心肌缺血/再灌注损伤中细胞胀亡产生机制的研究进展

背景 细胞胀亡和凋亡均可出现在心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)过程中.胀亡是一种特殊形式的非凋亡性细胞死亡方式,它的特征表现为细胞肿胀、起泡、细胞器肿胀、细胞膜通透性增加和核溶解. 目的 明确细胞胀亡在心肌缺血/再灌注(ischemia/reperfusion,I/R)发生、发展中的作用将有助于心肌保护研究的深入. 内容 阐述细胞胀亡的生物学特性、发生机制及与心肌I/RI. 趋向 通过对心肌I/RI中细胞胀亡的深入了解和研究,有可能带来心肌保护的新突破.     

中性粒细胞与心肌缺血/再灌注损伤

背景 现已明确,炎症过程是心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)最重要的致病因素之一,而中性粒细胞是炎症反应的核心介导者.针对中性粒细胞的这种致病作用,部分研究者提出了抗中性粒细胞治疗,但是治疗效果却不尽相同,甚至大相径庭.更有研究者指出,中性粒细胞在心肌I/RI中尚发挥着一定的有益作用.针对这种现状,我们在此将中性粒细胞与心肌I/RI作一综述. 目的 评价中性粒细胞在心肌I/RI致病机制中的作用,探索抗中性粒细胞治疗的方向.内容 包括中性粒细胞对心肌I/RI的致病作用,抗中性粒细胞治疗的现状及其当前存在矛盾之处. 趋向 通过全面理解中性粒细胞在心肌I/RI中的作用,为今后进行适度的抗中性粒细胞治疗提供参考,并为今后发展多靶向联合措施治疗心肌I/RI提供思路.     

阿司匹林对小鼠心肌缺血/再灌注损伤时心肌组织炎症反应的影响

目的:研究阿司匹林对小鼠心肌缺血/再灌注损伤（myocardial ischemia/reperfusion injury, MI/RI）时心肌组织炎症反应的影响。方法:将60只雄性C57BL/6小鼠按随机数字表法分为3组（每组20只）：假手术组（S组）、缺血/再灌注（ischemia/reperfusion, I/R...     

心肌缺血/再灌注损伤中微小RNA的作用研究进展

背景 心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)是临床最常见的损伤之一,微小RNA(microRNA,miRNA)参与了其进程. 目的 对心肌I/RI过程中miRNA作用的最新进展进行综述. 内容 回顾并展望miRNA在心肌缺血/再灌注中的作用. 趋向 miRNA与心肌I/RI密切相关,更多以miRNA为靶点的治疗会被用于心肌保护.     

微小RNA与心肌缺血/再灌注损伤研究进展

背景 近年研究表明微小RNA(microRNA,miR)参与了心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)的进程. 目的 综述miR参与心肌I/RI的研究进展. 内容 概述miR及与心肌I/RI有关的miR的作用,并作展望.趋势 miR与心肌I/RI密切相关.以miR为靶点的治疗将可能被用于心肌保护.     

热休克蛋白在缺血后处理器官保护中的作用

背景 缺血后处理(ischemic postconditioning,IPo)减轻器官缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)的效果确切,临床实用性强,成为近年来的研究热点.热休克蛋白(heat shock protein,HSP)是细胞应激反应的生物学标志及内源性保护蛋白,参与器官I/RI过程.目的 总结国内外对IPo与HSP在器官I/RI中作用的研究成果,为IPo器官保护机制的研究提供思路.内容 国内外学者研究证实IPo可以减轻多种器官的I/RI,并将其应用于临床,取得一定的疗效.HSP通过减轻再灌注过程中的氧化应激反应和炎症反应,减少细胞凋亡,保护细胞骨架的完整性,发挥细胞保护作用.趋势 IPo器官保护作用的机制研究应成为广大学者今后的研究方向,与其为临床应用提供理论基础.     

