H_2S对心肺复苏后脑损伤的作用及其机制
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摘要
[目的]1.按照Utstein模式对比分析电刺激法致心脏骤停模型和窒息法致心脏骤停模型的特点。2.初步探讨H2S供体NaHS在心肺复苏大鼠脑损伤中的作用。3.研究H2S对复苏后脑损伤的保护作用与抗炎反应的关系。4.研究H2S对复苏后脑损伤的保护作用与凋亡反应的关系。5.研究H2S对复苏后脑损伤的保护作用与氧化应激反应的关系。6.研究H2S的脑保护作用是否于上调缺氧诱导因子-1(hypoxia-inducible factor-1, HIF-1)有关。
[方法]第一部分分别采用经皮电刺激心外膜法制备大鼠心脏骤停模型和窒息法制备大鼠心脏骤停模型,比较两组大鼠在心脏骤停类型,诱发心脏骤停时间的差异。第二、三部分采用经皮电刺激心外膜法建立大鼠心跳骤停模型,随机(随机数字法)分为4组：(1)假手术组：仅行麻醉、气管插管及动静脉插管操作；(2)CPR组：进行模型制备及复苏；(3)CPR+硫氢化钠(NaHS)组：以NaHS作为H2S供体,在CPR开始前1分钟经股静脉给予100μg/kgNaHS,其余操作同CPR组；(4)CPR+AOAA(H2S合成酶CBS抑制剂)组：在CPR开始前1分钟经股静脉给予20mg/kgAOAA。分别对各组大鼠进行生存率、神经缺陷评分和形态学观察；用生化法测定各组大鼠在不同时间点脑组织H：S的表达水平,用Elisa方法测定各组大鼠不同时间点脑组织炎性因子TNF-α、IL-1β的表达；用PCR、免疫组化的方法测定各组大鼠脑组织凋亡相关因子Bax、Bcl-2的表达；用生化法测定各组大鼠脑组织氧化应激指标MDA、SOD的变化；用实时定量PCR、Western方法测定各组大鼠缺氧诱导因子-1基因及蛋白的表达。
[结果]经皮电刺激心外膜法致大鼠心脏骤停模型心脏骤停表现类型多样,可以表现为室颤、无脉性电活动和心电静止,窒息法仅表现为无脉性电活动和心电静止,无室颤发生；经皮电刺激心外膜法致大鼠心脏骤停模型诱发心脏骤停的时间明显短于窒息法致心脏骤停模型,差异有统计学意义(P<0.05)。与假手术组相比,CPR组TNF-α水平在3h、6h、9h、12h均有明显升高,差异有统计学意义(P<0.05),其含量在6h达到高峰；与CPR组相比,CPR+NaHS组TNF-a水平在3h、6h、9h、12h均明显降低,差异有统计学意义(P<0.05)；与CPR组相比,CPR+AOAA组TNF-α水平在3h、6h均有所增加,差异有统计学意义(P<0.05),在9h、12h有增高趋势,差异无统计学意义(P>0.05)。与假手术组相比,CPR组IL-1β水平在3h、6h、9h、12h均有明显升高,差异有统计学意义(P<0.05),其含量在9h达到高峰；与CPR组相比,CPR+NaHS组IL-1β水平在6h、9h、12h明显降低,差异有统计学意义(P<0.05),在3h有降低趋势,差异无统计学意义(P>0.05)；与CPR组相比,CPR+AOAA组IL-1β水平在3h、6h、9h均有所升高,差异有统计学意义(P<0.05),12h有升高趋势,差异无统计学意义(P>0.05)。与假手术组相比,CPR组Bax表达增高,差异有统计学意义(P<0.05),与CPR组相比,CPR+NaHS组Bax表达明显下降,差异有统计学意义(P<0.05),CPR+AOAA组表达与CPR组无明显差异(P>0.05)。与假手术组相比,CPR组Bcl-2基因表达有升高趋势,差异有统计学意义(P>0.05),与CPR组相比,CPR+NaHS组Bcl-2基因表达明显升高,差异有统计学意义(P<0.05),CPR+AOAA组表达下降,差异有统计学意义(P<0.05)。与假手术组相比,CPR组Bax/Bcl-2表达增高,差异有统计学意义(P<0.05),与CPR组相比,CPR+NaHS组Bax/Bcl-2表达明显下降,差异有统计学意义(P<0.05),CPR+AOAA组表达Bax/Bcl-2表达升高,差异有统计学意义(P<0.05)。与假手术组相比,CPR组SOD活性下降,差异有统计学意义(P<0.05)；与CPR组相比,CPR+NaHS组SOD活性增高,差异有统计学意义(P<0.05)；与CPR组相比,CPR+AOAA组SOD活性降低,差异有统计学意义(P<0.05)。与假手术组相比,CPR组MDA活性增高,差异有统计学意义(P<0.05)；与CPR组相比,CPR+NaHS组MDA活性降低,差异有统计学意义(P<0.05)；与CPR组相比,CPR+AOAA组MDA活性升高,差异有统计学意义(P<0.05)。实时定量PCR和Western结果均显示CPR组HIF-1α基因及蛋白表达水平较假手术组增高(P<0.05)；与CPR组相比,CPR+NaHS组HIF-1蛋白表达水平增高(P<0.05)；与CPR组相比,CPR+AOAA组HIF-1αmRNA表达水平有降低趋势,但差异无统计学意义(P<0.05)。
[结论]电刺激法所致心脏骤停模型诱导心脏骤停表现类型多样,诱发心脏骤停的时间明显短于窒息法心脏骤停,可作为心脏骤停模型制备的首选。H2S可以减轻大鼠复苏后脑损伤,给予H2S抑制剂AOAA则加重脑损伤。其脑保护机制与减轻炎症反应、减轻凋亡、减轻氧化应激反应有关,并通过上调缺氧诱导因子发挥脑保护作用。
【Objective】1. To compare cardiac arrest induced by asphyxiation with cardiac arrest induced by transcutaneous electrical epicardium stimulation according to utstein style, and to find out a standardized animal cardiac arrest model which is consistant with clinical practice.2. To investigate the effects of hydrogen sulfide on the injury of brain injury induced by cardiac arrest.3. To investigate the effects of H2S on inflammatory reaction.4. To investigate the effects of H2S on apoptosis reaction.5. To investigate the effects of H2S on oxidative stress.6. To investigate whether the effects of H2S is associated with HIF-1.
