远隔缺血处理在心肌保护中的研究进展

背景 在心血管手术围术期,远隔缺血处理作为一种无创性,启动机体自身内源性心肌保护的方法已被外科医师接受.然而,在临床非急性器官缺血时,由于受到时间,伦理上的约束,该处理很难开展. 目的 就远隔缺血处理的心肌保护作用作一综述. 内容 远隔缺血处理的发现、发展过程、临床应用及作用机制. 趋向 远隔缺血处理在溶栓治疗、血管成形和心脏外科手术等领域将有巨大的应用潜力.     

远隔后处理心肌保护的基础研究和临床应用转化

背景 在远离靶器官的组织(如肢体)实施后处理产生保护性信号(即远隔后处理)是提供内源性组织保护的一种措施.目的 综述远隔后处理的心肌保护效应、作用机制和临床应用转化现状.内容 在包括鼠、兔和猪在内的多个种属动物实验研究中,远隔后处理能够明显减轻心肌缺血/再灌注(ischemia/reperfusion,I/R)损伤、组织坏死和细胞凋亡.与远隔预处理一样,远隔后处理需要通过体液或神经信号转导通路传递或交流保护性因子或信号.靶器官保护机制的触发子包括G蛋白耦联受体配体、缺血代谢物和小分子热敏物质.有关远隔后处理改善临床结果或生物标记的临床研究结果令人鼓舞.趋向 与经典缺血预处理和后处理不同,有关远隔后处理心肌保护作用生理或分子机制的研究目前仍显不足.如果进一步的临床研究证实远隔后处理可改善患者的转归,其实践价值将是巨大的.     

肢体远隔缺血预处理对肝脏缺血/再灌注损伤保护作用的研究进展

背景 肝脏缺血/再灌注损伤(ischemic/reperfusion injury,I/RI)是影响临床肝脏手术和肝脏移植手术术后发病率和病死率的主要因素,肢体远隔缺血预处理(limb remote ischemic preconditioning,LRIPC)可以减轻肝脏I/RI.目的 综述LRIPC对肝脏I/RI保护作用的研究进展.内容 LRIPC的发展、保护作用的机制、保护作用的时相及LRIPC的建模方法.趋向 LRIPC应用于临床防治肝脏I/RI不失为一种可取的方案.     

远端组织缺血预处理对心脑保护作用的研究进展

缺血/冉灌注(ischemia reperfusion,I/R)损伤可导致局部和/或远端组织器官的损伤;缺血预处理(ischemic preconditioning,IPC)是对I/R损伤的一种有效处理方式;远端预处理(remote preconditioning,RPC)是继IPC后一种新兴的,更简单又经济的,高效的保护组织器官免受缺血损伤的策略,其机制涉及神经和/或体液两大因素的调节作用,在临床上已有试用.     

肝脏缺血预处理实验研究与临床进展

以往人们认为，反复短暂的组织器官缺血会产生累加性损伤，最终导致组织坏死，器官功能衰竭。然而近来研究表明，短暂缺血不仅不会造成高能磷酸储备的减少，而且能启动内源性保护机制，减轻随后而来的较长时间的缺血损害。1986年Murry发现并提出了人为地进行缺血干预可增加心肌耐受缺血的能力，称之为缺血“预处理”(ischemic preconditioning，IPC)。     

远端组织缺血预处理对心脑保护作用的研究进展

缺血/冉灌注(ischemia reperfusion,I/R)损伤可导致局部和/或远端组织器官的损伤;缺血预处理(ischemic preconditioning,IPC)是对I/R损伤的一种有效处理方式;远端预处理(remote preconditioning,RPC)是继IPC后一种新兴的,更简单又经济的,高效的保护组织器官免受缺血损伤的策略,其机制涉及神经和/或体液两大因素的调节作用,在临床上已有试用.     

远端组织缺血预处理对心脑保护作用的研究进展

缺血/冉灌注(ischemia reperfusion,I/R)损伤可导致局部和/或远端组织器官的损伤;缺血预处理(ischemic preconditioning,IPC)是对I/R损伤的一种有效处理方式;远端预处理(remote preconditioning,RPC)是继IPC后一种新兴的,更简单又经济的,高效的保护组织器官免受缺血损伤的策略,其机制涉及神经和/或体液两大因素的调节作用,在临床上已有试用.     