转录因子NF-E2相关因子2-氧化反应元件通路在抗心肌再灌注损伤中的作用

背景 转录因子NF-E2相关因子2(Nf-E2 related factor-2,Nrf2)抗氧化反应元件(antioxidant response element,ARE)通路广泛分布于机体心血管系统中,激活后可上调内源性抗氧化系统减轻心肌的氧化损伤. 目的 阐述Nrf2-ARE通路作为抗心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)的潜在靶点,并探讨其可能的保护机制.内容 Nrf2-ARE通路处于氧化应激、炎症反应的中心地位,介导编码抗氧化蛋白和二项解毒酶基因的基础表达和诱导表达;多种外源性化合物可以激活Nrf2-ARE通路,在转录水平上调节抗氧化蛋白及二项解毒酶基因的表达,增强内源性抗氧化系统的能力从而在减少氧自由基产生、抗炎症反应、减轻钙超载、抗心肌细胞凋亡等方面减轻心肌I/RI.趋向 激活Nrf2-A RE通路可为临床抗I/RI提供新的策略.     

肢体缺血后处理的研究进展

背景 对缺血/再獾注损伤(ischemia/reperfusion injury,I/RI)的下肢实施血管外科时,可引起诸如多器官功能障碍综合征(multiple organ dysfunction syndrome,MODS)和全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)的严重并发症,即再灌注综合征.肢体缺血后处理(limb ischemic postconditioning,LIPO)是指应用于血管重建术开始时减轻I/RI的一种有效治疗技术.目的 现就LIPO的作用机制及其应用研究作一综述. 内容 LIPO能够通过减少活性氧产物形成、抑制炎症反应、改善微循环和细胞能量代谢及减轻钙超载发挥对缺血组织器官的保护作用.趋向 LIPO的作用机制为I/RI的防治提出了一个新的方向研究,进一步地研究和理解其具体作用机制,将为临床应用这种无创干预措施提供有力的理论依据和有益的指导.     

缺血预处理和肢体远隔缺血后处理对大鼠心肌缺血/再灌注损伤中炎症反应影响的比较

目的 比较缺血预处理(ischemic preconditioning,IPC)和肢体远隔缺血后处理(limb remote ischemic postconditioning,LRIPOC)对大鼠心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)中炎症反应的影响. 方法 雄性SD大鼠80只,体重250 g～350 g,采用随机数字表法将其随机分为4组(每组20只):假手术组(S组)、缺血/再灌注组(I/R组)、IPC组和LRIPOC组.监测缺血/再灌注期间的心率(HR)和平均动脉压(MAP),并计算HR和收缩压乘积(rate pressure product,RPP)作为心肌氧耗指数.各组随机取10只大鼠,于再灌注30、60、120 min时采集颈静脉血样,采用ELISA法检测血清心肌肌钙蛋白(cardiac troponin I,cTnI)、磷酸肌酸激酶同工酶(creatine kinase-MB,CK-MB)、肿瘤坏死因子(tumor necrosis factor,TNF)-α、高迁移率组蛋白-1(high mobility group box-1 protein,HMGB-1)、细胞间黏附分子-1(intercellular adhesion molecule-1,ICAM-1)、白介素(interleukin,IL)-1、IL-6和IL-10的浓度;于再灌注120 min颈静脉采血后,采用伊文蓝和TTC双重染色法测定心肌梗死体积.各组随机取10只大鼠,于再灌注120 min处死后分别取缺血区和非缺血区心肌组织,采用ELISA法检测心肌TNF-α 、HMGB-1、ICAM-1、IL-1、IL-6和IL-10含量. 结果 I/R组、IPC组和LRIPOC组的心肌梗死体积值分别是(72±9)％、(36±13)％和(57±9)％,3组的血清cTnI浓度分别是(0.99±0.14)(0.37±0.08)、(0.54±0.07) μg/L,而3组的血清CK-MB浓度分别是(110±13)、(38±8)、(45±6) μg/L.与I/R组比较,IPC组和LRIPOC组心肌梗死体积、血清cTnI和CK-MB浓度显著降低,IPC组再灌注30、60、120 min时血清TNF-α 浓度、再灌注60、120 min时血清HMGB-1浓度、再灌注120 min时血清ICAM-1、IL-1和IL-6浓度显著降低,缺血区心肌组织内TNF-α 、HMGB-1、ICAM-1、IL-1和IL-6含量显著降低,非缺血区心肌组织内TNF电、ICAM-1、IL-1和IL-6含量显著降低(P＜0.05);LRIPOC组再灌注30、60、120 min时血清TNF-α 浓度、再灌注120 min时血清HMGB-1、ICAM-1、IL-1和IL-6浓度显著降低,缺血区与非缺血区心肌组织内 TNF-α、HMGB-1、ICAM-1、IL-1和IL-6的含量显著降低(P＜0.05).与IPC组比较,LRIPOC组的心肌梗死体积、血清cTnI和CK-MB浓度显著升高,再灌注60 min时血清TNF-α 浓度、再灌注120 min时血清HMGB-1和ICAM-1浓度显著升高,缺血区心肌组织内TNF-α 、ICAM-1、IL-1和IL-6含量显著升高,非缺血区心肌组织内ICAM-1、IL-1和IL-6含量显著升高(P＜0.05). 结论 IPC减轻大鼠心肌I/RI中炎症反应的作用强于LRIPOC,这可能是IPC对心肌I/RI保护作用强于LRIPOC的原因之一.     