[Methods] In Part 1, animals were randomly divided into two groups:one group received cardiac arrest induced by asphyxiation, the other group received cardiac arrest induced by transcutaneous electrical epicardium stimulation. Animals were randomly divided into four groups:sham group, cardiopulmonary resuscitation group (CPR group), CPR+NaHS group and CPR+AOAA group. Types of cardiac arrest were observed, and time of asphyxiation or electrical stimulation to cardiac arrest were recorded. In Part 2、Part 3、Part 4, animals were randomly divided into four groups:The rats of sham group were only anesthetized and intubated. CPR group、NaHS+CPR group and CPR+AOAA group received cardiac arrest by transcutaneous electrical epicardium stimulation. For CPR+NaHS group, NaHS (100ug/kg) was administrated via the femoral venous line 1 minute before CPR. For CPR+AOAA group, AOAA (20mg/kg) was administrated via the femoral venous line 1 minute before CPR. NDS value was scored and the morphological structures of brain were also observed. TNF-a and IL-1βwere detected by ELISA method; Bax and Bcl-2 expression were detected by PCR and immunohistochemical methods; MDA and SOD were determined; the expression of HIF-1 were also determined by real-time quantitative PCR and Western blot.
[Results] Cardiac arrest induced by transcutaneous electrical epicardium stimulation appeared VF, PEA, asytole. Cardiac arrest induced by asphyxiation appeared PEA, asytole. Time of asphyxiation to cardiac arrest was obviously longer than electrical stimulation to cardiac arrest(p＜0.05). Compared with sham group, the concentration of TNF-a were substantially elevated at 3h,6h,9h,12h(p<0.05), and it peaked 6h after CPR; Compared with CPR, the concentrations of TNF-a in CPR+NaHS were substantially decreased at 3h, 6h,9h,12h(p＜0.05), the concentrations of TNF-a in CPR+AOAA were substantially increased at 3h,6h(p＜0.05). Compared with sham group, the concentration of IL-1βwere substantially elevated at 3h,6h,9h,12h(p＜0.05), and it peaked 6h after CPR; Compared with CPR, the concentrations of IL-1βin CPR+NaHS were substantially decreased at 6h, 9h,12h(p＜0.05), the concentrations of TNF-a in CPR+AOAA were substantially increased at 3h,6h,9h(p＜0.05). Compared with sham group, the expression of Bax in CPR was increased(p＜0.05); Compared with CPR, the expression of Bax in CPR+NaHS group was decreased(p＜0.05); There were no obviously differences in CPR group and CPR+AOAA group. Compared with sham group, the expression of Bcl-2 in CPR was increased(p＞0.05); Compared with CPR, the expression of Bcl-2 in CPR+NaHS was obviously increased(p＜0.05); and the expression of Bcl-2 in CPR+AOAA was obviously decreased(p＜0.05). Compared with sham group, the ratio of Bax/Bcl-2 in CPR was increased(p＜0.05); Compared with CPR, the ratio of Bax/Bcl-2 in CPR+NaHS group was decreased(p＜0.05); and the ratio of Bax/Bcl-2 in CPR+AOAA group was increased(p＜0.05). Compared with sham group, the expression of SOD in CPR was decreased(p＜0.05); Compared with CPR, the expression of SOD in CPR+NaHS was obviously increased(p＜0.05); and the expression of SOD in CPR+AOAA was obviously decreased(p＜0.05). Compared with sham group, the expression of MDA in CPR was increased(p＜0.05); Compared with CPR, the expression of MDA in CPR+NaHS was obviously decreased(p＜0.05); and the expression of MDA in CPR+AOAA was obviously increased(p＜0.05). Compared with sham group, the expression of HIF-1 gene and protein was upregulated. Compared with CPR group, the expression of HIF-1 gene and protein in CPR+NaHS group was upregulated, and the expression of HIF-1 gene and protein in CPR+AOAA group has a lower trend(p＜0.05).
[Conclusion] The cardiac arrest model induced by transcutaneous electrical epicardium stimulation is more close to clinical practice, the standardization of model is superior to cardiac arrest induced by asphyxiation. Hydrogen sulfide can protect brain from injury, and administration of AOAA aggravated brain damage. The mechanism is associated with antiinflammation, relieving apoptosis, reducing oxidatie stress reaction relevant and upregualating HIF-1.
