小胶质细胞在缺血性脑卒中中作用机制的研究进展

正脑卒中是导致人们死亡和残疾的重要疾病之一,可分为缺血性和出血性脑卒中,其中缺血性脑卒中占绝大部分,并且由于缺血造成的一系列的反应会造成神经元的功能失调以及死亡~([1]),同时也可能破坏血脑屏障造成进一步的脑水肿与炎症反应~([2]),使病情进一步恶化。在缺血性脑卒中的病理机制中,炎症反应发挥着重要的作用。缺血性脑卒中之后,脑内固有的小胶质细胞被活化~([3])。最初研究认为小胶质细胞在急性期会加剧脑组织的损伤~([4]),但是随着研究的深入,     

调节性T细胞在缺血性脑卒中的作用

正Treg细胞(Regulatory T cells,调节性T细胞)在缺血性脑卒中炎性反应中起着重要作用,Treg细胞缺乏与功能低下是脑卒中炎性进展的重要原因,它能分泌抗炎因子,并且促进神经损伤修复,近来研究显示Treg细胞有治疗缺血性脑卒中的潜力。因而,进一步研究Treg细胞在缺血性脑卒中的作用具有重要意义。缺血性脑卒中是指由于脑的供血动脉狭窄或闭塞、脑血     

小胶质细胞与脑缺血

目前许多研究均支持免疫性炎症反应参与了缺血性中风后的脑损伤。脑缺血后数小时，受损脑区域的炎症反应开始启动，持续数天，使脑缺血所致的迟发性脑损伤加重、神经细胞的生物学功能预后更差，而中枢神经系统（CNS）最主要的免疫效应细胞小胶质细胞则是免疫性炎症反应的重要角色，尤其在半月带，小胶质细胞的活化异常活跃，活化的小胶质细胞与白细胞一样，会释放和分泌大量的前炎症因子、酶和神经营养因子，因此小胶质细胞在脑缺血损伤中的作用逐渐受到关注。深入研究小胶质细胞在脑缺血过程中的作用，将为临床治疗脑缺血提供新的途径。现将小胶质细胞在脑缺血病理过程中的功能、来源及免疫反应综述如下。     

酮体在缺血性脑卒中中的神经保护作用

缺血性脑卒中是脑血管病最常见的类型,严重影响人类健康和生命,目前缺乏有效的治疗手段。酮体(KB)通常在禁食状态或高脂饮食中通过脂肪酸氧化而产生,是营养缺乏状态下大脑的重要燃料来源。它已用于临床抗难治性癫痫的治疗,其安全性和有效性已得到国际公认。近年来发现酮体可能通过抗氧化应激、调节炎症反应、增加脑血流量、改善能量代谢、抑制胶质细胞增生等方面对缺血性脑卒中进行保护作用,为开发缺血性脑卒中的治疗、寻找其治疗靶点提供理论基础。     

小胶质细胞在出血性脑卒中发病机制中的研究进展

出血性脑卒中(intracerebral haemorrhage,ICH)是脑卒中致死率最高的类型,目前临床对其仍缺乏有效的治疗方法。小胶质细胞是ICH后第一个产生免疫应答的中枢神经系统细胞。ICH急性期脑损伤后,小胶质细胞可被诱导为经典的M1型(促炎作用)或补充替代的M2型(抗炎作用),其中,M1型抑制中枢神经系统的修复,M2型通过分泌抗炎因子和神经营养因子来促进组织的再生和修复。同时,小胶质细胞与星形胶质细胞、神经元、少突胶质细胞以及T淋巴细胞生理病理上具有紧密联系,其M1型和M2型极化与其他神经细胞产生不同的交互作用,这些均在ICH的病理过程中具有至关重要的作用。基于此,本文对ICH后小胶质细胞和其他神经细胞的相互作用的关键分子机制进行综述。     

免疫炎症与脑卒中的基础及临床研究

脑卒中因其高发病率、高致残率和高死亡率的特点,已成为危害人类健康的重大疾病。急性缺血性脑卒中发病后,血脑屏障遭到破坏,大量免疫细胞涌入中枢神经系统并与中枢神经系统内的免疫细胞相互作用,从而进一步放大炎症反应,加重缺血性脑损伤。免疫炎症反应贯穿于缺血性脑卒中的损伤和修复过程,其中小胶质细胞发挥着重要作用。本文对急性缺血性脑卒中的炎症损伤机制进行了总结,并介绍了当前有关免疫调节剂干预脑卒中的临床试验,继而提出脑卒中临床试验面临的问题以及对未来脑卒中免疫治疗的展望。     

组织型纤溶酶原激活剂对神经血管单元功能影响的研究进展

组织型纤溶酶原激活剂(tPA)是体内重要的丝氨酸蛋白激酶,已被美国FDA批准用于急性缺血性脑卒中超早期溶栓治疗。tPA也在神经血管单元中广泛表达,通过与不同细胞表面受体相互作用介导细胞信号传导,在不同的病理过程中发挥重要作用,影响神经元、胶质细胞和血脑屏障的功能。本文就近年来该领域的研究进展做一综述。     