miRNA在缺血预处理保护心肌缺血/再灌注损伤中的研究进展

背景microRNAs(miRNAs)是一类由动物、 植物和病毒基因组编码的约由22个核苷酸组成的小分子单链RNA.近年来发现它在缺血预处理(ischemic preconditioning,IPC)中发挥着重要作用,有望成为研究治疗心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)的新靶点.目的 阐述不同miRNA在IPC保护心肌I/RI中的作用及其可能机制.内容IPC是经典的保护心肌I/RI的方法,IPC后心肌中miRNA表达谱发生改变,其中miR-1、miR-21、miR-133b-5p、miR-199a、miR-144/451可能通过不同的基因调节机制影响IPC保护心肌I/RI.趋向将miRNA与靶基因、 信号调节通路相结合将是未来研究miRNA调节IPC保护心肌I/RI的重要趋势.     

Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury

Reperfusion of the ischemic heart is necessary to prevent irreversible injury of the myocardium, which leads to permanent organ dysfunction. However, reperfusion in itself leads to myocardial ischemia/reperfusion (I/R) injury, which is characterized by an acute inflammatory response mediated by activated inflammatory cells, chemokines, cytokines, and adhesion molecules. The molecular mechanisms of myocardial I/R injury are not completely known. Tissue factor (TF) and thrombin, two potent procoagulant and proinflammatory mediators, are recognized to play significant roles in myocardial I/R injury. To investigate the role of TF and thrombin in myocardial I/R injury, we used rabbit and murine in situ coronary artery ligation models. Increased TF mRNA, antigen, and activity were found in ischemic cardiomyocytes. Administration of an inhibitory antirabbit TF monoclonal antibody before or during the onset of ischemia resulted in a significant reduction in infarct size. Functional inhibition of thrombin with hirudin also reduced the infarct size. However, defibrinogenating rabbits with ancrod had no effect on infarct size, suggesting a requirement of thrombin generation but not fibrin deposition in myocardial I/R injury.     