[方法]第一部分分别采用经皮电刺激心外膜法制备大鼠心脏骤停模型和窒息法制备大鼠心脏骤停模型,比较两组大鼠在心脏骤停类型,诱发心脏骤停时间的差异。第二、三部分采用经皮电刺激心外膜法建立大鼠心跳骤停模型,随机(随机数字法)分为4组：(1)假手术组：仅行麻醉、气管插管及动静脉插管操作；(2)CPR组：进行模型制备及复苏；(3)CPR+硫氢化钠(NaHS)组：以NaHS作为H2S供体,在CPR开始前1分钟经股静脉给予100μg/kgNaHS,其余操作同CPR组；(4)CPR+AOAA(H2S合成酶CBS抑制剂)组：在CPR开始前1分钟经股静脉给予20mg/kgAOAA。分别对各组大鼠进行生存率、神经缺陷评分和形态学观察；用生化法测定各组大鼠在不同时间点脑组织H：S的表达水平,用Elisa方法测定各组大鼠不同时间点脑组织炎性因子TNF-α、IL-1β的表达；用PCR、免疫组化的方法测定各组大鼠脑组织凋亡相关因子Bax、Bcl-2的表达；用生化法测定各组大鼠脑组织氧化应激指标MDA、SOD的变化；用实时定量PCR、Western方法测定各组大鼠缺氧诱导因子-1基因及蛋白的表达。
[结果]经皮电刺激心外膜法致大鼠心脏骤停模型心脏骤停表现类型多样,可以表现为室颤、无脉性电活动和心电静止,窒息法仅表现为无脉性电活动和心电静止,无室颤发生；经皮电刺激心外膜法致大鼠心脏骤停模型诱发心脏骤停的时间明显短于窒息法致心脏骤停模型,差异有统计学意义(P<0.05)。与假手术组相比,CPR组TNF-α水平在3h、6h、9h、12h均有明显升高,差异有统计学意义(P<0.05),其含量在6h达到高峰；与CPR组相比,CPR+NaHS组TNF-a水平在3h、6h、9h、12h均明显降低,差异有统计学意义(P<0.05)；与CPR组相比,CPR+AOAA组TNF-α水平在3h、6h均有所增加,差异有统计学意义(P<0.05),在9h、12h有增高趋势,差异无统计学意义(P>0.05)。与假手术组相比,CPR组IL-1β水平在3h、6h、9h、12h均有明显升高,差异有统计学意义(P<0.05),其含量在9h达到高峰；与CPR组相比,CPR+NaHS组IL-1β水平在6h、9h、12h明显降低,差异有统计学意义(P<0.05),在3h有降低趋势,差异无统计学意义(P>0.05)；与CPR组相比,CPR+AOAA组IL-1β水平在3h、6h、9h均有所升高,差异有统计学意义(P<0.05),12h有升高趋势,差异无统计学意义(P>0.05)。与假手术组相比,CPR组Bax表达增高,差异有统计学意义(P<0.05),与CPR组相比,CPR+NaHS组Bax表达明显下降,差异有统计学意义(P<0.05),CPR+AOAA组表达与CPR组无明显差异(P>0.05)。与假手术组相比,CPR组Bcl-2基因表达有升高趋势,差异有统计学意义(P>0.05),与CPR组相比,CPR+NaHS组Bcl-2基因表达明显升高,差异有统计学意义(P<0.05),CPR+AOAA组表达下降,差异有统计学意义(P<0.05)。与假手术组相比,CPR组Bax/Bcl-2表达增高,差异有统计学意义(P<0.05),与CPR组相比,CPR+NaHS组Bax/Bcl-2表达明显下降,差异有统计学意义(P<0.05),CPR+AOAA组表达Bax/Bcl-2表达升高,差异有统计学意义(P<0.05)。与假手术组相比,CPR组SOD活性下降,差异有统计学意义(P<0.05)；与CPR组相比,CPR+NaHS组SOD活性增高,差异有统计学意义(P<0.05)；与CPR组相比,CPR+AOAA组SOD活性降低,差异有统计学意义(P<0.05)。与假手术组相比,CPR组MDA活性增高,差异有统计学意义(P<0.05)；与CPR组相比,CPR+NaHS组MDA活性降低,差异有统计学意义(P<0.05)；与CPR组相比,CPR+AOAA组MDA活性升高,差异有统计学意义(P<0.05)。实时定量PCR和Western结果均显示CPR组HIF-1α基因及蛋白表达水平较假手术组增高(P<0.05)；与CPR组相比,CPR+NaHS组HIF-1蛋白表达水平增高(P<0.05)；与CPR组相比,CPR+AOAA组HIF-1αmRNA表达水平有降低趋势,但差异无统计学意义(P<0.05)。
[结论]电刺激法所致心脏骤停模型诱导心脏骤停表现类型多样,诱发心脏骤停的时间明显短于窒息法心脏骤停,可作为心脏骤停模型制备的首选。H2S可以减轻大鼠复苏后脑损伤,给予H2S抑制剂AOAA则加重脑损伤。其脑保护机制与减轻炎症反应、减轻凋亡、减轻氧化应激反应有关,并通过上调缺氧诱导因子发挥脑保护作用。
【Objective】1. To compare cardiac arrest induced by asphyxiation with cardiac arrest induced by transcutaneous electrical epicardium stimulation according to utstein style, and to find out a standardized animal cardiac arrest model which is consistant with clinical practice.2. To investigate the effects of hydrogen sulfide on the injury of brain injury induced by cardiac arrest.3. To investigate the effects of H2S on inflammatory reaction.4. To investigate the effects of H2S on apoptosis reaction.5. To investigate the effects of H2S on oxidative stress.6. To investigate whether the effects of H2S is associated with HIF-1.
