促红细胞生成素对缺血/再灌注心肌保护作用的研究进展

背景 促红细胞生成素(erythropoietin,EPO)是一种造血刺激因子,过去20多年中用于临床多种原因所致的贫血.随着对EPO及其受体在心血管方面作用的认识,增加了EPO在生理和病理生理方面作用的理解. 目的 将心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)减轻到最低限度. 内容 研究EPO在心脏中的表达及其在心肌保护中所涉及的传导机制,EPO在动物心血管疾病实验模型中起到心肌保护作用及目前EPO心肌保护作用的临床相关研究. 趋向 近年来,EPO心肌保护作用临床研究的报道逐渐增多,为临床心肌保护提供了新的方向,但需要更深入研究EPO的心肌保护作用.     

促红细胞生成素预处理对缺血-再灌注心脏保护作用的研究进展

促红细胞生成素(EPO)原本是机体缺氧状态下分泌的刺激骨髓造血细胞,促进红系祖细胞增生分化的糖蛋白激素.近年来的研究表明,EPO尚具有多种非血液系统生理效应,是一种多功能的组织保护因子,其中包括对心脑等重要脏器缺血-再灌注损伤的保护作用.本文就EPO及其受体的结构,对缺血-再灌注心肌的保护作用及可能的机制等作一综述.     

促红细胞生成素衍生物的肾脏保护作用研究现状与展望

促红细胞生成素(EPO)除了具有造血活性外,还可通过抗凋亡、抗炎、抗氧化应激等途径对肾组织产生保护作用。但大剂量全身性地使用会引发高血压、红细胞增多症、血栓形成等严重的血源性不良反应。近年来的研究发现EPO衍生物可起到与EPO类似的肾脏保护作用而无明显的血源性副作用。该文概括EPO主要的肾脏保护作用机制,并重点介绍EPO衍生物在肾损伤中的保护作用及其机制,旨在对EPO衍生物的研究现状有一个科学认识。     

红细胞生成素在脊髓损伤中抑制细胞凋亡的作用

红细胞生成素(erythropoietin;EPO)是细胞因子超家族的成员之一,除具有促进祖红细胞的增生、分化和成熟的功能外,还具有抗血管痉挛、抗凋亡和抗炎等多种功能。EPO及其受体不仅存在于造血系统中,还存在于中枢和周围神经系统中,EPO除对多种原因引起的脑损伤具有保护作用外,对急性脊髓损伤及其继发性损伤也具有保护作用。近期研究发现其中最主要的保护机制是抑制细胞的凋亡。目前研究认为,抑制神经元细胞凋亡是EPO短期神经保护作用的基础,而EPO的神经营养作用则具有长期保护效果。但其抑制细胞凋亡的细胞内信号传导途径、对神经细胞的营养作用需要进一步的研究。     

促红细胞生长素对神经保护作用及其机制

促红细胞生长素（erythropoietin,EPO)目前临床上治疗肾性贫血的主要药物。近年研究发现EPO在中枢神经系统内在大量分布及其受体的广泛表达，对中枢神经系统的发育起着重要的调节作用并对各种中枢神经系统损伤有很好的保护作用。本文针对EPO作为一个神经保护剂，对其神经保护作用和其保护机制作简要综述。     

促红细胞生成素在急性肾损伤治疗中的应用及作用机制

急性肾损伤（acute kidney injury,AKI）是一组临床综合征,近年来急性肾损伤的发生率及其死亡率逐年增长,故探索一些新的药物治疗方式引起人们广泛关注。促红细胞生成素（erythropoietin,EPO）是一种糖蛋白,目前临床上主要应用于肾性贫血的治疗,近年来有研究发现EPO拥有许多治疗贫血之外的组织保护功能：如抗氧化应激、抗凋亡、抗炎、促进肾小管上皮细胞及血管生成、促干细胞迁移等等;本文将对近几年EPO在急性肾损伤治疗中的应用及作用机制作一综述。     

吸入麻醉药预处理对心肌保护的作用机制

吸入麻醉药对心肌具有预处理作用，这为术中心肌保护的研究和应用提供了新的方向。目前有关吸人麻醉药预处理的机制尚未完全阐明，本文简要综述了吸人麻醉药在ATP敏感性钾通道开放、细胞膜受体一抑制性G蛋白-PKC信号通路激活、心肌微血管保护等方面的研究进展。     