肢体缺血预适应的远程脏器保护作用

肢体和内脏等严重的缺血再灌注（IR）损伤可引起全身炎性反应（SIRS）并伤及远隔器官,但短时间IR却有缺血预适应（ischemia preconditioning,IPC）作用,能提高脏器的缺氧耐受。近年来动物实验中不同脏器间的远程预适应现象（remote preconditioning,RPC）日益受到关注,如肠缺血的心肌保护、肝缺血的肾保护作用等。     

阿片类药物减轻急性缺血/再灌注损伤及相关机制

背景 缺血预处理对于器官缺血/再灌注损伤（ischemia/reperfusion injury,I/RI）具有强大的保护作用,但其临床应用受到时机以及伦理学的限制.近年来有研究发现阿片类药物预处理以及后处理对组织器官I/RI同样具有保护作用,其既不损伤器官又能产生与缺血预处理相同的效果,是更为可行的治疗措施. 目的 在将阿片类药物处理推广至临床应用前,仍需进行更多大规模的临床研究.拟就阿片类处理减轻I/RI的发展过程及其作用机制进行探讨. 内容 阿片类药物处理I/RI的几种方式及其机制. 趋向 阿片类药物处理比较其他损伤性处理方式更易操作,且对I/RI同样具有保护作用,有望成为日后治疗的热点之一.     

远隔缺血处理内源性心肌保护介质的研究进展

背景 作为远隔缺血处理(remote ischemic conditioning,RIPC)心肌保护最重要的效应因子,内源性介质已引起越来越多研究者的关注.目的 综述RIPC心肌保护作用介质的相关研究.内容 动物实验研究证实RIPC后收集动物的血液或冠脉流出液亦可对其他动物的心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)发挥明显的保护作用,但其机制尚未完全阐明.通过归纳目前的动物研究,作者从内源性保护介质的提出、成份鉴定及特性、细胞内信号机制进行系统描述.同时,概括来自人类的一些相关证据.趋势 需要进一步研究来明确内源性介质的主要效应成份,为心肌保护药物开发提供新的思路.     

MicroRNA-1和microRNA-21在缺血预处理、后处理及远端预处理中的表达变化

目的 通过离体缺血-再灌注心脏模型,观察缺血预处理(IPC)、缺血后处理(IPO)和肢体远端预处理(RIPC)后心脏microRNA1(miRNA-1)和microRNA21 (miRNA-21)的表达变化,以及它们所调控靶蛋白热休克蛋白70 (HSP70)和程序性细胞死亡4(PDCD4)表达变化,期望从miRNA调控水平揭示心脏的内源性保护机制.方法 取Sprague-Dawley (SD)大鼠心脏,建立离体Langendorff心肌缺血-再灌注模型,随机分为4组(每组12只),对照组、IPC组、IPO组和RIPC组.检测各组血流动力学指标,蛋白印迹法(Western blotting)检测PpDCD4、HSP70、B细胞淋巴瘤/白血病-2(Bc1-2)和Bc1-2相关X蛋白(Bax)含量,taqman探针法检测miRNA-1和miRNA-21含量,末端脱氧核苷酸转移酶介导的原位缺口标记法(TUNEL)检测心肌细胞凋亡,2,3,5-氯化三苯基四氮唑(TTC)法检测心肌梗死面积. 结果 IPC组心肌的miRNA-1和miRNA-21表达明显高于对照组,但RIPC组和IPO组心肌的miRNA-1表达较对照组明显降低( P＜0.05).IPC组、RIPC组和IPO组心肌中HSP70、PDCD4和Bax蛋白含量较对照组明显减少(P＜ 0.05),Bc1-2蛋白含量各组间差异无统计学意义.IPC组、RIPC组和IPO组左室心肌梗死面积/左室总面积以及心肌细胞凋亡率明显低于对照组(P＜ 0.05). 结论 miRNA-1和miRNA-21在缺血预处理、缺血后处理和远端预处理后,表达变化是不同的,同时各处理组中miRNA与其靶蛋白并不都是负性调节关系.     