[Methods] In Part 1, animals were randomly divided into two groups:one group received cardiac arrest induced by asphyxiation, the other group received cardiac arrest induced by transcutaneous electrical epicardium stimulation. Animals were randomly divided into four groups:sham group, cardiopulmonary resuscitation group (CPR group), CPR+NaHS group and CPR+AOAA group. Types of cardiac arrest were observed, and time of asphyxiation or electrical stimulation to cardiac arrest were recorded. In Part 2、Part 3、Part 4, animals were randomly divided into four groups:The rats of sham group were only anesthetized and intubated. CPR group、NaHS+CPR group and CPR+AOAA group received cardiac arrest by transcutaneous electrical epicardium stimulation. For CPR+NaHS group, NaHS (100ug/kg) was administrated via the femoral venous line 1 minute before CPR. For CPR+AOAA group, AOAA (20mg/kg) was administrated via the femoral venous line 1 minute before CPR. NDS value was scored and the morphological structures of brain were also observed. TNF-a and IL-1βwere detected by ELISA method; Bax and Bcl-2 expression were detected by PCR and immunohistochemical methods; MDA and SOD were determined; the expression of HIF-1 were also determined by real-time quantitative PCR and Western blot.
[Results] Cardiac arrest induced by transcutaneous electrical epicardium stimulation appeared VF, PEA, asytole. Cardiac arrest induced by asphyxiation appeared PEA, asytole. Time of asphyxiation to cardiac arrest was obviously longer than electrical stimulation to cardiac arrest(p＜0.05). Compared with sham group, the concentration of TNF-a were substantially elevated at 3h,6h,9h,12h(p<0.05), and it peaked 6h after CPR; Compared with CPR, the concentrations of TNF-a in CPR+NaHS were substantially decreased at 3h, 6h,9h,12h(p＜0.05), the concentrations of TNF-a in CPR+AOAA were substantially increased at 3h,6h(p＜0.05). Compared with sham group, the concentration of IL-1βwere substantially elevated at 3h,6h,9h,12h(p＜0.05), and it peaked 6h after CPR; Compared with CPR, the concentrations of IL-1βin CPR+NaHS were substantially decreased at 6h, 9h,12h(p＜0.05), the concentrations of TNF-a in CPR+AOAA were substantially increased at 3h,6h,9h(p＜0.05). Compared with sham group, the expression of Bax in CPR was increased(p＜0.05); Compared with CPR, the expression of Bax in CPR+NaHS group was decreased(p＜0.05); There were no obviously differences in CPR group and CPR+AOAA group. Compared with sham group, the expression of Bcl-2 in CPR was increased(p＞0.05); Compared with CPR, the expression of Bcl-2 in CPR+NaHS was obviously increased(p＜0.05); and the expression of Bcl-2 in CPR+AOAA was obviously decreased(p＜0.05). Compared with sham group, the ratio of Bax/Bcl-2 in CPR was increased(p＜0.05); Compared with CPR, the ratio of Bax/Bcl-2 in CPR+NaHS group was decreased(p＜0.05); and the ratio of Bax/Bcl-2 in CPR+AOAA group was increased(p＜0.05). Compared with sham group, the expression of SOD in CPR was decreased(p＜0.05); Compared with CPR, the expression of SOD in CPR+NaHS was obviously increased(p＜0.05); and the expression of SOD in CPR+AOAA was obviously decreased(p＜0.05). Compared with sham group, the expression of MDA in CPR was increased(p＜0.05); Compared with CPR, the expression of MDA in CPR+NaHS was obviously decreased(p＜0.05); and the expression of MDA in CPR+AOAA was obviously increased(p＜0.05). Compared with sham group, the expression of HIF-1 gene and protein was upregulated. Compared with CPR group, the expression of HIF-1 gene and protein in CPR+NaHS group was upregulated, and the expression of HIF-1 gene and protein in CPR+AOAA group has a lower trend(p＜0.05).
[Conclusion] The cardiac arrest model induced by transcutaneous electrical epicardium stimulation is more close to clinical practice, the standardization of model is superior to cardiac arrest induced by asphyxiation. Hydrogen sulfide can protect brain from injury, and administration of AOAA aggravated brain damage. The mechanism is associated with antiinflammation, relieving apoptosis, reducing oxidatie stress reaction relevant and upregualating HIF-1.
引文
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[16]Nagai Y, Tsugane M, Oka J, et al. Hydrogen sulfide induces calcium waves in astrocytes. FASEB J,2004,18:557-559.
[17]Kimura Y, Kimura H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J,2004,18:1165-1167.
[18]Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science,2005,308:518.
[19]Idris AH, Becker LB, Ornato JP, et al. Utstein-style guidelines for uniform reporting of laboratory CPR research. Resuscitation 1996,33(1):69-84.
[20]Song F, Shan Y, Cappello F, et al. Apoptosis is not involved in the mechanism of myocardial dysfunction after resuscitation in a rat model of cardiac arrest and cardiopulmonary resuscitation. Crit care med 2010;38(5):1329-34.
[21]Lin JY, Liao XX, Li H,et al. Model of cardiac arrest in rats by transcutaneous electrical epicardium stimulation. Resuscitation 2010;81(9):1197-204.
[22]Chen MH, Lu JY, Xie L, et al. What is the optimal dose of epinephrine during cardiopulmonary resuscitation in a rat model [J]. American Journal of Emergency Medicine 2010,28(3):284-290.
