细胞凋亡与肝移植缺血再灌注损伤

背景：肝脏缺血再灌注损伤是影响肝脏移植效果的重要因素,细胞凋亡是移植肝缺血再灌注损伤的重要机制之一。 目的：就近年来细胞凋亡与移植肝缺血再灌注损伤的研究做一综述,为抗细胞凋亡在减轻器官缺血再灌注损伤的临床应用提供参考依据。 方法：由第一作者检索1990/2010 PubMed数据库及中国期刊全文数据库有关细胞凋亡及器官移植缺血再灌注损伤的关系的文献,检索词为“apoptosis,organ transplantation,ischemia-reperfusion injury”。排除重复性研究。计算机初检得到339篇文献,最终纳入39篇文献进行下一步分析。 结果与结论：文章从肝脏移植缺血再灌注损伤中的细胞凋亡,移植肝缺血再灌注损伤中细胞凋亡发生的机制,移植肝缺血再灌注损伤中细胞凋亡的基因表达变化,抗凋亡治疗与防治肝移植缺血再灌注损伤几方面进行了叙述。细胞凋亡与移植肝缺血再灌注损伤有着密切的关系。而抑制细胞凋亡可以有效的减轻移植肝的缺血再灌注损伤,对提高移植物的存活率有着重要的意义。     

诱导血红素加氧酶-1表达在器官移植中的保护作用

器官移植术中及术后移植器官的缺血再灌注损伤(ischemia-repeffusion injury,IRI)和免疫排斥反应一直困扰着外科医生.血红素加氧酶-1(heme oxygenase-1,HO-1)是血红素代谢过程中的限速酶,广泛分布于哺乳动物的各种组织细胞中.血红素在它的催化下降解代谢为一氧化碳(CO)、胆绿素和游离铁离子.HO-1在氧化应激、炎性反应、低氧和缺血等状态下均能高度表达.HO-1及其催化血红素代谢产物主要通过抗炎性反应、抗氧化反应、调节同种异体反应性T细胞的活性及增殖、抗内皮细胞凋亡、抑制内皮细胞活化等作用机制,对移植器官起到抗IRI和抗免疫排斥作用,从而增加移植器官成活率及延长其存活时间.     

右美托咪定抗缺血再灌注损伤的信号通路

背景：右旋美托咪定具有抗缺血再灌注损伤的作用，但对其信号通路全面、系统的综述较少。目的：重点对右旋美托咪定在抗氧化应激、抑制炎症、抗凋亡、自噬等机制方面的信号通路进行综述。方法：计算机检索PubMed数据库、中国知网、万方数据库及维普数据库的相关文章，英文检索词为“ischemia-reperfusion injury,dexmedetomidine,signal path,oxidative stress,inflammation,apoptosis”；中文检索词为“缺血再灌注损伤，右旋美托咪定，信号通路，氧化应激，炎症，凋亡”。排除重复性研究及部分相关性较低的基础类文章，最终纳入57篇文献进行评价。结果与结论：(1)右旋美托咪定主要通过抗氧化应激损伤、抗炎、抗细胞凋亡和自噬等多种机制发挥器官保护作用，这其中又涉及众多通路，主要包括Nrf2及其下游蛋白抗氧化应激通路、Toll样受体4家族和核因子κB相关抗炎通路、JAK2/STAT3相关抗炎通路、胆碱能抗炎通路，而且胆碱能通路是众多核因子κB信号通路的上游机制；(2)PI3K/Akt通路依据其激活的下游信号不同发挥不同的作用，抑制NL...     