Mediators in polytrauma – pathophysiological significance and clinical relevance

Multiple trauma induces an inflammatory response syndrome of the whole body that is triggered by (a) hemorrhage inducing an ischemia/reperfusion (I/R) syndrome and (b) fractures or organ contusions inducing tissue-repair processes. I/R injury generates oxyradical/proteolytic metabolites and adhesion molecules, while tissue and endothelial injury directly stimulate complement, coagulation and kinin pathways. Membrane-derived phospholipase A₂ and lipid mediators potentiate cellular interactions and increase microvascular permeability. The tissue-repair process mediates macrophage/monocyte and T-cell activation which releases pro- and anti-inflammatory cytokines. Mediator action follows a “three-level model”, proposing that depending on the degree of traumatic injury cellular and humoral responses may spread from a cellular to an organ and then a systemic level. The systemic response can result in a severe immunological dys-homeostasis that potentially hazards the survival of the trauma patient by uncontrollable cellular dysfunction, appearing clinically as multiple organ-dysfunction syndrome. Blood-mediator concentrations often parallel the inflammatory process; initially, high levels of cytokines are followed by severe organ dysfunction. However, interpretation of these data remains difficult due to distinct beneficial or detrimental effects of mediators on the different levels of inflammation and missing prognostic threshold values, indicating a risk of adverse effects. Future studies must determine pro- and anti-inflammatory mediators directly, during the intensive care therapy, and evaluate their clinical relevance prospectively for the different levels of inflammation at local and systemic sites. Received: 12 January 1998     

Molecular biology of apoptosis in ischemia and reperfusion.

This study reviews the current understanding of the mechanisms that mediate the complex processes involved in apoptosis secondary to ischemia and reperfusion (I/R) and is not intended as a complete literature review of apoptosis. Several biochemical reactions trigger a cascade of events, which activate caspases. These caspases exert their effect through downstream proteolysis until the final effector caspases mediate the nuclear features characteristic of apoptosis, DNA fragmentation and condensation. Within the context of ischemia, the hypoxic environment initiates the expression of several genes involved in inflammation, the immune response, and apoptosis. Many of these same genes are activated during reperfusion injury in response to radical oxygen species generation. It is plausible that inhibition of specific apoptotic pathways via inactivation or downregulation of those genes responsible for the initiation of inflammation, immune response, and apoptosis may provide promising molecular targets for ameliorating reperfusion injury in I/R-related processes. Such inhibitory mechanisms are discussed in this review. Important targets in I/R-related pathologies include the brain during stroke, the heart during myocardial infarction, and the organs during harvesting and/or storage for transplantation. In addition, we present data from our ongoing research of specific signal transduction-related elements and their role in ischemia/reperfusion injury. These data address the potential therapeutic application of anti-inflammatory and anti-ischemic compounds in the prevention of I/R damage.     

Recombinant Human Erythropoietin Restrains Oxidative Stress in Streptozotocin-induced Diabetic Rats Exposed to Renal Ischemia Reperfusion Injury

BackgroundRenal ischemia/reperfusion (I/R) injury (RI/RI) is a common complication of diabetes mellitus (DM) in surgical practice. Oxidative stress plays a crucial role in this process. Recombinant human erythropoietin (rhEPO) is usually used to treat anemia resulting from several diseases. However, the functional involvement of rhEPO in diabetic RI/RI remains unclear. The present study was intended to investigate the antioxidant role of rhEPO on RI/RI in DM rats.MethodsThe bilateral renal arteries and veins of streptozotocin-induced diabetic rats were subjected to 45 minutes of ischemia followed by 1, 6, and 24 hours of reperfusion with or without rhEPO pretreatment at the beginning of an I/R procedure. The renal tissue pathomorphology, renal function, oxidative stress, and inflammatory response were evaluated by detection of a series of indices by hematoxylin-eosin staining, commercial kits, enzyme-linked immunosorbent assay, and spectrophotofluorometry, respectively.ResultsCompared to the I/R group, renal function was significantly advanced in the erythropoietin group, whose subjects were also subjected to renal tissue injury, oxidative stress, and inflammation.ConclusionThese results suggest that rhEPO preconditioning can attenuate diabetic RI/RI through regulating endogenous antioxidant activity.     

Toll-Like Receptor Signaling in Liver Ischemia and Reperfusion

ABSTRACT

Liver ischemia–reperfusion (I/R) injuries are significant clinical challenges implicated in various hepatic surgical procedures and transplantations. Associated with varying degrees of insult, the hallmark of I/R is the excessive inflammatory response potentiated by the host immune system. Toll-like receptors (TLRs), known to play an important role in pathogen-derived inflammation, are now thought to participate in I/R injury-derived inflammation signaling pathways. Endogenous particles (proteins, cytokines, nucleic acids) that are released from damaged host cells bind to TLR2, TLR4, and TLR9, resulting in even further injury by subsequent inflammatory reactions and activation of the innate immune system. This review aims to systematically examine the current literature about TLR signaling mechanisms, allowing for a greater understanding of the precise role of TLRs in hepatic I/R injuries.     