远隔缺血预处理对肺损伤患者预后的临床研究Meta分析

目的 系统性评价远隔缺血预处理(remote ischemic preconditioning,RIPC)对各种原因导致的肺损伤的影响.方法 通过检索PubMed、Embase、Medline、中国知网(CNKI)、维普中文期刊全文数据库、中国生物医学文献数据库、中国生物医学期刊引文数据库,根据纳入标准和排除标准,检索出相关随机对照临床研究文献,并提取主要评估指标(ICU停留时间及机械通气时间)和次要评估指标[术后24 h血清IL-6、TNF-α、IL-8浓度及肺泡动脉氧分压差(alveolar-arterial oxygen tension gradient,A-aDO2)、氧合指数(oxgension index,PaO2/FiO2)、呼吸指数(respiratory index,RI)],采用RevMan5.3和STATA 12.0软件进行Meta分析. 结果 共纳入前瞻性随机对照研究8篇,476例患者,其中RIPC组237例,对照组239例.与对照组相比,RIPC可以减少患者术后ICU停留时间及机械通气时间,并降低术后24 h血清TNF-α浓度(P＜0.05),其标准均数差(standard mean difference,SMD)和95％CI分别为-0.03(-0.41,-0.05)、-0.2(-0.39,-0.01)、-0.85(-1.35,0.34). 结论 RIPC可以减少患者术后ICU停留时间和机械通气时间,改善肺损伤患者的临床预后.     

Exploring effects of remote ischemic preconditioning in a pig model of hypothermic circulatory arrest

Objectives. During aortic and cardiac surgery, risks for mortality and morbidity are inevitable. Surgical setups involving deep hypothermic circulatory arrest (DHCA) are effective to achieve organ protection against ischemic injury. The aim of this study was to identify humoural factors mediating additive protective effects of remote ischemic preconditioning (RIPC) in a porcine model of DHCA. Design. Twenty-two pigs were randomized into the RIPC group (n?=?11) and the control group (n?=?11). The RIPC group underwent four 5-minute hind limb ischemia-reperfusion cycles prior to cardiopulmonary bypass and DHCA. All animals underwent identical surgical procedures including 60?min DHCA at 18?°C. Blood samples were collected from vena cava and sagittal sinus at several time points. After the 8-hour follow-up period, the brain, heart, and kidney tissue samples were collected for tissue analyses. Results. Serum levels of brain damage marker S100B recovered faster in the RIPC group, after 4?hours of the arrest, (p?Conclusions. The faster recovery of S100B, lower systemic lactate levels and favourable regional antioxidant response suggest possible neuronal cellular and mitochondrial protection by RIPC, whereas better cardiac index underlines functional effects of RIPC. The exact humoural factor remains unclear.     

远隔缺血预处理对老年小鼠神经认知功能及小胶质细胞和突触后致密蛋白95的影响

目的探讨远隔缺血预处理(RIPre)对老年小鼠神经认知功能及小胶质细胞和突触后致密蛋白95(PSD95)的影响。方法采用异氟醚麻醉+腹腔探查术建立围术期神经认知障碍(PND)模型。15月龄老年雄性C57BL/6小鼠,随机分为四组:对照组(C组)、缺血预处理组(RIPre组)、手术麻醉组(S组)和手术麻醉+缺血预处理组(S+RIPre组)。RIPre组和S+RIPre组于PND模型建立前行远隔缺血-再灌注,小鼠后肢血流阻断5 min后血液复流5 min,共重复缺血-复灌3次。术后第3天行旷场实验,第4、5天分别行条件性恐惧实验训练和测试。每组另外取6只小鼠于术后取海马组织,采用Western blot法检测术后第3天海马离子钙结合适配器分子1(Iba1)和PSD95蛋白含量,ELISA法检测术后第3天海马IL-6浓度。结果与C组比较,S组中央区域停留时间明显减少,僵直反应百分比明显降低,术后第3天海马IL-6浓度明显升高,PSD95蛋白含量明显降低,Iba1蛋白含量明显升高(P0.05)。与S组比较,S+RIPre组中央区域停留时间明显延长,僵直反应百分比明显增加,术后第3天海马IL-6浓度明显降低,PSD95蛋白含量明显升高,Iba1蛋白含量明显降低(P0.05)。结论 RIPre可减轻异氟醚麻醉手术诱发的老龄小鼠神经认知功能障碍,其作用机制可能是RIPre抑制小胶质细胞过度激活,从而减轻对突触可塑性的损伤,并减弱海马神经炎症反应。     