[23]Chen MH, Liu TW, Xie L,et al. Ventricular fibrillation induced by transoesophag-eal cardiac pacing:a new model of cardiac arrest in rats. Resuscitation 2007; 74(3): 546-51.
[24]Befnto AM, Cardoso LF, Timerman S, et al. Preliminary in hospital experience with a fully automatic external cardioverter defibrillator. Resuscitation,2004,63:11.
[25]Field JM, Hazinski MF, Sayre MR, et al. Part 1:executive summary:2010 American Heart Association Guidelines for cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010,122:S640-S656
[26]Singh N, Sharma G, Mishra V, et al. hypoxia inducible factor-1:its potential role in cerebral ischemia._Cell Mol Neurobiol.2012 Feb 2. [Epub ahead of print]
[27]Neumar RW, Bircher NG, Sim KM, et al. Epinephrine and sodium bicarbonate during CPR following asphyxial cardiac arrest in rats. Resuscitation,1995,29(3):249-63.
[28]Kimura Y, Kimura H:Hydrogen sulfide protects neurons from oxidative stress. FASEB J,2004,18:1165-1167.
[29]Blackstone E, Roth MB. Suspended animation-like state protects mice from lethal hypoxia. Shock,2007,27:370-2.
[30]Qu K, Chen CP, Halliwell B, et al.Hydrogen sulfide is a mediator of cerebral ischemic damage. Stroke 2006,37:889-893.
[31]Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. The J Neuroscience,1996,16(3):1066-1071.
[32]Frijns CJ, Kappelle LJ. Inflammatory cell adhesion molecules in ischemic cerebro-vascular disease. Stroke 2002;33:2115-2122.
[33]Barone FC, Arvin B, White RF, et al. Tumor necrosis factor-a:a mediator of focal ischemic brain injury.Stroke 1997;28:1233-1244.
[34]Castillo J, Davalos A, Alvarez-Sabin J, et al. Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 2002;58:624-629
[35]Bin X, Liu XW. Interleukin-1 changing in cerebral cortex and hippocampus after all brain ischemia reperfusion. Chin Clin Recov(Chin)2002:6:50-54.
[36]Allan SM, Parker LC, Collins B, et al. Cortical cell death induced bylL-1is mediated via actions in the hypothalamus of the rat. Proc Natl Acad Sci USA 2000;97:5580-5585.
[37]Scorrano L, Korsmeyer SJ. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members.Biochem Biophys Res Commun,2003,304(3):437-444.
[38]Budde MW, Roth MB. Hydrogen sulfide increases HIF-1 activity independent of VHL-1 in C.elegans [J]. Mol Biol Cell.2010,21(1):212-217.
[39]Fandrey J, Gassmann M. Oxygen sensing and the activation of the hypoxia inducible factor 1 (HIF-1) [J]. Adv Exp Med Biol.2009,648:197-206.
[40]Snyder CM, Chandel NS. Mitochondrial regulation of cell survival and death during low-oxygen conditions[J]. Antioxid Redox Signal,2009,11(11):2673-2683.
[41]Liu Y, Morgan JB, Coothankandaswamy V, et al. The Caulerpa Pigment Caulerpin Inhibits HIF-1 Activation and Mitochondrial Respiration. J Nat Prod.2009,72 (12): 2104-9.
[42]Yang XM, Wang YS, Zhang J, et al. Role of PI3K/Akt and MEK/ERK in mediating hypoxia-induced expression of HIF-1 alpha and VEGF in laser-induced rat choroidal neovascularization. Invest Ophthalmol Vis Sci.,2009,50(4):1873-9.
[43]Hu Y, Chen X, Pan TT, et al. Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways. Pflugers Arch 2008,455:607-616.
[1]Gunn B, Wong R, et al.Noxious gas exposure in the outback:two cases of hydrogen sukfide toxicity. Emerg Med 2001; 13(2):240-246.
[2]Guidotti TL. Hydrogen sulfide:advances in understanding human toxicity. Int J Toxicol 2010; 29(6):569-581.
[3]Calvert JW, Coetzee WA, Lefer DJ. Novel insights into hydrogen sulfide mediated cytoprotection. Antioxid Redox Signal 2010;12:1203-17.
[4]Nagao M, Linden DR, Duenes JA, et al. Mechanisms of action of the gasotransmitter hydrogen sulfide in modulating contractile activity of longitudinal muscle of rat ileum. J Gastrointest Surg 2011; 15(1):12-22.
[5]Liu WQ, Chai C, Li XY, et al. The cardiovascular effects of central hydrogen sulfide are related to K(ATP) channels activation. Physiol Res 2011; 60(5):729-738.
[6]Waqner CA. Hydrogen sulfide:a new gaseous signal molecule and blood pressure regulator. J Nephrol 2009; 22(2):173-176.
[7]Predmore BL, Julian D, Cardounel AJ, et al. Hydrogen sulfide increases nitric oxide production from endothelial cells by an akt-dependent mechanisms. Front Physiol, 2011; 2(12):104.
[8]Yang G, Wu L, Jiang B, et al. H2S as a physiologic vasorelaxant:hypertension in mice with deletion of cystathionine gammalyase. Science 2008; 322(5901):587-590.
[9]Koenitzer JR, Isbell TS,Patel HD,et al. Hydrogen sulfide mediates vasoactivity in an O2-dependent manner. Am J Physiol Heart Circ Physiol 2007;292:1953-60.
