反应性星形胶质细胞与轴突再生

星形胶质细胞是中枢神经系统中最丰富的胶质细胞类型,中枢神经系统损伤后,星形胶质细胞在形态和分子表达上发生变化形成反应性星形胶质细胞。反应性星形胶质细胞对轴突再生有着双重影响。一方面,反应性星形胶质细胞能分泌神经营养因子,具有神经保护和修复作用;另一方面,反应性星形胶质细胞若过度增殖形成胶质瘢痕,则抑制轴突再生,不利于神经功能恢复。     

反应性星形胶质细胞的异质性及其在神经变性疾病中的作用

正几乎在所有中枢神经系统(central nervous system,CNS)疾病中,均可观察到星形胶质细胞(astrocyte,AST)活化的现象,包括脑感染、脊髓损伤、脑卒中、癫痫等,AST活化在以上疾病进程中具有重要作用~([1])。在CNS病变中,AST经历增生、活化等过程,最终转变成反应性星形胶质细胞(reactive astrocytes,RAS)~([2,3])。传统观念认为RAS阻碍神经修复,但新近研究表明RAS具有极大的异质性,可划分为     

大鼠局灶性脑缺血损伤后星形胶质细胞和神经元的动态变化

目的探讨脑缺血损伤后星形胶质细胞和神经元在时间和空间上的动态变化。方法健康雄性Wistar大鼠48只．随机分为假手术组、缺血0．5～24h组，采用大脑中动脉线栓模型．结合组织学和SP免疫组化方法，动态观察缺血不同时间神经元和星形胶质细胞分布、形态．通过组织化学染色，观察星形胶质细胞的周长和积分光度值的改变。结果星形胶质细胞对缺血极为敏感；缺血灶周边区和对侧半球反应性星形胶质细胞增生明显；反应性星形胶质细胞分布区神经元损伤较轻。结论反应性星形胶质细胞参与脑保护及促进损伤神经元修复。     

7β-羟基胆固醇减少铁离子所致的大鼠脑反应性胶质增生

目的研究7β-羟基胆固醇(7βOHCH)抗脑损伤后反应性星形胶质细胞增生的作用及其意义。方法 在大鼠脑皮质注射铁离子致胶质细胞增生，损伤部位同时注入含7βOHCH脂质体悬液或不含7βOHCH脂质体悬液，用免疫组化和图像分析技术观察各组大鼠脑损害改变及胶质纤维酸性蛋白阳性细胞数。结果 注入铁离子的大鼠脑损伤周围皮质有大量炎性细胞浸润，胶质纤维酸性蛋白阳性细胞数比对照组明显增多，注入7βOHCH的大鼠脑损伤周围皮质细胞结构、胶质纤维酸性蛋白阳性细胞数与对照组相似。结论 7βOHCH对反应性星形胶质细胞增生有明显抑制作用，为防止脑损伤后反应性胶质增生和帮助脑功能恢复提供了又一途径。     

神经系统损伤后星形胶质细胞激活的研究进展

中枢神经系统损伤后星形胶质细胞的反应对创伤愈合具有重要作用。文中就损伤后星形胶质细胞激活、增生和迁移的调控机制及信号通路进行综述。     

低能激光照射及嗅鞘细胞移植在脊髓损伤中的应用

脊髓损伤是一种严重危害人类健康的疾病，因其少突胶质细胞不能形成轴突迁移引导的通道，并分泌抑制因子，以及星形胶质细胞在损伤区快速反应性增生形成胶质瘢痕，抑制轴突的生长，使脊髓损伤的治疗成为目前医学领域的一个棘手问题。嗅鞘细胞具有良好的轴突再生和准确形成靶特异性突轴连接的能力；低能激光照射对神经系统及嗅鞘细胞的作用包括，保留甚至促进受损神经元的活性，减少瘢痕的形成，阻止神经元的退行性改变，又能通过干拢一些因素而增强嗅鞘细胞的活性。嗅鞘细胞移植及低能激光照射在脊髓损伤的修复中具有重要的作用。     

