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.     

Is remote preconditioning as effective as direct ischemic preconditioning in preventing spinal cord ischemic injury?

BACKGROUND: Spinal cord injury remains a devastating complication of thoracic and thoracoabdominal aortic operations. The aim of this study was to assess the affectivity of direct ischemic preconditioning (PC) and remote PC in preventing spinal cord ischemic injury in an experimental model. MATERIALS AND METHODS: Thirty-eight New Zealand white rabbits were divided into five groups: One group served as Sham group (n = 7). Rabbits in other groups had their abdominal aorta cross-clamped for 40 min. Before aortic occlusion, aorta was clamped twice at the same site of aortic occlusion for 5 min followed by 15 min of reperfusion after each ischemic episode in one group (Direct PC, n = 8), left renal artery was clamped twice for 5 min followed by 15 min of reperfusion after each renal ischemic episode in one group (Remote PC, n = 8), left renal artery was first clamped for 5 min followed by 15 min of reperfusion and then aorta was clamped for 5 min followed by 15 min of reperfusion in one group (Remote + Direct PC, n = 8), and no PC method was used in Control group (n = 7). RESULTS: In all PC groups, neurological status of rabbits (Tarlov score) at post-ischemia 24th and 48th hours was better than the control group (P < 0.05), but worse than Sham group (P < 0.05). Mean viability index values in PC groups were higher than control group (P < 0.01). Post-ischemia serum NSE and MDA levels obtained in all three PC groups were significantly lower than control group (P < 0.05 and P < 0.01). CONCLUSIONS: The use of direct ischemic PC and/or remote PC is an effective way of reducing spinal cord ischemic injury because of aortic occlusion, while direct PC is more effective. The combined use of direct PC and remote PC did not provide better protection.     

吗啡预处理对缺血性心肌保护作用的研究进展

实验研究证实吗啡可以模拟缺血预处理.近年来吗啡预处理的心肌保护作用在在体、离体和心肌细胞3种动物模型都得到实验证实,其保护作用分为两个时相:即时相和延迟相.吗啡预处理的心肌保护作用主要由阿片受体介导,与线粒体KATP通道、诱导型NO合酶和环氧化酶等有关.将来在研究其分子机制的同时也会加强对其临床应用的研究.     

Is Remote Ischemic Conditioning of Benefit to Patients Undergoing Kidney Transplantation?

Renal ischemia-reperfusion injury (IRI), an inevitable event during kidney transplantation procedure, can result in delayed graft function or even primary nonfunction. In addition to strategies to limit IRI such as advancements in organ allocation systems and preservation of organs, and reduction in cold and warm ischemia time, remote ischemic conditioning (RIC) has attracted much attention in recent years. With promising findings and data suggesting a potential benefit of RIC in animal kidney transplantation models, a few clinical trials have investigated the use of RIC in human kidney transplantation. Unfortunately, the findings from these investigations have been inconclusive due to a number of factors such as diverse time points of RIC, limited sample size, and complexity of kidney transplant patients. This brief commentary aims to discuss the effects of RIC on clinical outcomes and proinflammatory cytokines in patients undergoing kidney transplantation.     

远隔处理——来自心脏之外的内源性心肌保护作用

背景 虽然缺血预处理(ischemia preconditioning,IPC)仍然是目前已知的最强大内源性心肌保护措施,但是各种原因其临床应用受到了限制.远隔于心脏之外的其他器官或组织经历短暂缺血后可使心肌对后继的长时间缺血更加耐受,即远隔缺血预处理(remote ischemic preconditioning,RIPC)的心肌保护作用.目前的研究已经将远隔处理的保护作用从单一的心肌保护领域扩展到了对全身众多器官或组织的保护作用中.在将远隔处理推荐作为临床工作的常规措施之前,仍需更多大规模的临床研究评估和优化其保护作用.目的 探讨远隔处理的心肌保护作用及研究进展.内容对远隔处理的发现、发展过程中的文献进行综述,并通过现有研究结果剖析远隔处理内在作用机制.趋向 远隔处理具有较光明的临床应用前景,通过对其作用机制和影响因素进行深入研究有助于获得更好的心肌保护干预策略.     