Two episodes of remote ischemia preconditioning improve motor and sensory function of hind limbs after spinal cord ischemic injury

Objectives: To investigate the effect of one and two remote ischemia preconditioning episodes (1-RIPC or 2-RIPC, respectively) on neuro-protection after spinal cord ischemic injury (SCI) in rats.Design: Experimental animal study.Setting: College of Medicine, King Khalid University, Abha, KSA.Interventions: Male rats (n = 10/group) were divided into control, sham, SCIRI, 1-RIPC + SCIRI, and 2-RIPC + SCIRI. SCI was induced by aortic ligation for 45 min and each RIPC episode was induced by 3 cycles of 10 min ischemia/10 min perfusion. The two preconditioning procedures were separated by 24 h.Outcome measures: after 48 h of RIPC procedure, Tarlov’s test, withdrawal from the painful stimulus and placing/stepping reflex (SPR) were used to evaluate the hind limbs neurological function. SC homogenates were used to measure various biochemical parameters.Results: Motor and sensory function of hind limbs were significantly improved and levels of MDA, AOPPs, PGE2, TNF-α, and IL-6, as well as the activity of SOD, was significantly decreased in SC tissue in either 1 or 2 episodes of RIPC intervention. Concomitantly, levels of total nitrate/nitrite and eNOS activity were significantly increased in both groups. Interestingly, except for activity of SOD, eNOS and levels of nitrate/nitrite, the improvements in all neurological biochemical endpoint were more profound in 2-RIPC + SCIRI compared with 1-RIPC + SCIRI.Conclusion: applying two preconditioning episodes of 3 cycles of 10 min ischemia/10 min perfusion, separated by 24 h, boost the neuro-protection effect of RIPC maneuver in rats after ischemic induced SCI in rats.     

Review of remote ischemic preconditioning: from laboratory studies to clinical trials

Abstract

In remote ischemic preconditioning (RIPC) short periods of non-lethal ischemia followed by reperfusion of tissue or organ prepare remote tissue or organ to resist a subsequent more severe ischemia-reperfusion injury. The signaling mechanism of RIPC can be humoral communication, neuronal stimulation, systemic modification of circulating immune cells, and activation of hypoxia inducible genes. Despite promising evidence from experimental studies, the clinical effects of RIPC have been controversial. Heterogeneity of inclusion and exclusion criteria and confounding factors such as comedication, anesthesia, comorbidities, and other risk factors may have influenced the efficacy of RIPC. Although the cardioprotective pathways of RIPC are more widely studied, there is also evidence of benefits in CNS, kidney and liver protection. Future research should explore the potential of RIPC, not only in cardiac protection, but also in patients with threatening ischemia of the brain, organ transplantation of the heart, liver and kidney and extensive cardiovascular surgery. RIPC is generally well-tolerated, safe, effective, and easily feasible. It has a great prospect for ischemic protection of the heart and other organs.     