促红细胞生成素与肾缺血再灌注损伤

缺血再灌注损伤(IRI)在肾移植过程中是不可避免的，近来研究发现促红细胞生成素(EPO)能显著减轻肾脏的IRI，保护肾脏的结构和功能。本文综述了EPO在肾脏缺血再灌注损伤中的作用及可能机制。     

低氧诱导因子-1/低氧反应元件通路在心肌保护中的研究进展

背景 低氧诱导因子-1 (hypoxia inducible factor-1,HIF-1)是目前公认的在缺氧状态下发挥重要作用的核转录因子,其活化后可介导低氧反应保护作用,在一定程度上能够减轻心肌的缺血/再灌注损伤(ischemic reperfusion injury,I/RI).目的 探究HIF-1/低氧反应元件(hypoxia response element,HRE)通路是如何被激活并发挥心肌保护的作用. 内容 从HIF-I的概述、调节以及HIF-1/HRE通路的激活机制及其心肌保护作用方面进行综述,并以HIF-1为靶点探究后处理的心肌保护作用的机制,对其在心肌保护作用中与其他关键性的转录因子之间的内在联系作一简要综述. 趋向 后处理能否激活HIF-1/HRE通路诱导红细胞生成素(erythropoietin,EPO)、血红素加氧酶1(hemeoxygenase1,HO-1)、诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)和血管内皮生长因子(vascular endothelial growth factor,VEGF)等保护性蛋白的表达,以减轻心肌I/RI,尚需进一步探讨.     

促红细胞生成素与缺氧性脑损伤

促红细胞生成素(erythropoietin,EPO)是神经系统的一种神经营养因子和神经保护因子.EPO及其受体(erythro-poietin receptor,EPOR)在神经元、星形胶质细胞、少突胶质细胞、小胶质细胞和血管内皮细胞都可表达.脑组织缺氧缺血性损伤首先激活低氧诱发因子-1(HIF-1).后者促进EPO的分泌和表达,EPO和EPOR结合引发下游信号的级联反应表现出脑保护作用,其脑保护作用体现在抗凋亡、抗氧化、抗炎症等方面.众多动物实验和临床应用都证实重组人红细胞生成素(recombi-nant human erythmpoietin,rhEPO)对脑缺氧缺血性疾病具有脑保护作用.     

Discovering erythropoietin's extra-hematopoietic functions: biology and clinical promise

A greatly expanded understanding of the biology of endogenous erythropoietin (EPO) has emerged since the early 1990s. Originally viewed as the renal hormone dedicated to erythrocyte production, it is now clear that EPO is produced locally by many other tissues in response to physical or metabolic stress. In its autocrine-paracrine roles, EPO mediates preconditioning (ischemic tolerance) and specifically limits the destructive potential of tumor necrosis factor alpha and other proinflammatory cytokines in the brain, heart, kidney, and other tissues. As local production of EPO is generally suppressed following injury, administration of exogenous EPO has been a successful therapeutic approach in preclinical and clinical studies, for example, following ischemia-reperfusion and toxin-induced renal injuries, and in human stroke. The therapeutic time window of tissue protection by EPO is typically very wide in experimental models, showing effectiveness when administered before, during, or after an insult and raising optimism for a high clinical potential. Although there is progress in understanding the signaling pathways responsible for EPO's tissue-protective actions that are similar to, but not as redundant as, those employed for erythrocyte maturation, much work remains to be carried out. Experimental observations also suggest the existence of EPO receptor (EPOR) isoforms mediating EPO's diverse biological activities and have identified a tissue-protective receptor complex consisting of the EPOR and the beta common receptor (CD131) subunit that is also employed by granulocyte-macrophage colony-stimulating factor, interleukin-3 and interleukin-5. Successfully engineered analogues of EPO that selectively activate tissue protection without stimulating hematopoiesis confirm the concept of a tissue-protective receptor and have significant potential utility in the investigational and therapeutic arenas.     

Experimental models of acute renal failure and erythropoietin: what evidence of a direct effect?