[10]Sojitra B, Bulani Y, Putcha UK, et al. Nitric oxide synthase inhibition abrogates hydrogen sulfide-induced acrdioprotection in mice. Mol Cell Biochem 2012; 360(1-2): 61-9.
[11]Qingyou Z, Junbao D, Weijin Z, et al. Impact of hydrogen sulfide on carbon monoxide/heme oxygenase pathway in the pathogenesis of hypoxic pulmonary hypertension. Biochem Biophys Res Commun 2004; 317(1):30-37.
[12]Xu YX, Wang YY, Jia XG, et al. The relationship between endogenous hydrogen sulfide system and pulmonary hypertension induced by hypoxic hypercapnia. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2011; 27(3):300-304.
[13]陈娣,潘昊,李醇文等.硫化氢在脓毒症大鼠心肌损伤中的作用.中华急诊医学杂志,2012,21(1)：48-53.
[14]Chad K, John W. Hydrogen sulfide and ischemia-reperfusion injury. Pharmacol Res 2010; 62(4):289-297.
[15]Dongo E, Hornyak I, Benko Z, et al. The cardioprotective potential of hydrogen sulfide in myocardial ischemia/reperfusion injury. Acta Physiol Hung 2011; 98(4): 369-381.
[16]Johansen D, Ytrehus K, Baxter GF. Exogenous hydrogen sulfide protects against regional myocardial I-R injury. Basic Res Cardiol 2006;101:53-60.
[17]Sivarajah A, Collino M, Yasin M, et al. Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R. Shock,2009,31(3): 267-274.
[18]Ji Y, Pang QF, Xu G, et al. Exogenous hydrogen sulfide postconditioning protects isolated rat hearts against ischemia-reperfusion injury. Eur J P harmacol 2008; 587(1-3):1-7.
[19]Elord JW,Calvert JW, Morrison J, et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA 2007; 104:15560-65.
[20]Szabo G, Veres G, Radovits T, et al. Cardioprotective effects of hydrogen sulfide. Nitric Oxide 2011; 25(2):201-210.
[21]Sodha NR, Clements RT, Feng J, et al. The effects of therapeutic sulfide on myocardial apoptosis in response to I-R injury. Eur J Cardiothorac Surg 2008; 33:906-913.
[22]Dieterich S, Bieligk U, Beulich K, et al. Gene expression of antioxidative enzymes in the human heart:increased expression of catalase in the end-stage failing heart. Circulation 2000; 101:33-39.
[23]Bliksoen M, Kaljusto ML, Vaage J, et al. Effects of hydrogen sulfide on ischaemia-reperfusion injury and ischaemic preconditioning in the isolated,perfused rat heart. Eur J Cardiothorac Surg 2008; 34:344-349.
[24]Yao X, Tan G, He C, et al. Hydrogen sulfide protects cardiomyocytes from myocardial ischemia-reperfusion injury by enhancing phosphorylation of apoptosis repressor with caspase recruitment domain. Tohoku J Exp Med 2012; 226(4):275-285.
[25]Ryazantseva NV, Novitsky VV, Starikova EG, et al. Role of hydrogen sulfide in the regulation of cell apoptosis. Bull Exp Biol Med 2011; 151(6):702-704.
[26]Kimura H, Nagai Y, Umemura K, et al. Physiological roles of hydrogen sulfide: synapic modulation, neuroprotection, and smmoth muscle relaxation. Antioxid. Redox Signal 2005; 7:795-803.
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[33]Mikami Y, Shibuya N, Kimura Y, et al. Hydrogen sulfide protects the retina from light-induced degeneration by the modulation of Ca2+influx. J Biol Chem 2011; 286(45):39379-86.
[34]Lee M, Schwab C, Yu S, et al. Astrocytes produce the anti-inflammatory and neuroprotective agent hydrogen sulfide. Neurobiol Aging2009; 30(10):1523-34.
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[43]Fu Z, Liu X, Geng B, et al. Hydrogen sulfide protects rat lung from ischemia-reperfusion injury. Life Sci 2008;82:1 196-1202,
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[46]潘昊,陈娣,兰秀彩,杨光田.硫化氢在脓毒症大鼠肠粘膜损伤中的作用.感染、炎症、修复,2010,11(4)：195-199.
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[54]Xu Z, Prathapasinghe G, Wu N, et al. Ischemia-reperfusion reduces cystathionine-beta-synthase-mediated hydrogen sulfide generation in the kidney. Am J Physiol Renal Physiol 2009; 297:F27-35.
[55]Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation like state in mice. Science 2005; 308:518.
[56]Volpato GP, et al. Cardiovascular response to breathing hydrogen sulfide in a murine model:separating the effects of body temperature. Aps Intersociety Meeting web set.
[57]Blackstone E, Roth MB. Suspended animation-like state protects mice from lethal hypoxia. Shock 2007; 27:370-2.
[58]Volpato GP, Searles R, Yu B, Scherrer-Crosbie M, Bloch KD, Ichinose F, Zapol WM. Inhaled hydrogen sulfide:a rapidly reversible inhibitor of cardiac and metabolic function in the mouse. Anesthesiology 2008;108:659-68.
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[2]Neumar RW, Nolan JP, Adrie C, et al. Post-cardiac arrest syndrome:epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the international liaison committee on resuscitation.Circulation,2008,118(23):2452-2483.
[3]Laver S, Farrow C, Turner D, et al. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med,2004,30:2126-2128.
[4]Mongardon, N. et al. Postcardiac arrest syndrome:from immediate resuscitation to long term outcome. Annals of Intensive Care,2011.1(1):45-56.