氢气在缺血再灌注损伤性疾病及器官移植中的研究进展

在多种疾病的发生发展及器官移植的过程中,缺血再灌注损伤（I/R）是重要的病理生理学基础。氢气作为一种新的抗氧化剂,在多种器官缺血再灌注疾病和器官移植模型中的作用被广泛研究。这里,我们回顾与氢气治疗相关的缺血再灌注损伤性疾病及器官移植的研究进展,讨论氢气在器官缺血再灌注损伤中的保护效应和作用机制,并对未来研究进行展望。大量实验证据表明,氢气能够通过选择性抗氧化减少氧化应激,对抗炎症,减少凋亡,在不同的缺血再灌注疾病模型及器官移植中发挥显著的保护治疗作用。氢气对缺血再灌注损伤的作用研究为未来氢气医学临床应用奠定了基础,但相关机制和临床研究仍然需要进一步加强。     

丹参对皮瓣缺血再灌注损伤的影响及机制

背景:大量研究资料表明皮瓣缺血再灌注损伤是一系列复杂的病理生理过程,其具体机制尚未完全阐明。而中药丹参作为整形外科皮瓣移植后的常用药物,具有减轻缺血再灌注损伤、减少皮瓣坏死的作用。目的:综述丹参对皮瓣缺血再灌注损伤保护作用机制的研究进展。方法:应用计算机检索Elsevier数据库和CNKI数据库中1980-01/2010-04关于丹参对皮瓣缺血再灌注损伤保护作用方面的文章,在标题和摘要中以"丹参,皮瓣,缺血再灌注损伤"或"salvia miltiorrhizae,flap,ischemia-reperfusion"为检索词进行检索。根据纳入标准选择50篇文献进行综述。结果与结论:关于丹参对防治心、肝、脑、肾、肠道等器官缺血再灌注损伤的研究较多,大量研究表明丹参可从细胞水平、基因水平、微循环方面,多条途径、多种机制减轻缺血再灌注损伤。但丹参对皮瓣缺血再灌注损伤的研究较少,其确切的作用机制目前尚不完全明确。因此关于丹参对皮瓣缺血再灌注损伤的保护作用机制将成为进一步的研究方向。     

血红素加氧酶-1在心血管疾病中的作用研究新进展

血红素加氧酶-1是一种应激蛋白, 除了促进血红素代谢, 还具有抗炎、抗凋亡、抗增生和抗氧化应激等许多重要生物学作用。这一功能广泛的氧化酶系统参与心血管系统的病理生理过程,它的作用涉及血压的调控、抗动脉粥样硬化的发生发展、预防缺血/再灌注损伤和冠状动脉介入治疗后再狭窄的发生。     

血红素加氧酶-1生物学特性及在心肌梗死中的作用

血红素加氧酶（Heme Oxygenase，HO）是血红素降解过程中的限速酶，其在体内有三种形式：HO-1、HO-2、HO-3。近年来许多研究表明HO-1具有抗炎、抗凋亡等作用以及在心脏缺血／再灌注损伤等应激反应中起着重要的保护作用^[1,2]。     

肝缺血再灌注对胆管细胞凋亡及胆汁淤积的影响

<正>缺血再灌注损伤是指缺血后的再灌注不仅不能使组织、器官功能恢复,反而加重了组织、器官功能障碍和结构损伤的一种病理生理过程,是影响移植肝存活率的一个重要因素。肝再灌注时不仅对肝细胞产生损伤作用,同时对肝内胆道的胆管细胞也有损伤,从而使胆道发生病变[1]。本文旨在讨论缺血再灌注损伤中Bcl-2通过对胆管细胞凋亡的保护作用,从而进一步探     

间充质干细胞来源外泌体治疗缺血再灌注损伤分子机制及研究进展

缺血再灌注损伤导致脑、心、肝、肠和肾器官受损和组织坏死等问题目前尚无良好解决办法,而间充质干细胞及其分泌的外泌体因具有抗炎、细胞生成和抗凋亡等作用使得修复器官缺血再灌注损伤成为可能。近年来,大量研究关于间充质干细胞来源外泌体修复器官缺血再灌注损伤的分子机制。文章对间充质干细胞来源外泌体治疗缺血再灌注损伤分子机制、保护各器官缺血再灌注损伤的优缺点作一简要综述,并对该技术未来研究方向提出展望,以期探索出更具有应用价值的研究。     