The kidney can achieve a structural and functional recovery after the damage induced by ischemia and reperfusion. This is due to the regeneration of epithelial tubular cells, the intervention of immature cells mainly localized in the medulla, and a small number of bone marrow-derived stem cells. In many instances, however, recovery is delayed or does not occur at all. The mechanisms allowing the renal cells to de-differentiate still need to be clarified in order to find a therapeutic approach that can amplify this ability and then stop the fibroid involution and the progression toward renal failure. Several authors have hypothesized a protective effect of EPO against ischemic and cytotoxic renal damage and observed that patients precociously treated with EPO showed a slower progression of renal failure. EPO has been demonstrated to have proliferative and anti-apoptotic effects in ischemia-reperfusion models in the brain and cell cultures. Moreover, EPO can mobilize stem cells and increase the plasmatic levels and the renal expression of VEGF. These effects seem to be dose-dependent and could be due to the activation of signal transduction systems, like Jak and STAT. In the presence of high doses of exogenous EPO or during the treatment with long-acting EPO-like molecules, non-specific receptors may be activated through a low-affinity link. Further investigations are needed to determine new therapeutic applications for EPO and other analogous hormones. Very long-acting molecules or molecules with cyto-protective but no erythropoietic effect may represent useful tools in the study of the molecular mechanisms underlying EPO's action and may have a rapid and safe therapeutic application.     

Unexpected renal actions of erythropoietin

Erythropoietin (EPO) in the renal cortex is synthesized by fibroblast-like cells that are in direct contact with capillaries and adjacent tubular cells. Prompted by this anatomical relationship, we asked whether renal cells express EPO receptors (EPORs) through which EPO could act as a renotropic cytokine. We found that all regions of human, rat and mouse kidney, mesangial and proximal and distal tubular cells express authentic EPORs. Similar EPOR expression was detected in kidney cancer cells, and in cyst epithelia from polycystic kidneys. In vitro, EPO stimulated mitogenesis in all normal and malignant cells, and cell survival and motogenesis in injured tubular cells. Since the normal kidney is essentially unresponsive to EPO, we hypothesized that EPO's cytokine effects in the kidney are revealed when tubular cells are induced to proliferate by a prior insult, as occurs in acute renal failure. Accordingly, we found that EPO treatment of rats with 'ischemic' acute renal failure afforded renoprotection and accelerated functional recovery.     

Effects of erythropoietin on posttraumatic place learning in fimbria-fornix transected rats after a 30-day postoperative pause

Human recombinant erythropoietin (EPO) has been shown to exert neuroprotective effects following both vascular and mechanical brain injury. Previously, we showed that behavioral symptoms associated with mechanical lesions of the hippocampus are nearly abolished due to EPO treatment. In these studies, the EPO administration took place simultaneously with the infliction of brain injury and the rehabilitation training started 6-7 days postoperatively. In the present study, we tested whether the therapeutic effect of EPO on the acquisition of an allocentric eight-arm radial maze spatial task also manifests itself if the rehabilitative training is postponed. Postoperatively, the animals were left without any specific stimulation for 30 days. The current results show an improved behavioral performance of the EPO-treated lesioned group relative to the saline-treated lesioned group, and confirm EPO's therapeutic effect even in case of postponed rehabilitation. However, compared to the control group, the EPO-treated lesioned group demonstrated an impaired task acquisition. All subjects eventually recovered functionally. Subsequently, the animals were given behavioral challenges during which the cue constellation in the room was changed. The challenges revealed that, although the EPO-treated lesion group had achieved the same level of task proficiency as the control group, the cognitive mechanisms mediating the task performance in the EPO-treated lesion group (as well as in the saline-treated lesion group) were dissimilar from those mediating the task in the control group. Both the EPO-treated and the saline-treated lesion group demonstrated an increased dependency on the original cue configuration.     

Erythropoietin and progression of CKD

In patients with primary as well as secondary chronic kidney disease (CKD), anemia has been identified as an independent risk factor for progression. In these patients anemia is thought to be a surrogate parameter for tissue hypoxia that perpetuates preexisting renal tissue injury, and treatment of anemia with recombinant human erythropoietin (rHuEPO) was therefore expected to retard progression. However, results of recently published large trials in patients with CKD did not fulfill these expectations. The reason for the discrepant findings may be distinct molecular pathways and/or EPO tissue receptor affinities that mediate the effect of EPO on erythropoiesis and tissue protection by EPO. A pivotal intracellular pathway is the activation of Akt (i.e., serine/threonine protein kinase B), but further potential pathways have been identified that may play an important role in tissue protection. In this study, we review data on the non-hematological effects of rHuEPO in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogue substances that are not related to anemia correction.     