Oxytocin Ameliorates the Immediate Myocardial Injury in Rat Heart Transplant Through Downregulation of Neutrophil-Dependent Myocardial Apoptosis

Background

Cardiac oxytocin (OT) is structurally identical to that found in the hypothalamus, indicating that this active form of OT is derived from the same gene. The abundance of OT and its receptors in atrial myocytes suggests that, directly and/or via the release of the cardiac hormone atrial natriuretic peptide, this hormone regulates the force of cardiac contractions. Previous studies have demonstrated a role of OT in myocardial inflammatory responses. We sought to study protective myocardial and anti-inflammatory effects of OT in the immediate post-transplant period.

Methods

We grouped adult male Albino rats into sham, control, and OT-treated groups. Control and treated groups underwent heterotopic cervical heart transplantation. Myocardial injury was assessed by measuring plasma cardiac troponin I, and myocardial proinflammatory cytokines as well as by performing histopathologic assessments injury score, and of apoptotic degree. Myocardial myeloperoxidase, neutrophil infiltration, neutrophil chemotactic mediators as well as formation of reactive oxygen and reactive nitrogen species were measured in the myocardium at 3 hours after reperfusion to assess neutrophil-dependent myocardial injury.

Results

OT downregulates neutrophil chemotactic molecules — KC/CXCL1 and MIP-2/CXCL2. The decrement in myocardial PMN infiltration was associated with reduced reactive oxygen and reactive nitrogen species formation in the myocardium at 3 hours after reperfusion following global ischemia. OT reduced postmyocardial ischemia/reperfusion apoptotic processed.

Conclusion

OT ameliorated immediate myocardial injury in heart grafts, through downregulation of the inflammatory response, of reactive oxygen species, and of neutrophil dependent apoptosis.     

Can ischemic preconditioning alone really protect organs from ischemia reperfusion injury in transplantation

Organ transplantation is the only choice for treatment of end-stage disease. The ischemia reperfusion injury (I/RI) occurring after cold ischemia is an unavoidable injury during transplantation, which is also one of the main causes of graft failure. Multiple mechanisms have been postulated to explain tissue injury that occurs after I/RI. It is well-known that ischemic preconditioning (IPC), a short period of ischemia followed by reperfusion, arouses the endogenous mechanism of protection against a sustained ischemic insult. Can ischemic preconditioning alone really protect organs from ischemia reperfusion injury in transplantation?     

Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against renal ischemia/reperfusion injury by inhibiting inflammation

Hypoxia-induced inflammation is the critical pathological feature of acute kidney injury (AKI). Activation of hypoxia-inducible factor (HIF) signaling is considered as a central mechanism of body adapting to hypoxia. Hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 (Roxadustat) is a first-in-class HIF stabilizer for the treatment of patients with renal anemia. The current study aimed to investigate whether FG-4592 could protect against ischemia/reperfusion (I/R)-induced kidney injury via inhibiting inflammation. Here, efficacy of FG-4592 was evaluated in a mice model of I/R-induced AKI. Interestingly, improved renal function and renal tubular injuries, combined with reduced kidney injury molecule-1 were observed in the mice with FG-4592 administration. Meanwhile, inflammation responses in FG-4592-treated mice were also strikingly attenuated, as evidenced by the decreased infiltration of macrophages and neutrophils and down-regulated expression of inflammatory cytokines. In vitro, FG-4592 treatment significantly protected the tubular epithelial cells against hypoxia-induced injury, with suppressed inflammation and cell injuries. In summary, FG-4592 treatment could protect against the I/R-induced kidney injury possibly through diminishing tubular cells injuries and suppression of sequence inflammatory responses. Thus, our findings definitely offered a clinical potential approach in treating AKI.