不同预处理对大鼠肝移植供肝保护作用的探讨

目的 通过应用缺血、加热等多种手段对大鼠供肝进行移植术前的预处理,比较各种预处理方法对大鼠肝移植供肝缺血再灌注损伤的保护作用. 方法 将SD大鼠50只,随机分为5组:半肝缺血预处理组、脾脏缺血预处理组、热休克预处理组、热休克+缺血预处理组及手术对照组,分别进行肝脏预处理后行模拟原位肝移植术,术后检测胆汁流量,术后24 h检测血清ALT,AST,ALP水平并观察肝脏形态学变化. 结果 半肝缺血预处理组、热休克预处理组移植后胆汁分泌量多于对照组,血清ALT,AST水平明显低于对照组(P<0.05);热休克+缺血预处理组的血清ALT水平低于对照组(P<0.05),胆汁分泌量及血清AST与对照组没有显著差异;脾脏缺血预处理组的胆汁分泌量多于对照组,血清ALT水平低于对照组(P<0.05). 结论 肝脏缺血预处理初始阶段保护作用最明显,将缺血及热休克预处理两种方法联合处理大鼠时,其保护作用弱于单独缺血或单独热休克的预处理方法;脾脏缺血预处理也具有保护肝脏的作用.     

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.     

肝切除及肝移植术中缺血预处理的临床研究进展

缺血再灌注损伤一直是肝切除及肝移植术中存在的问题,是术后肝功能衰竭和移植物无功能的主要原因,而缺血预处理能减轻这种损伤。文中综述了近年来缺血预处理及其在临床应用中的研究进展,探讨了该技术在临床上的实用价值。     

远隔缺血预处理在瓣膜置换手术中的心肌保护作用

目的评估远隔缺血预处理在瓣膜置换手术中对心肌的保护作用。方法选取风湿性心脏病行瓣膜置换术的患者80例,将其随机分为远隔缺血预处理组(A组)和对照组(B组),每组各40例,分别于术前(T1)、开放主动脉前5 min(T2)、开放主动脉后30 min(T3)、开放主动脉后4 h(T4)和开放主动脉后24 h(T5)5个时相,动态观察患者心率、平均动脉压、心肌钙蛋白Ⅰ(cardiac troponinⅠ,cTnⅠ)、B型钠尿肽(B-brain natriuretic peptide,BNP)的变化。结果 1两组患者性别、年龄、体重、射血分数、手术类型、体外循环转流时间、主动脉阻断时间、在ICU停留时间和住院时间的差异无统计学意义(P0.05);2两组患者的心率和平均动脉压在手术后均明显升高(P0.001),但各时点两组患者心率、平均动脉压的差异无统计学意义(P0.05);3两组患者的cTnⅠ在T3、T4、T5较术前有明显升高(P0.001),远隔缺血预处理组患者在T3、T4和T5时相cTnⅠ较对照组明显下降(P0.001);4两组患者在T2、T4时相的BNP较术前明显下降,T5时相的BNP较术前明显升高(P0.001),远隔缺血预处理组患者在T5时BNP较对照组明显下降(P0.001)。结论在术中阻断时间和体外循环时间无差别的情况下,远隔缺血预处理减轻了心肌的缺血再灌注损伤,在瓣膜置换手术中对心肌起到了保护作用,具有一定的临床应用价值。     

缺血预处理对肢体缺血再灌注损伤的影响

目的　观察缺血预处理 (IPC)对肢体缺血再灌注损伤的影响。方法　选择 2 0例需充气止血带止血进行手术的患者 ,随机分为对照组 (n =10 )和IPC组 (n =10 )。IPC组患者术前应用 3次 5min循环缺血 ,间隔 5min再灌注预处理后在止血带下进行手术 ;对照组直接在止血带下进行手术。在肢体缺血前和再灌注 30min、90min、180min分别取静脉血检测血清肌酸磷酸激酶 (CPK)、谷草转氨酶(AST)、乳酸脱氢酶 (LDH)、丙二醛 (MDA)和过氧化物歧化酶 (SOD)水平。结果　随着肢体缺血再灌注时间的延长 ,血中CPK、AST、LDH、MDA含量逐渐升高 ,而SOD活性逐渐降低。IPC组在缺血前及再灌注同时间 ,血中CPK、AST、LDH、MDA含量低于对照组 (P <0 0 5 ,P <0 0 1) ;而SOD活性高于对照组 (P <0 0 5 ,P <0 0 1)。结论　IPC能有效地减轻肢体缺血再灌注损伤程度 ,减轻脂质过氧化反应 ,提高肢体缺血耐受性     