间充质干细胞治疗皮瓣缺血再灌注损伤的作用机制及优势

背景：间充质干细胞因具有抗氧化、抑制炎症反应和诱导血管新生等作用而被用于皮瓣缺血再灌注损伤中。目的：综述间充质干细胞在治疗皮瓣缺血再灌注损伤方面的作用机制和最新进展，为其进一步理论研究和临床合理应用提供依据。方法：检索CNKI中国期刊全文数据库、万方数据库和PubMed数据库收录的相关文献。中文检索词为“间充质干细胞；皮瓣缺血再灌注损伤；条件培养基；外泌体；氧化应激；炎症反应；血管新生”。英文检索词为“mesenchymal stem cells;flap ischemia reperfusion injury;Conditioned medium;exosomes;Oxidative stress;Inflammatory reaction;Angiogenesis”。检索2010年以来相关文献，通过阅读文章剔除研究内容与文章主题关系不大、质量较差及内容陈旧文献，最终纳入74篇文献进行归纳总结。结果与结论：(1)间充质干细胞在抗氧化、抑制炎性反应及诱导血管新生等方面作用显著，在治疗皮瓣缺血再灌注损伤中蕴含着巨大潜力。(2)然而，间充质干细胞自身的缺陷及近年来治疗效果的下降使间充质干细...     

Heme oxygenase-1: unleashing the protective properties of heme

Heme oxygenase (HO)-1 catabolizes heme into three products: carbon monoxide (CO), biliverdin (which is rapidly converted to bilirubin) and free iron (which leads to the induction of ferritin, an iron-binding protein). HO-1 serves as a "protective" gene by virtue of the anti-inflammatory, anti-apoptotic and anti-proliferative actions of one or more of these three products. Administration of CO, biliverdin, bilirubin or iron-binding compounds is protective in rodent disease models of ischemia-reperfusion injury, allograft and xenograft survival, intimal hyperplasia following balloon injury or as seen in chronic graft rejection and others. We suggest that the products of HO-1 action could be valuable therapeutic agents and speculate that HO-1 functions as a "therapeutic funnel", mediating the beneficial effects attributed to other molecules, such as interleukin-10 (IL-10), inducible nitric oxide synthase (NOS2; iNOS) and prostaglandins. This Review is the third in a series on the regulation of the immune system by metabolic pathways.     

A central role of heme oxygenase-1 in cardiovascular protection

The intrinsic defense mechanisms of the body are critical in protecting tissues from injury in response to pathological stress. Heme oxygenase-1 (HO-1), a stress response protein, is induced in response to various pathological stimuli to serve a cytoprotective function. By degrading the oxidant heme and generating the antioxidant bilirubin and anti-inflammatory molecule carbon monoxide, HO-1 may protect cell from injury due to oxidative and pathological stress. Oxidative stress in the heart caused by ischemia and reperfusion leads to cardiomyocyte death and subsequent myocardial infarction. Vascular diseases including atherosclerosis, graft failure, and restenosis are all associated with reactive oxygen species-induced injury and inflammation. Given that cardiovascular disease is the leading cause of death worldwide, there is considerable interest in developing new strategies for preventing and treating cardiovascular disease. Since HO-1 is induced in the heart and blood vessels in response to various stresses, a role of HO-1 has been implicated in cardiovascular homeostasis. Numerous studies using pharmacological method or genetic approach have since demonstrated the cardiovascular protective function of HO-1. Importantly, a number of studies have associated human HO-1 gene promoter polymorphisms with risk for vascular diseases. Taken together, HO-1 has a great therapeutic potential for cardiovascular disease.     

Therapeutic Potential of HO-1 in Autoimmune Diseases

Heme oxygenase-1 (HO-1), the inducible isoform of heme oxygenase (HO), has raised a lot of concerns in recent years due to its multiple functions. HO-1 was found to be a pivotal cytoprotective, antioxidant, anti-apoptotic, immunosuppressive, as well as anti-inflammatory molecule. Recent studies have clarified its significant functions in many diseases with substantial findings. In autoimmune diseases, HO-1 may have promising therapeutic potential. Here, we briefly reviewed recent advances in this field, aiming at hopefully exploring the potential therapeutic roles of HO-1, and design HO-1-based strategies for the treatment of autoimmune diseases.     