缺血性脑卒中后微血管形成

缺血性脑卒中的发病率及致残率高，严重危害了人类健康。尽快恢复缺血区的血供，挽救濒死的神经元、神经胶质细胞和神经内皮细胞是治疗缺血性脑卒中的关键。治疗性血管新生为其提供了新思路。有关脑缺血后新血管形成的病理过程、机制及其调控因素已成为研究的热点。本文就缺血性脑卒中后微血管形成及治疗性血管新生的有关问题综述如下。     

小胶质细胞体外培养的研究新进展

组成中枢神经系统的细胞大部分是神经胶质细胞,包括大胶质细胞(星型胶质细胞和少突胶质细胞)和小胶质细胞;小胶质细胞是中枢神经系统的主要免疫细胞,具有提呈抗原、分泌多种细胞因子、吞噬病原体和坏死组织的作用,被认为是脑内的单核巨噬细胞.由于小胶质细胞在颅内免疫反应中的重要作用,对于小胶质细胞的研究已成为热点;小胶质细胞的体外培养是小胶质细胞功能研究的重要途径,本文将对近年来小胶质细胞的体外培养研究进展作一综述.     

缺血性卒中免疫调节治疗的研究进展

在缺血性卒中的病理过程中,免疫系统通过固有免疫反应和适应性免疫反应发挥着重要 的作用。缺血性卒中发生后,一方面通过激活的免疫细胞释放破坏性细胞因子,损伤血管内皮,破 坏血脑屏障和神经元,并在淋巴细胞与特异性抗原结合后诱发适应性免疫反应,加重神经元损伤; 另一方面通过清除坏死组织,释放保护性细胞因子,调节免疫抑制等途径减轻神经元损伤。免疫调 节治疗为卒中的治疗提供了一个新的方向,以芬戈莫德、米诺环素、那他珠单抗等药物为代表的免疫 调节药物在缺血性卒中动物模型实验和临床研究中都呈现出较好的疗效。本文就缺血性卒中免疫调 节治疗的研究进展做一综述。     

Elevated levels of anti-heat shock protein antibodies in patients with cerebral ischemia

One of the important mechanisms involved in the development of vascular lesions leading to ischemic stroke could be an immune response to heat shock proteins (hsp). For carotid atherosclerosis and myocardial infarction, an association with an increase in anti-hsp 65 antibodies has been demonstrated. The aim of our study was (1) to investigate whether ischemic stroke is associated with a humoral immune response to hsp; (2) to study the connection between anti-hsp antibodies and other stroke risk factors; (3) to estimate if the elevated levels of anti-hsp antibodies could be an independent risk factor for stroke. We examined 180 patients (in the first 48 h after stroke onset) and 64 age-matched healthy controls. The levels of IgG and IgM antibodies to hsp 65 and 70 were measured by ELISA. Ischemic stroke was connected with a significant elevation of anti-hsp 65 and anti-hsp 70 antibody levels (IgG and IgM) compared with controls (p < 0.0001). The multifactorial logistic regression analysis showed that increased levels of anti-hsp 65 and anti-hsp 70 IgG antibodies are independent risk factors for stroke. Our results suggest that humoral immunity to hsp is common in stroke patients and that elevated levels of anti-hsp antibodies could be triggering factors for stroke.     

Immunological consequences of ischemic stroke

The treatment of ischemic stroke is one of the great challenges in modern neurology. The localization and the size of the infarct determine the long‐term disability of stroke survivors. Recent observations have revealed that stroke also alters the function of the immune system and vice versa: At the site of the infarct, a local inflammatory response develops that enhances brain lesion development. In experimental stroke, proof‐of‐concept studies confirm that inhibition of this immune response reduces lesion volume and improves outcome. In the peripheral blood of stroke patients, though, lymphocytopenia and monocyte dysfunction develop. These changes reflect a clinically relevant impairment of bacterial defense mechanisms because they are associated with an enhanced risk to acquire post‐stroke infections. Stress hormones have been identified as important mediators of stroke‐induced immune suppression. The pharmacological inhibition of beta adrenergic receptors, but not the inhibition of steroids, is effective in reducing infection and improving clinical outcome in experimental stroke; catecholamine release therefore appears causally related to stroke‐induced immune suppression. Strong evidence supports the hypothesis that these immune alterations impact the clinical course of stroke patients. Thus, the development of new therapeutic strategies targeted to alter the immunological consequences of stroke appears promising. However, to date, the beneficial effects seen in experimental stroke have not been successfully translated into a clinical trial. This brief review summarizes the current understanding of the immunological consequences of ischemic stroke. Finally, we propose a concept that links the peripheral immune suppression with the development of local inflammation.     