Ischaemic preconditioning of the brain,mechanisms and applications

Summary Background. The concept of ischaemic preconditioning was introduced in the late 1980s. The concept emerged that a brief subcritical ischaemic challenge could mobilize intrinsic protective mechanisms that increased tolerance against subsequent critical ischaemia. Tissues with a high sensitivity against ischaemia, i.e. myocardium and central nervous system, present the most promising targets for therapeutic application of ischaemic preconditioning. During the last years the mechanisms of neuronal preconditioning were systematically studied and a number of molecular regulation pathways were discovered to participate in preconditioning. The purpose of the present review is to survey the actual knowledge on cerebral preconditioning, and to define the practical impact for neurosurgery. Methods. A systematic medline search for the terms preconditioning and postconditioning was filed. Publications related to the nervous system were selected and analysed. Findings. Preconditioning can be subdivided into early and late mechanisms, depending on whether the effect appears immediately after the nonlethal stress or with a delay of some hours or days. In general early effects can be linked to adaptation of membrane receptors whereas late effects are the result of gene up- or downregulation. Not only subcritical ischaemia can trigger preconditioning but also hypoxia, hyperthermia, isoflurane and other chemical substances. Although a vast amount of knowledge has been accumulated regarding neural preconditioning, it is unknown whether the effects can be potentiated by pharmacological or hypothermic neuroprotection during the critical ischaemia. Furthermore, although the practical importance of these findings is obvious, the resulting protective manipulations have so far not been transferred into clinical neurosurgery. Postconditioning and remote ischaemic preconditioning are additional emerging concepts. Postconditioning with a series of mechanical interruptions of reperfusion can apparently reduce ischaemic damage. Remote ischaemic preconditioning refers to the concept that transient ischaemia for example of a limb can lead to protection of the myocardium and possibly the brain. Conclusion. Possible cumulative neuroprotection by preconditioning and pharmacological protection during critical ischaemia should be studied systematically. Easy to apply methods of preconditioning, such as the application of volatile anaesthetics or erythropoietin some hours or days prior to planned temporary ischaemia, should be introduced into the practice of operative neurosurgery.     

多次缺血预处理诱导脑侧枝循环重建对脑缺血保护的实验研究

目的：采用右侧颈总动脉多次缺血预处理,并逐次递增缺血时间,诱导右侧大脑侧枝循环建立,观察右侧颈动脉永久性阻断缺血后的脑保护作用。方法：家兔48只随机分为对照组和实验组,每组24只。对照组为假手术组．手术操作同实验组．但实验期间不实施球囊充气阻断颈动脉血流。实验组为右颈总动脉压迫组,压迫方法采用颈总动脉外充气球囊压迫技术．实施压迫时囊内充气压为160mmHg;每次压迫时间根据,预实验公式计算：次缺血时间：次数X5＋40（min）进行,每日2次,直到压迫时间达4h（总时间为20d）。各组分别在实验开始后第1、10和20d,分别采用数字剪影脑血管造影（DSA）方法．观察家兔右侧大侧枝循环建立情况：并于实验第20d用注射器将内囊充气压力达160mmHg后不放气．持续完全阻断右侧右侧颈总动脉血流．观察记录家兔神经功能评分：随后取脑组织标本。光镜下对比观察二组相同部位神经元的病理学及新生血管数量的变化．并比较两组缺血侧脑组织含水量。结果：实验期间二组家兔之间均没有观察到兴奋、躁动．嗜睡．活动、行为及胺。体运动障碍等异常症状。从DSA显像结果表明,在实施右侧颈总动脉外压造缺血预处理的第10d。造影剂已经通过willis环进入右侧大脑动脉,与压迫第1d比较右侧血管显影非常清晰．但与左侧比较右。后外上段侧枝未见显影。在实旗压迫处理的第20d,DSA血管显像左右两侧无差异．右后外上段血管显影也非常清晰。神经功能缺失评分和脑组织含水量实验组明显小于对照组。（P〈0．05）。右侧（缺血i：侧）,病理标本。在400倍镜一个视野下的毛细血管密度,实验组为5．3±0．5对照组为3．5±0．4,实验明显多于对照组（P〈0．05）。结论：多次缺血预处理能够诱导大脑Willis环及其相应的侧枝循环重建．对右侧颈总动脉完全缺血具有明显的保护作用。     