Upregulation of antioxidant nuclear factor erythroid 2-related factor 2 and its dependent genes associated with enhancing renal ischemic preconditioning renoprotection using levosimendan and cilostazol in an ischemia/reperfusion rat model

IntroductionIschemic preconditioning (Ipre) provides protection against renal ischemia-reperfusion (I/R) injury with its associated remote organ damage. This study examined the enhancing protective effect of Ipre with levosimendan or cilostazol in I/R-induced kidney and lung injury in a rat model.Material and methodsRats were divided into: sham-operated, I/R control, Ipre control, I/R + cilostazol or levosimendan and Ipre + cilostazol or levosimendan. Drugs were given 30 min before left renal I/R or 4 cycles of Ipre just before renal ischemia.ResultsThe Ipre combined with the implemented drugs enhanced physiological antioxidant defense genes including renal nuclear factor erythroid 2-related factor 2 (Nrf2) and its dependent genes heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1) and improved malondialdehyde and superoxide dismutase renal tissue levels. The combined effect improved I/R consequences for blood urea, creatinine, and creatinine clearance and improved blood oxygenation and metabolic acidosis. Moreover, the combination improved the renal soluble intercellular adhesion molecule (ICAM), tumor necrosis factor α (TNF-α) and interlukin-6 (IL-6) with histopathological improvement of tubular necrosis with a decrease in the apoptotic marker caspase-3 and an increase in the anti-apoptotic Bcl-2 expression.ConclusionsCilostazol or levosimendan potentiates the renoprotective effect of Ipre against renal I/R injury, associated with upregulation of antioxidant genes Nrf2, HO-1, and NOQ-1 expression.     

Therapeutic applications of bilirubin and biliverdin in transplantation

Bilirubin is the end product of heme catabolism by heme oxygenases. The inducible form of these enzymes is heme oxygenase-1 (HO-1), which is the rate-limiting enzyme that can degrade heme into equimolar quantities of carbon monoxide (CO), biliverdin, and free iron. Biliverdin is very rapidly converted to bilirubin by the enzyme biliverdin reductase, and free iron upregulates the expression of ferritin. HO-1 is a ubiquitous stress protein and is induced in many cell types by various stimuli. Induced HO-1 exerts antiinflammatory effects and modulates apoptosis. Expression of HO-1 in vivo suppresses the inflammatory responses in endotoxic shock, hyperoxia, acute pleurisy, and organ transplantation, as well as ischemia-reperfusion injury, and thereby provides salutary effects in these conditions. Accumulating evidence indicates that biliverdin/bilirubin can mediate the protective effects of HO-1 in many disease models, such as IRI and organ transplantation, via its antiinflammatory, antiapoptotic, antiproliferative, and antioxidant properties, as well as its effects on the immune response. This review attempts to summarize these protective roles as well as the molecular mechanisms by which biliverdin/bilirubin benefit IRI and solid-organ transplantation, including chronic rejection, and islet transplantation.     

Heme oxygenase-1 protects brain from acute excitotoxicity

Heme oxygenase is a rate-limiting enzyme that degrades heme, a pro-oxidant, into carbon monoxide, iron, and bilirubin. Heme oxygenase has two active isoforms: heme oxygenase-1 and heme oxygenase-2. Heme oxygenase-1 can be induced by various insults. Several investigators have postulated that it has cytoprotective activities, although its role in the nervous system is not fully understood, especially considering that normally heme oxygenase-2 accounts for the vast majority of heme oxygenase activity in the brain. Here, the basal effect of heme oxygenase-1 was investigated in acute glutamatergic excitotoxicity to test the hypothesis that N-methyl-D-aspartate-induced acute toxicity in brain is attenuated by heme oxygenase-1. N-methyl-D-aspartate was unilaterally injected into the striatum of wildtype and heme oxygenase-1 knockout mice. After 48 h, brains were harvested, sectioned, and stained with Cresyl Violet to measure the lesion size. Lesion volume was significantly (P<0.05) greater in brains of heme oxygenase-1 knockout mice (15.2+/-3.1 mm(3); n=10) than in those of wildtype mice (6.2+/-1.5 mm(3); n=11). In addition, Western blot analysis indicated no detectable differences between wildtype and heme oxygenase-1 knockout mouse brains in the levels of the glutamate or N-methyl-D-aspartate receptors studied. To test whether heme oxygenase-1 could specifically protect neurons, mouse primary neuronal cell cultures of wildtype and heme oxygenase-1 knockout mice were treated with or without N-methyl-D-aspartate. Cell viability of the heme oxygenase-1 knockout neurons was significantly less than that of wildtype neurons at each of the N-methyl-D-aspartate concentrations tested (12.8+/-1.3%, 16.0+/-1.4%, and 18.4+/-1.8% at 30, 100, and 300 microM N-methyl-D-aspartate, respectively). These results indicate that heme oxygenase-1 provides neuroprotection against acute excitotoxicity and suggest that potential intervention that can increase heme oxygenase-1 activity within the brain should be considered as a therapeutic target in acute and potentially chronic neurological disorders.     

