右美托咪定对脏器缺血/再灌注损伤的保护作用机制

背景 右美托咪定(dexmedetomidine,Dex)是一种新型高选择性α2-肾上腺素受体(alpha-2-adrenergic receptor,α2-AR)激动剂,Dex除具有镇静、镇痛、围术期交感阻滞的作用外,大量的研究表明Dex对多脏器的缺血/再灌注损伤(ischemidreperfusion injury,I/RI)具有保护作用. 目的 综述国内外Dex对多脏器I/RI保护机制的研究进展,为Dex脏器保护机制的研究提供思路. 内容 Dex通过减轻再灌注过程中的氧化应激反应,降低炎性因子的表达,减少机体细胞凋亡,保护红细胞变形能力来发挥脏器保护作用. 趋势 随着Dex对多脏器I/RI的保护机制不断被阐明,将为其临床应用提供更为深入的理论基础.     

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.     

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.     

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.     

瑞芬太尼对缺血/再灌注损伤保护作用及可能机制的研究进展

背景 瑞芬太尼是一种新型的阿片受体激动剂,具有独特的快速起效和快速清除的优点,是麻醉过程中常用的镇痛药物.近来,发现瑞芬太尼对重要器官的缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)具有保护作用. 目的 回顾瑞芬太尼的基本理化特点及药代学特点,并讨论其对I/RI的保护作用和可能的作用机制. 内容 大量研究表明瑞芬太尼对心脏、肝脏、神经系统和肾脏的I/RI均有保护作用.其作用机制尚未明了,可能与阿片受体、蛋白激酶C与ATP敏感性钾离子通道、一氧化氮与一氧化氮合酶、抗凋亡通道等有关. 趋向 瑞芬太尼对于I/RI的保护作用,将进一步增加其临床应用价值,也为围术期器官保护提供新的思路.     

阿片受体激动剂预处理对器官缺血/再灌注损伤的保护作用

背景 μ、κ、δ、ε、σ及λ等多种阿片受体广泛存在于体内各器官,它们各自有其特异的内源性配体,发挥不同的生物效应,其对缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)器官的保护作用已引起医学界的广泛关注.目的 综述阿片受体激动剂对I/RI器官的保护作用的研究进展.内容 阿片受体激动剂...     

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.     

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.     

氢分子治疗缺血/再灌注损伤的研究进展

背景 活性氧在缺血/再灌注损伤(ischemia/reperfusion,Ⅰ/RI)中发挥重要作用.越来越多的研究表明氢气(hydrogen,H2)通过选择性清除活性氧簇(reactive oxygen species,ROS)保护各种细胞、组织、器官免受氧化损伤. 目的 分析总结氢对Ⅰ/R损伤的治疗作用及其可能机制,为更好地认识H2并将其应用于临床奠定基础. 内容 H2对Ⅰ/RI的作用机制并不明确,就H2对各器官Ⅰ/RI的治疗及可能机制进行阐述,并对H2作为一种治疗性气体在医学方面的应用前景做出展望.趋向 H2治疗Ⅰ/RI具有广阔的临床应用前景,但为了识别H2作用的确切机制及验证H2在临床上的治疗潜力还有很多工作要做.     

右美托咪定心脏保护作用的研究进展

背景 右美托咪定（dexmedetomidine,Dex）是高选择性α2肾上腺素能受体激动剂,具有镇静、镇痛、降低交感神经张力等作用,同时无呼吸抑制及脑电干扰等副作用,现已广泛应用于重症监护病房（ICU）及围术期辅助镇静。近期研究发现Dex具有心脏保护作用,如抗缺血/再灌注损伤（ischemia/repeffusion injury,I/RI）、抗心律失常等。 目的 对Dex心脏保护作用的研究进展作一综述,为其合理应用提供参考。内容 介绍Dex对心脏的保护作用及其相关机制。 趋向 深入研究Dex心脏保护作用及其机制有望改善相关患者的预后。     

炎症反应在心肌缺血/再灌注损伤中作用的研究进展

背景 心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)是指在缺血心肌恢复血流灌注后,细胞代谢功能障碍和结构破坏反而加重的现象,并且伴随有以炎症细胞浸润和细胞因子产生为特征的炎症反应.目前认为,炎症反应是I/RI的重要病理机制之一,再灌注诱发的炎症反应及其介质可加重心肌I/RI,而...     