Microglia-associated neuroinflammation is a potential therapeutic target for ischemic stroke

Microglia-associated neuroinflammation plays an important role in the pathophysiology of ischemic stroke. Microglial activation and polarization, and the inflammatory response mediated by these cells play important roles in the development, progression and outcome of brain injury after ischemic stroke. Currently, there is no effective strategy for treating ischemic stroke in clinical practice. Therefore, it is clinically important to study the role and regulation of microglia in stroke. In this review, we discuss the involvement of microglia in the neuroinflammatory process in ischemic stroke, with the aim of providing a better understanding of the relationship between ischemic stroke and microglia.     

炎症反应与缺血性卒中

炎症反应是缺血性卒中后病理生理的核心内容,其过程涉及免疫和炎症细胞,不同途径 和来源的被激活的炎症因子共同参与。早期小胶质细胞、中性粒细胞被激活,随之淋巴细胞的聚集 和浸润也增加了对脑细胞的损伤;但也有研究发现,在特定刺激下,中性粒细胞可以从促炎表型向 抗炎表型转变,进而保护脑细胞;淋巴细胞中部分T细胞亚型可以抑制促炎因子的表达、调节淋巴细 胞的活性,从而起到脑保护作用。另外,在缺血性卒中后,除脑内局部的炎症反应外,外周循环的炎 性反应和免疫抑制也参与其病理机制。免疫调节有望成为未来缺血性卒中治疗的靶点。     

The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice

The development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, a flavonoid, has multiple biological effects, including neuroprotective and antiinflammatory properties. We analyzed the effects of fisetin on infarct size and the inflammatory response in a mouse model of stroke, temporary middle cerebral artery occlusion, and on the activation of immune cells, murine primary and N9 microglial and Raw264.7 macrophage cells and human macrophages, in an in vitro model of inflammatory immune cell activation by lipopolysaccharide (LPS). Fisetin not only protected brain tissue against ischemic reperfusion injury when given before ischemia but also when applied 3 hours after ischemia. Fisetin also prominently inhibited the infiltration of macrophages and dendritic cells into the ischemic hemisphere and suppressed the intracerebral immune cell activation as measured by intracellular tumor necrosis factor α (TNFα) production. Fisetin also inhibited LPS-induced TNFα production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor κB activation and JNK/Jun phosphorylation. Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia.     

Immunomodulators and microRNAs as neurorestorative therapy for ischemic stroke

Most of all strokes are ischemic due to occlusion of a vessel, and comprise two main types, thrombotic and embolic. Inflammation and immune response play an important role in the outcome of ischemic stroke. Pharmaceutical and cell-based therapies with immunomodulatory properties could be of benefit in treating ischemic stroke. Possible changes in microRNAs brought about by immunomodulatory treatments may be important. The pharmaceutical studies described in this review have identified several differentially regulat-ed miRNAs associated with disregulation of mRNA targets or the upregulation of several neuroprotective genes, thereby highlighting the potential neuroprotective roles of specific miRNAs such as miR-762, -1892,-200a, -145. MiR-124, -711, -145 are the strongly associated miRNAs predicted to mediate anti-inflamma-tory pathways and microglia/macrophage M2-like activation phenotype. The cell-based therapy studies reviewed have mainly utilized mesenchymal stem cells or human umbilical cord blood cells and shown to improve functional and neurological outcomes in stroke animals. MiR-145 and miR-133b were implicated in nerve cell remodeling and functional recovery after stroke. Human umbilical cord blood cells decreased proinflammatory factors and promoted M2 macrophage polarization in stroke diabetic animals.     

缺血性卒中与免疫反应

【摘要】 免疫和炎症反应是缺血性卒中病理过程的重要组成部分,自然免疫和适应性免疫都参与
这一过程。免疫反应不仅仅造成炎性损伤,引起外周血和免疫器官出现相应的免疫调节,还在缺血
性脑损伤后的脑组织修复和重建中发挥重要作用。抑制缺血诱导的炎症反应和进行免疫调节具有脑
保护和脑组织修复/重建作用,可能是缺血性脑损伤的一种新的治疗途径。目前关于缺血性脑损伤
的免疫治疗还存在诸多问题,需要深入了解免疫系统功能和脑缺血损伤之间的相互作用,以确保免疫
治疗的可行性、有效性和安全性。     

CD4+CD25+Treg细胞与缺血性卒中的研究进展

调节性T细胞（regulatory T cell,Treg）是T细胞的一种重要亚群,对于维持机体免疫自稳、防止自身免疫病等具有重要的作用。目前认为,免疫炎性反应贯穿于缺血性卒中发生发展的全过程,脑缺血及缺血后的再灌注所引发的免疫炎性反应在脑缺血再灌注损伤中发挥重要作用。Treg细胞作为负性免疫调节作用细胞,能够明显抑制脑缺血再灌注损伤引起的局部炎性反应,具有一定的脑保护作用。本文综述了CD4⁺CD25⁺Treg细胞在缺血性卒中发病机制中的作用。