[5]Johansen D, Ytrehus K, Baxter GF. Exogenous hydrogen sulfide(H2S) protects against reginal myocardial ischemia-reperfusion injury-evidence for a role of KATP channel, Basic Res Cardiol,2006,101(1):53-60.
[6]Ji Y, Pang QF, Xu G, et al. Exogenous hydrogen sulfide postconditioning protects isolated rat hearts against ischemia-reperfusion injury. Eur J Pharmacol,2008,587(1-3): 1-7.
[7]Elord JW, Calvert JW, Morrison J, et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA.2007,104(39):15560-15565.
[8]Jha S, Calvert JW, Duranski MR, et al. Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury:Role of antioxidant and antiapoptotic aignaling. Am J Physiol Heart Circ Physiol.2008,295(2):H801-806.
[9]Fu Z, Liu X, Geng B, et al. Hydrogen sulfide protects rat lung from ischemia-reperfusion injury. Life Sci,2008,82(23-24):1196-1202.
[10]Xu Z, Prathapasinghe G, Wu N, et al. Ischemia-reperfusion reduces cystathionine-β-synthase-mediated hydrogen sulfide generation in the kidney. Am J Physiol Renal Physiol,2009,297:F27-35.
[11]Kimura H. Hydrogen sulfide induces cyclic AMP and modulates the NMD A receptor. Biochem Biophys Res Commun,2000,267:129-33.
[12]Dello Russo C, Tringali G, Ragazzoni E, et al. Evidence that hydrogen sulfide can modulate hypothalamo-pituitary-adrenal axis function:in vitro and in vivo studies in the rat. J Neuroendocrinol,2000,12:225-233.
[13]Eto K, Asada T, Arima K, et al. Brain hydrogen sulfide is severely decreased in Alzheimer's disease. Biochem Biophys Res Commun,2002,293:1485-1488.
[14]Kamoun P, Belardinelli MC, Chabli A, et al. Endogenous hydrogen sulfide overproduction in Down syndrome. Am J Med Genet A,2003,116:310-311.
[15]Qu K, Chen CP, Halliwell B, et al. Hydrogen sulfide is a mediator of cerebral ischemic damage. Stroke,2006,37:889-93.
[16]Nagai Y, Tsugane M, Oka J, et al. Hydrogen sulfide induces calcium waves in astrocytes. FASEB J,2004,18:557-559.
[17]Kimura Y, Kimura H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J,2004,18:1165-1167.
[18]Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science,2005,308:518.
[19]Idris AH, Becker LB, Ornato JP, et al. Utstein-style guidelines for uniform reporting of laboratory CPR research. Resuscitation 1996,33(1):69-84.
[20]Song F, Shan Y, Cappello F, et al. Apoptosis is not involved in the mechanism of myocardial dysfunction after resuscitation in a rat model of cardiac arrest and cardiopulmonary resuscitation. Crit care med 2010;38(5):1329-34.
[21]Lin JY, Liao XX, Li H,et al. Model of cardiac arrest in rats by transcutaneous electrical epicardium stimulation. Resuscitation 2010;81(9):1197-204.
[22]Chen MH, Lu JY, Xie L, et al. What is the optimal dose of epinephrine during cardiopulmonary resuscitation in a rat model [J]. American Journal of Emergency Medicine 2010,28(3):284-290.
[23]Chen MH, Liu TW, Xie L,et al. Ventricular fibrillation induced by transoesophag-eal cardiac pacing:a new model of cardiac arrest in rats. Resuscitation 2007; 74(3): 546-51.
[24]Befnto AM, Cardoso LF, Timerman S, et al. Preliminary in hospital experience with a fully automatic external cardioverter defibrillator. Resuscitation,2004,63:11.
[25]Field JM, Hazinski MF, Sayre MR, et al. Part 1:executive summary:2010 American Heart Association Guidelines for cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010,122:S640-S656
[26]Singh N, Sharma G, Mishra V, et al. hypoxia inducible factor-1:its potential role in cerebral ischemia._Cell Mol Neurobiol.2012 Feb 2. [Epub ahead of print]
[27]Neumar RW, Bircher NG, Sim KM, et al. Epinephrine and sodium bicarbonate during CPR following asphyxial cardiac arrest in rats. Resuscitation,1995,29(3):249-63.
[28]Kimura Y, Kimura H:Hydrogen sulfide protects neurons from oxidative stress. FASEB J,2004,18:1165-1167.
[29]Blackstone E, Roth MB. Suspended animation-like state protects mice from lethal hypoxia. Shock,2007,27:370-2.
[30]Qu K, Chen CP, Halliwell B, et al.Hydrogen sulfide is a mediator of cerebral ischemic damage. Stroke 2006,37:889-893.
[31]Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. The J Neuroscience,1996,16(3):1066-1071.
[32]Frijns CJ, Kappelle LJ. Inflammatory cell adhesion molecules in ischemic cerebro-vascular disease. Stroke 2002;33:2115-2122.
[33]Barone FC, Arvin B, White RF, et al. Tumor necrosis factor-a:a mediator of focal ischemic brain injury.Stroke 1997;28:1233-1244.
[34]Castillo J, Davalos A, Alvarez-Sabin J, et al. Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 2002;58:624-629
[35]Bin X, Liu XW. Interleukin-1 changing in cerebral cortex and hippocampus after all brain ischemia reperfusion. Chin Clin Recov(Chin)2002:6:50-54.