The effects of dexamethasone on human patellar tendon stem cells: Implications for dexamethasone treatment of tendon injury

Injection of Dexamethasone (Dex) is commonly used in clinics to treat tendon injury such as tendinopathy because of its anti‐inflammatory capabilities. However, serious adverse effects have been reported as a result of Dex treatment, such as impaired tendon healing and tendon rupture. Using both in vitro and in vivo approaches, this study was to determine the effects of Dex treatment on the proliferation and differentiation of human tendon stem cells (hTSCs), which can directly impact tendon healing. We found that Dex treatment stimulated cell proliferation at lower concentrations (<1,000 nM), whereas a high concentration (1,000 nM) decreased cell proliferation. Moreover, at all concentrations used (5, 10, 100, and 1,000 nM), Dex treatment induced non‐tenocyte differentiation of hTSCs, as evidenced by a change in cell shape, a nearly complete suppression of collagen type I expression, and an upregulation of non‐tenocyte related genes (PPARγ and Sox‐9), which was especially evident when higher concentrations (>10 nM) of Dex were used. Implantation of Dex‐treated hTSCs for a short time (3 weeks) resulted in the extensive formation of fatty tissues, cartilage‐like tissues, and bony tissues. These findings suggest that Dex treatment in clinics may cause a paradoxical effect on the injured tendons it is supposed to treat: by inducing non‐tenocyte differentiation of hTSCs, Dex treatment depletes the stem cell pool and leads to the formation of non‐tendinous tissues (e.g., fatty and cartilage‐like tissues), which make tendon susceptible to rupture. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:105–110, 2012     

右美托咪定预处理对大鼠心肌缺血/再灌注损伤时心肌组织高迁移率族蛋白B1的影响

目的 探讨右美托咪定(dexmedetomidine,Dex)预处理对大鼠心肌缺血/再灌注损伤(myocardial ischemia/reperfusion injury,MFRI)时心肌组织高迁移率族蛋白B1(high mobility group box-1 protein,HMGB1)表达量的影响. 方法 健康雄性SD大鼠52只,体重250～300 g,按随机数字表法分为4组(每组13只):假手术组(S组)、缺血/再灌注(ischemia/reperfusion,I/R)组(I/R组)、Dex+I/R组(D组)、Dex+育亨宾+I/R组(D/Y组).结扎左冠状动脉前降支30 min,恢复灌注120 min制备MI/RI模型.再灌120 min时采血ELISA法测定血清中IL-6、TNF-α浓度,随后处死大鼠摘取心脏,用2,3,5-氯化三苯基四氮唑(2,3,5-triphenyltetrazolium chloride,TTC)染色法测定心肌梗死面积,Western blot法测定心肌组织HMGB1蛋白的表达量. 结果 与S组比较,I/R组血清中IL-6、TNF-α含量[(336±41)、(636±25) ng/L]均显著增高(P＜0.05),心肌梗死面积明显增大(P＜0.05),心肌组织HMGB1蛋白表达量明显升高(P＜0.05);与豫组比较,D组血清中IL-6、TNF-α含量[(153±10)、(233±9) ng/L]均明显降低(P＜0.05),心肌梗死面积明显减少(P＜0.05),心肌组织HMGB1蛋白表达量显著降低(P＜0.05);与D组比较,D/Y组血清中IL-6、TNF-α含量[(230±20)、(386±32) ng/L]均显著增高(P＜0.05),心肌梗死面积明显增大(P＜0.05),心肌组织HMGB1蛋白表达量明显升高(P＜0.05). 结论 Dex预处理减轻MI/RI心肌组织HMGB1的表达量,减轻I/R损伤的炎症反应.Dex通过α2受体发挥保护作用.     

