantly increased (P<0.01) in both septic and endotoxic shock (P<0.01). Endogenous H(2)S and NO contents all negatively correlated with BP, cardiac function and the degree of hypoglycemia (P<0.01). CONCLUSIONS: The results of our study demonstrated that endogenous vascular H(2)S increased in rats with septic shock and endotoxic shock. It was suggested that endogenous H(2)S was involved in physiological and pathophysiological process during shock.     

硫化氢对离体大鼠心室肌细胞ATP依赖的钾通道外向电流的影响

目的 观察内源性及外源性硫化氢(hydrogen sulfide,H2S)对大鼠离体心室肌细胞ATP依赖的钾通道(KATP)外向电流的影响,以探讨H2s对心窜肌细胞的作用.方法 对大鼠离体心脏采用胶原酶酶解法得到单个心室肌细胞,采用膜片钳全细胞技术记录DL-propargylglycine(PPG)及不同浓度硫氢化钠(NaHS,外源性H2S的供体)干预前后的KATP什电流.结果 经PPG(200 μmol/L)干预后,KATP峰电流密度(+70 mV)显著减小[干预前后分别为(5.3258±0.7556)pA/pF比(3.7856±0.4312)pA/pF,P＜0.01],且具有时间依赖性.经NaHS(9.375、18.75、37.5、75、150μmoL/L)干预后,KATP峰电流密度呈浓度依赖性增大,至150 μmol/L时峰电流密度明显增大[(6.6310±0.6092)pA/pF比(9.0949±1.0259)pA/pF,P＜0.01].结论 内源性及外源性H2s均可以开放大鼠离体心室肌KATP通道,使KATP电流增加.     

Hydrogen sulfide and erectile function: a novel therapeutic target

Hydrogen sulfide (H(2)S) is a gaseous transmitter involved in the control of vascular homeostasis. H(2)S is formed endogenously from L-cysteine or L-methionine by two enzymes, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), and normally circulates in blood. Studies from the past few years have demonstrated the involvement of H(2)S in erectile mechanisms in animal and human tissues. Exogenous H(2)S relaxes human and animal tissues in vitro and increases intracavernous pressure in experimental animal models. Electrical field stimulation studies on animal and human tissues have demonstrated that endogenous H(2)S is involved in the physiological control of penile tone. In humans, both CBS and CSE are widely expressed on trabecular muscle, implying that the smooth muscle component is the major source of H(2)S. Thus, the L-cysteine-H(2)S pathway may represent a promising target for development of new therapeutics for erectile dysfunction.     

心肌梗死后晚期血管开通前后血浆内源性硫化氢含量的变化及其意义（英文）

目的：探讨心肌梗死后晚期血管开通前后血浆内源性硫化氢含量的变化及其意义。方法：选择冠脉造影明确的,未经溶栓的初次心肌梗死患者60例,分为单纯前降支近段闭塞后成功开通组（20例）、单纯右冠近段完全闭塞后成功开通组（20例）和双支病变闭塞后成功开通组（20例）,用分光光度法检测各组血管开通前后内源性硫化氢含量。结果：与血管开通前内源性硫化氢水平比较,开通后前降支病变组[（24.44±3.27）μmol/L比（37.47±2.38）μmol/L]、右冠病变组[（24.48±3.60）μmol/L比（37.22±2.56）μmol/L]、双支病变组[（20.41±2.22）μmol/L比（30.34±2.37）μmol/L]内源性硫化氢水平明显升高（P均〈0.05）。结论：心肌梗死后晚期开通血管使血浆内源性硫化氢含量显著增加;对患者的预后是有益的。