肢体远隔缺血预处理对心肺转流心脏瓣膜置换术患者肺功能的影响

目的评价肢体远隔缺血预处理(remote ischemic preconditioning,RIPC)对心肺转流(cardiopulmonary bypass,CPB)心脏瓣膜置换术患者肺功能的影响。方法择期在CPB下行心脏瓣膜置换术患者70例,男32例,女38例,年龄18~70岁,体重45~90 kg,ASAⅡ或Ⅲ级,采用随机数字表法将患者分为两组,每组35例。R组于气管插管后10 min采用测压袖带在患者右上肢上臂,给予3个循环的5 min缺血(袖带充气,压力≥200 mm Hg)及5 min再灌注(袖带放气至0 mm Hg)处理。C组将袖带绑于患者右上肢,但不进行充气及放气操作。分别于气管插管后10 min(T_0)、主动脉开放后1 h(T_1)、术后6 h(T_2)、12 h(T_3)、24 h(T_4)采集桡动脉血样,进行血气分析,计算氧合指数(PaO_2/FiO_2)和肺泡动脉血氧分压差(A-aDO_2),肺动态顺应性(Cd)和肺静态顺应性(Cs)。记录出院时肺部不良事件情况。结果与T0时比较,T_1~T_4时两组PaO_2/FiO_2明显降低,T_2~T_4时A-aDO_2明显降低,T_3时C组Cs、Cd明显升高,T_2、T_3时R组Cs、Cd明显升高(P0.05)。与C组比较,T_2、T_3时R组Cs、Cd明显提高,T0~T4时PaO_2/FiO_2、A-aDO_2两组差异无统计学意义。与C组比较,R组肺部不良事件发生率明显降低(P0.05)。结论肢体远隔缺血预处理能够改善心脏瓣膜置换术患者的肺顺应性,减少术后肺部不良事件的发生。     

Modulation of Remote Ischemic Preconditioning by Proinflammatory Cytokines in Renal Transplant Recipients

Aim: Remote ischemic preconditioning (RIPC) has been used as a strategy to reduce acute renal injury and ischemia-reperfusion injury (IRI) in renal transplantation (RT) with controversial results. Objective: To determine if RIPC modifies IRI in cadaveric RT recipients through inflammatory mediators and graft function. Methods: Twenty-nine RT recipients were studied, 12 in the control group (CG) and 17 in the RIPC group. RIPC which was performed on donors using a pneumatic tourniquet placed on both thighs for 10 min followed by the determination of IL-1, IL-6, TNF-α, VEGF, and ICAM-1, and hematological and biochemical parameters in different phases of RT. Results: Serum creatinine levels were significantly lower in the RIPC group versus the CG at 15 and 30 days; however, the estimated glomerular filtration rate (eGFR) showed no significant difference in any phase between either group, only TNF-α showed significantly higher values in the RIPC group versus the CG in almost all phases of the study, meanwhile IL6 was increased at 72 hours (hr) and 30 days, IL1 at 72 hr and 15 days and ICAM-1 post reperfusion, contrary to this VEGF showed a decrease at 7 and 15 days. Conclusion: RIPC did not improve eGFR or serum creatinine; however, it modifies the inflammatory response in RT recipients.     

Ischemic Preconditioning to Prevent Lethal Ischemic Spinal Cord Injury in a Swine Model

Objective: Paraplegia is a serious complication of thoracic and thoracoabdominal aortic operations and is the result of ischemic spinal cord injury induced by low perfusion pressure during cross-clamping of the aorta. Ischemic preconditioning (IPC) of the heart or brain with reversible sublethal ischemic injury induces resistance to subsequent lethal ischemia. The aim of this study is to investigate whether ischemic tolerance can be induced by IPC of the spinal cord in a swine model. Study Design: The animals were randomly divided into three groups: the sham group (n = 3), control group (n = 6) and IPC group (n = 8). In the sham group, we performed a left thoracotomy without any ischemic injury. In the IPC group, the swine received a reversible ischemic spinal cord injury by aortic clamping for 20 min, whereas in the control group, no aortic cross-clamping was performed. Forty-eight hours later, the animals in both the IPC and control groups underwent aortic clamping for 30 min. Neurological examination was done 24 h later, and then the animals were euthanized for histopathology and a malonedialdehyde spectrophotometry assay of the spinal cord tissue. Results: A statistically significant difference in neurological outcome was observed between the control and IPC groups at 24 h after ischemic injury. The incidence of paraplegia and severe paresis was 100% in the control group and 62.5% in the IPC group (p =. 028). Between control and IPC groups, there was no statistically significant difference in histopathology and only a borderline statistical difference in the malonedialdehyde assay of the ischemic spinal cord (p =. 0745). Conclusion: In this study, IPC induced protection against a 30-min ischemic insult of the spinal cord, although complete recovery was not achieved (standing up or walking). We expect that combining this IPC with other existing protective methods might lead to a synergistic effect, which warrants further investigation.