FTY720 for treatment of ischemia-reperfusion injury following complete renal ischemia in C57/BL6 mice

BACKGROUND: Organ dysfunction followed by single-organ or even multiorgan failure due to ischemia-reperfusion injury (I/RI) is a common problem in liver and heart transplantation. Various approaches had been attempted to prevent this I/RI. One is the administration of FTY720, a synthetic structural analogue of sphingosine, which induces T-lymphocyte homing with consecutive lymphopenia. The purpose of this study was to evaluate the effect of intraoperative FTY720 administration following controlled bilateral kidney ischemia in comparison to steroid or placebo application. METHODS: Male c57BL6/J mice (n = 115; body weight 25 to 30 g) received either FTY720 (1 mg/kg body weight) or steroids or saline solution. Ischemia was applied for 30 or 60 minutes with subsequent follow-up for 48 hours. At termination all surviving animals were sacrificed. RESULTS: Following 30 minutes of ischemia, FTY720, but neither steroid nor vehicle treatment showed significant protective effects on long-term survival after controlled bilateral warm kidney ischemia. Fluorescein-activated cell sorting (FACS) analysis showed a significant T-lymphocyte depletion in peripheral blood after FTY720 treatment, which was not observed after steroid or vehicle treatment. CONCLUSION: The improved long-term survival shown in this study might be due to a protective effect of FTY720 to prevent I/RI, which may be mediated by the lymphocyte depletion shown in the FACS analysis.     

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?     

Dexamethasone enhances the effects of parathyroid hormone on human periodontal ligament cells in vitro

Periodontal ligament cells (PDL) are thought to play a major role in promoting periodontal regeneration. Recent studies, focused on characterizing PDL cells, have been directed at establishing their osteoblast-like properties and determining biological mediators and/or factors that induce osteoblastic cell populations in the PDL. The glucocorticoid, dexamethasone (Dex), has been shown to selectively stimulate osteoprogenitor cell proliferation and to induce osteoblastic cell differentiation in many cell systems. In the present study the ability of Dex to modulate parathyroid hormone (PTH)-stimulated cAMP synthesis in cultured human PDL cells was examined. PDL cells, obtained from premolar teeth extracted for orthodontic reasons, were cultured with Dex (0–1000 nM) for 7 days prior to PTH (1–34) stimulation. The exposure of PDL cells to Dex resulted in a dose-dependent increase in cAMP production in response to PTH stimulation. This response was seen in cells obtained from three different patients. The first significant Dex effect was seen on day 7 when compared to day 1 for 100 nM Dex. PTH (1–34) stimulation caused a dose-dependent increase in cAMP synthesis after Dex (1000 nM) treatment for 7 days. Conversely, stimulation of the cells with PTH (7–34) (0–1000 nM) did not increase cAMP production in PDL cells after Dex treatment. Forskolin- (1 M) and isoproterenol- (1 M) stimulated cAMP synthesis was not augmented by Dex treatment. Dex treatment did not alter calcitonin-(1 M) stimulated cAMP production in PDL cells. Glucocorticoid enhancement of PTH-stimulated cAMP synthesis in these cells supports the presence of an osteoblast-like population in the PDL, in vitro.     

Development of mineralized nodules in fetal rat mandibular osteogenic precursor cells: requirement for dexamethasone but not for beta-glycerophosphate

We have reported that a cell population obtained from fetal rat mandible with neutral protease (Pro I) has a unique differentiation sequence in which the elevation of alkaline phosphatase (ALPase), calcium accumulation, and collagen synthesis occurs simultaneously. In this report, we further characterized Pro I-released population of cells by studying the effect of dexamethasone (Dex) or β-glycerophosphate (β-GP) on the formation of bone nodules. The formation of bone nodules in Pro I-released population of cells (ProIRPC) was augmented by the addition of Dex (10⁻⁷ M) from days 3 to 14, suggesting that Pro IRPC contained osteoprogenitor (OP) cells. A 24-hour pulse treatment of ProIRPC released population of cells with Dex on days 9 and 12 resulted in an increase in the number of nodules but treatment on days 3, 6, or 15 did not. The number of bone nodules formed in Pro IRPC pulse treated with Dex on day 9 was comparable with that in Pro IRPC treated with Dex from days 3 to 14. Dex caused an earlier elevation of ALPase, in which maximal expression was observed on day 10. β-GP caused a prolonged elevation of ALPase, but did not affect the formation of bone nodules. Unlike Pro I-released population of cells, rat calvarial cells did not form mineralized nodules without β-GP, and showed that a Dex-responsive period on bone nodule formation in rat calvarial cells was at preconfluency (days 0 and 1). Thus, it appeared that the Dex-induced differentiation of early OP cells in Pro IRPCs occurred during the limited period from day 9 to day 12. Pro IRPC was found to have an unique characteristic that bone nodule formation was not affected by β-GP. Received: 22 July 1998 / Accepted: 26 July 1999