[36]Allan SM, Parker LC, Collins B, et al. Cortical cell death induced bylL-1is mediated via actions in the hypothalamus of the rat. Proc Natl Acad Sci USA 2000;97:5580-5585.
[37]Scorrano L, Korsmeyer SJ. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members.Biochem Biophys Res Commun,2003,304(3):437-444.
[38]Budde MW, Roth MB. Hydrogen sulfide increases HIF-1 activity independent of VHL-1 in C.elegans [J]. Mol Biol Cell.2010,21(1):212-217.
[39]Fandrey J, Gassmann M. Oxygen sensing and the activation of the hypoxia inducible factor 1 (HIF-1) [J]. Adv Exp Med Biol.2009,648:197-206.
[40]Snyder CM, Chandel NS. Mitochondrial regulation of cell survival and death during low-oxygen conditions[J]. Antioxid Redox Signal,2009,11(11):2673-2683.
[41]Liu Y, Morgan JB, Coothankandaswamy V, et al. The Caulerpa Pigment Caulerpin Inhibits HIF-1 Activation and Mitochondrial Respiration. J Nat Prod.2009,72 (12): 2104-9.
[42]Yang XM, Wang YS, Zhang J, et al. Role of PI3K/Akt and MEK/ERK in mediating hypoxia-induced expression of HIF-1 alpha and VEGF in laser-induced rat choroidal neovascularization. Invest Ophthalmol Vis Sci.,2009,50(4):1873-9.
[43]Hu Y, Chen X, Pan TT, et al. Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways. Pflugers Arch 2008,455:607-616.
[1]Gunn B, Wong R, et al.Noxious gas exposure in the outback:two cases of hydrogen sukfide toxicity. Emerg Med 2001; 13(2):240-246.
[2]Guidotti TL. Hydrogen sulfide:advances in understanding human toxicity. Int J Toxicol 2010; 29(6):569-581.
[3]Calvert JW, Coetzee WA, Lefer DJ. Novel insights into hydrogen sulfide mediated cytoprotection. Antioxid Redox Signal 2010;12:1203-17.
[4]Nagao M, Linden DR, Duenes JA, et al. Mechanisms of action of the gasotransmitter hydrogen sulfide in modulating contractile activity of longitudinal muscle of rat ileum. J Gastrointest Surg 2011; 15(1):12-22.
[5]Liu WQ, Chai C, Li XY, et al. The cardiovascular effects of central hydrogen sulfide are related to K(ATP) channels activation. Physiol Res 2011; 60(5):729-738.
[6]Waqner CA. Hydrogen sulfide:a new gaseous signal molecule and blood pressure regulator. J Nephrol 2009; 22(2):173-176.
[7]Predmore BL, Julian D, Cardounel AJ, et al. Hydrogen sulfide increases nitric oxide production from endothelial cells by an akt-dependent mechanisms. Front Physiol, 2011; 2(12):104.
[8]Yang G, Wu L, Jiang B, et al. H2S as a physiologic vasorelaxant:hypertension in mice with deletion of cystathionine gammalyase. Science 2008; 322(5901):587-590.
[9]Koenitzer JR, Isbell TS,Patel HD,et al. Hydrogen sulfide mediates vasoactivity in an O2-dependent manner. Am J Physiol Heart Circ Physiol 2007;292:1953-60.
[10]Sojitra B, Bulani Y, Putcha UK, et al. Nitric oxide synthase inhibition abrogates hydrogen sulfide-induced acrdioprotection in mice. Mol Cell Biochem 2012; 360(1-2): 61-9.
[11]Qingyou Z, Junbao D, Weijin Z, et al. Impact of hydrogen sulfide on carbon monoxide/heme oxygenase pathway in the pathogenesis of hypoxic pulmonary hypertension. Biochem Biophys Res Commun 2004; 317(1):30-37.
[12]Xu YX, Wang YY, Jia XG, et al. The relationship between endogenous hydrogen sulfide system and pulmonary hypertension induced by hypoxic hypercapnia. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2011; 27(3):300-304.
[13]陈娣,潘昊,李醇文等.硫化氢在脓毒症大鼠心肌损伤中的作用.中华急诊医学杂志,2012,21(1)：48-53.
[14]Chad K, John W. Hydrogen sulfide and ischemia-reperfusion injury. Pharmacol Res 2010; 62(4):289-297.
[15]Dongo E, Hornyak I, Benko Z, et al. The cardioprotective potential of hydrogen sulfide in myocardial ischemia/reperfusion injury. Acta Physiol Hung 2011; 98(4): 369-381.
[16]Johansen D, Ytrehus K, Baxter GF. Exogenous hydrogen sulfide protects against regional myocardial I-R injury. Basic Res Cardiol 2006;101:53-60.
[17]Sivarajah A, Collino M, Yasin M, et al. Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R. Shock,2009,31(3): 267-274.
[18]Ji Y, Pang QF, Xu G, et al. Exogenous hydrogen sulfide postconditioning protects isolated rat hearts against ischemia-reperfusion injury. Eur J P harmacol 2008; 587(1-3):1-7.
[19]Elord JW,Calvert JW, Morrison J, et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA 2007; 104:15560-65.
[20]Szabo G, Veres G, Radovits T, et al. Cardioprotective effects of hydrogen sulfide. Nitric Oxide 2011; 25(2):201-210.
[21]Sodha NR, Clements RT, Feng J, et al. The effects of therapeutic sulfide on myocardial apoptosis in response to I-R injury. Eur J Cardiothorac Surg 2008; 33:906-913.
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