Erythropoietin as neuroprotective and neuroregenerative treatment strategy: comprehensive overview of 12 years of preclinical and clinical research

Erythropoietin (EPO), originally discovered as hematopoietic growth factor, has direct effects on cells of the nervous system that make it a highly attractive candidate drug for neuroprotection/neuroregeneration. Hardly any other compound has led to so much preclinical work in the field of translational neuroscience than EPO. Almost all of the >180 preclinical studies performed by many independent research groups from all over the world in the last 12 years have yielded positive results on EPO as a neuroprotective drug. The fact that EPO was approved for the treatment of anemia >20 years ago and found to be well tolerated and safe, facilitated the first steps of translation from preclinical findings to the clinic. On the other hand, the same fact, naturally associated with loss of patent protection, hindered to develop EPO as a highly promising therapeutic strategy for application in human brain disease. Therefore, only few clinical neuroprotection studies have been concluded, all with essentially positive and stimulating results, but no further development towards the clinic has occurred thus far. This article reviews the preclinical and clinical work on EPO for the indications neuroprotection/neuroregeneration and cognition, and hopefully will stimulate new endeavours promoting development of EPO for the treatment of human brain diseases.     

Myocardial protection: some problems and recent progress]

One of the great advances in cardiac surgery in the past 20 years has been the concept of myocardial protection "cardioplegia". But even now, there are some controversies about the methods for myocardial protection. In this review, controversy between crystalloid and blood cardioplegia, between extracellular and intracellular cardioplegic solution are discussed. And then the recent advances in cardioplegia, terminal warm blood cardioplegia, retrograde infusion of cardioplegic solution and cardioplegia in infants are reviewed.     

Erythropoietin‐mediated protection in kidney transplantation: nonerythropoietic EPO derivatives improve function without increasing risk of cardiovascular events

The protective, nonerythropoietic effects of erythropoietin (EPO) have become evident in preclinical models in renal ischaemia/reperfusion injury and kidney transplantation. However, four recently published clinical trials using high‐dose EPO treatment following renal transplantation did not reveal any protective effect for short‐term renal function and even reported an increased risk of thrombosis. This review focusses on the current status of protective pathways mediated by EPO, the safety concerns using high EPO dosage and discusses the discrepancies between pre‐clinical and clinical studies. The protective effects are mediated by binding of EPO to a heteromeric receptor complex consisting of two β‐common receptors and two EPO receptors. An important role for the activation of endothelial nitric oxide synthase is proposed. EPO‐mediated cytoprotection still has enormous potential. However, only nonerythropoietic EPO derivatives may induce protection without increasing the risk of cardiovascular events. In preclinical models, nonerythropoietic EPO derivatives, such as carbamoylated EPO and ARA290, have been tested. These EPO derivatives improve renal function and do not affect erythropoiesis. Therefore, nonerythropoietic EPO derivatives may be able to render EPO‐mediated cytoprotection useful and beneficial for clinical transplantation.     

Erythropoietin ameliorates renal dysfunction during endotoxaemia.

BACKGROUND: Sepsis has a high mortality (50-80%) when associated with acute renal failure (ARF). Oxidant injury and proinflammatory cytokines and chemokines have been shown to increase with endotoxaemia-related ARF. Since erythropoietin (EPO) has been demonstrated to possess anti-oxidant and anti-inflammatory properties, EPO may have therapeutic efficacy for treating ARF associated with endotoxaemia. METHODS: Wild-type mice were given 2.5 mg/kg of intraperitoneal (i.p.) endotoxin, lipopolysaccharide (LPS), and studied 16 h later. Thirty minutes prior to LPS, the mice were given either EPO or vehicle. RESULTS: During endotoxaemia, EPO was found to significantly attenuate the renal dysfunction, as assessed by glomerular filtration rate (48.1 +/- 12.4 microl/min vs 136.7 +/- 30.2, P < 0.05). Renal blood flow and mean arterial pressure were not significantly different between the two groups. The renal dysfunction during endotoxaemia was associated with a decrease in renal superoxide dismutase (SOD). The EPO-related renal protection was associated with reversal of the effects of endotoxin on renal SOD. CONCLUSION: This is the first demonstration of a renal protective effect of EPO on endotoxin-related renal dysfunction.