Intermittent Ischemic Preconditioning Protects Against Hepatic Ischemia-Reperfusion Injury and Extensive Hepatectomy in Steatotic Rat Liver

ABSTRACT

Background: Hepatic steatosis causes severe liver damage and has deleterious effects when associated with ischemia-reperfusion mechanisms. Ischemic preconditioning (IPC) protects lean liver against prolonged ischemia by improving micro-circulation and reducing lipid peroxidation. We investigated the effect of intermittent IPC on liver ischemia-reperfusion injury (IRI) and extensive hepatectomy in severe hepatic steatosis. Methods: Severe hepatic steatosis was performed by 12–14 weeks of choline-free diet in 108 Wistar rats. We induced 30-minute ischemia-reperfusion manipulations and extensive hepatectomy with or without prior IPC in steatotic livers and after 6 and 24 hours of reperfusion blood transaminases, and IL6, TNFα, NO and Lactate in blood and liver tissue were measured. Results: Steatotic rats subjected to hepatic ischemia-reperfusion alone after extensive hepatectomy, showed severe liver damage with significantly increased values of AST, ALT, TNFα and Lactate and significantly reduced IL6 and NO, while no one rat survived for more than 29 hours. On the contrary, steatotic rats subjected to intermittent IPC, 24 hours before ischemia-reperfusion, presented increased 30-day survival (67%), lower values of AST, ALT, TNFα and Lactate, and increased IL6 and NO levels. Simple and intermittent IPC manipulations, 1 hour before the IRI and extended hepatectomy, did not prolong survival more than 57 and 98 hours, respectively. Simple IPC, 24 hours before IRI and extended hepatectomy had the lowest possible survival (16.7%).Conclusions: Hepatic steatosis and IRI after major liver surgery largely affect morbidity and mortality. Intermittent IPC, 24 hours before IRI and extensive hepatectomy, presents higher 30-day survival and improved liver function parameters.     

心肌保护临床研究和应用进展

心肌保护近年来的发展多注重基础研究紧密联系临床，积极转化为临床实践，心肌保护液的添加成分、减轻炎症反应的策略、缺血预调在临床方面的应用都是学者们高度关注的重要部分，能够转化到临床，成为有效的心肌保护措施。     

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.     

腺苷A1受体激动剂诱导心脏缺血预处理延迟效应的实验研究

目的探讨腺苷A1受体激动剂能否诱导心脏缺血预处理的延迟保护及其与锰-超氧化物歧化酶(Mn-SOD)表达的关系.方法按随机数字表法将60只鼠分为6组,每组10只.A组:用腺苷A1受体激动剂2-氯环戊腺苷(CCPA)预处理; B组:为缺血对照,静脉注射生理盐水;C组:注射反义全巯代磷酸化寡核苷酸(ODN)后再注射生理盐水;D组、E组和F组在预处理前分别静脉注射Mn-SOD反义ODN、意义ODN、错配ODN.观察左心室压力变化最大速率(±dp/dtmax)的恢复率,肌酸激酶同工酶(CK-MB)释放活性,心肌三磷酸腺苷(ATP)、丙二醛(MDA)含量和Mn-SOD活性.结果 A组、E组和F组±dp/dtmax恢复率、心肌ATP含量和Mn-SOD活性均高于B组、C组和D组(P<0.05,0.01),而CK-MB释放活性和MDA含量均低于B组、C组和D组(P<0.05).结论腺苷A1受体激动剂可诱导预处理的延迟效应,减轻心肌缺血-再灌注损伤,其机制与Mn-SOD的高表达有关.