丹参对大鼠移植肝血红素氧合酶1表达的影响

背景：器官移植前使用丹参预处理能够保护组织缺血-再灌注损伤,改善移植器官存活率。 目的：观察含丹参的冷灌注液对同种异体大鼠移植肝脏中血红素氧合酶1表达的影响,以及对供体肝脏缺血-再灌注损伤的保护作用。 方法：将SD雄性大鼠随机分成UW液组(术中使用UW液灌注保存)、丹参+UW液组(术中使用丹参+UW液灌注保存)、ZnPP预处理组(移植前24 h腹腔内注射ZnPP,术中使用丹参+UW液灌注保存),建立稳定的大鼠同种异体肝移植模型。同时取10只正常大鼠作为正常对照。 结果与结论：丹参+UW液组和UW液组血清总胆红素、谷丙转氨酶、谷草转氨酶水平明显低于ZnPP预处理组(P < 0.01)。血红素氧合酶1mRNA及其蛋白在丹参+UW液组中较UW组表达更明显,在ZnPP预处理组中表达明显受到抑制(P< 0.05)。丹参+UW液组肝脏Suzuki标准评分明显低于ZnPP预处理组及UW液组(P < 0.05)。表明丹参能上调同种异体的大鼠移植肝脏中血红素氧合酶1 mRNA及其蛋白的表达,减轻供肝缺血-再灌注损伤,保护移植大鼠肝脏。     

诱导HO-1基因表达的信号通路

血红素氧合酶（HO）的诱导型HO-1与其催化血红素降解生成的产物胆红素和CO一道，组成了机体重要的内源性保护系统，广泛参与抗炎与多种急慢性氧化应激损伤。多种理化因素通过不同的细胞内信号转导通路诱导HO-1的表达，这些信号通路涉及丝裂原活化蛋白激酶（MAPKs）、蛋白激酶C(PKC)、cAMP依赖的蛋白激酶A(PKA)、cGMP依赖蛋白激酶G（PKG）、酪氨酸蛋白激酶（TPK）、蛋白磷酸酶（PPs）、磷脂酰肌醇（-3）激酶（PI3K）/Akt     

血红素氧合酶对大鼠肺缺血再灌注损伤的保护作用

探讨血红素氧合酶 1(HO 1)对大鼠肺缺血再灌注损伤 (I/R)的保护作用。Wistar大鼠随机分成假手术 (sham)组、I/R组、Hemin组和ZnPP IX组。采用夹闭大鼠左肺门 30min ,再灌注 12 0min ,分别观察各组HO 1活性 ,肺组织形态学变化 ,肺湿干重比、伊文思蓝含量、支气管肺泡灌洗液 (BALF)中细胞计数及蛋白含量变化。与sham组比较 ,I/R组和hemin组肺组织HO 1活性显著增高 (P <0 0 1) ,ZnPP IX组能取消hemin诱导的HO 1活性增高 (P <0 0 1)。光镜下可见I/R组和ZnPP IX组肺组织水肿 ,部分动物肺泡腔中可见出血 ,并伴有局部肺不张 ,而hemin组肺组织形态学改变明显减轻。Hemin组肺湿干重比、伊文思蓝含量、BALF中细胞数和蛋白含量均低于I/R组和ZnPP IX组 ,但仍高于sham组 (P <0 0 1)。结果提示 ,HO 1对在体大鼠肺I/R损伤具有部分保护作用