中枢神经系统损伤与胶质纤维酸性蛋白

中枢神经系统损伤时,星形细胞由常态转化为反应状态,这些反应性星形细胞在中枢神经系 统对损伤的反应中起着重要作用,其转化的生化特征是星形细胞内胶质纤维酸性蛋白的增多。本文就中枢神经系统损伤时星形细胞的反应作一综述。     

星形胶质细胞在多发性硬化发病中的作用机制

星形胶质细胞是中枢神经系统中数量最多的胶质细胞,其生理功能为支持和营养神经元,参与免疫调节和神经递质代谢,支持血-脑脊液屏障,调节神经细胞内、外离子浓度等。星形胶质细胞在多发性硬化(multiple sclerosis,MS)中反应性增生,此现象称为星形胶质细胞活化。活化的星形胶质细胞一方面产生一些具有神经损伤的细胞因子,另一方面能分泌有利于神经系统恢复的因子来促进神经生长和修复。因而星形胶质细胞在MS中具有双重角色。在MS发病机制中明确星形胶质细胞在不同发病阶段的作用倾向,可能为MS的治疗提供新的治疗策略。     

缺血预处理后海马CA1区反应性星形胶质细胞增生与迟发性神经元缺血耐受性的关系

目的 探讨缺血预处理后海马CA1区反应性星形胶质细胞增生与迟发性神经元缺血耐受性的关系。方法 实验动物被随机分为手术组、缺血组、预缺血组、预缺血后再缺血组。阴断沙土鼠双侧颈总动脉造成前脑缺血模型。采用细胞特异性抗原胶质纤维酸性蛋白（GFAP）免疫组化法标记星形胶质细胞。结果 预缺血后1－7天,海马CA1区GFAP阳性的星形胶质细胞数轻度增加,至28天时增生非常显著（P＜0．01）。预缺血后1－7天再缺血,海马CA1区存活正常神经元数逐渐下降,预缺血后28天再缺血又显著增加（P＜0．01）。结论 缺血预处理后,神经元可出现迟发性缺血耐受,反应性星形胶质细胞增生可能起了重要作用。     

体外星形胶质细胞损伤后炎症模型的建立及应用

目的建立胶质细胞损伤后体外炎症模型，探讨轻度低温、槲皮素及清蛋白对白细胞黏附及胶质细胞损伤的影响。方法利用原代培养的成熟星型胶质细胞采用体外划伤方式造成细胞损伤，然后与白细胞共培养建立星形胶质细胞损伤后体外炎症模型。将共培养的细胞放入CO2孵箱中，将温度控制在32℃的亚低温状态，探讨轻度低温、槲皮素及清蛋白对白细胞黏附及胶质细胞损伤的影响。结果白细胞主要黏附于损伤边缘的胶质细胞，并对其有损伤用。32℃亚低温可明显降低白细胞对胶质细胞的黏附和损伤，但无白细胞存在时其作用不明显。槲皮素和清蛋白对白细胞的黏附无显著影响，对胶质细胞无保护作用。结论低温主要通过降低白细胞黏附达到保护胶质细胞作用，对单纯的细胞机械损伤无明显保护作用，提示胶质细胞损伤后的反应性增生不是介导白细胞黏附的关键因素。     

Astrocytes: biology and pathology

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.     

Reactive astrocytes as therapeutic targets for CNS disorders

Reactive astrogliosis has long been recognized as a ubiquitous feature of CNS pathologies. Although its roles in CNS pathology are only beginning to be defined, genetic tools are enabling molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. It is now clear that reactive astrogliosis is not simply an all-or-nothing phenomenon but, rather, is a finely gradated continuum of molecular, cellular, and functional changes that range from subtle alterations in gene expression to scar formation. These changes can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Dysfunction of either astrocytes or the process of reactive astrogliosis is emerging as an important potential source of mechanisms that might contribute to, or play primary roles in, a host of CNS disorders via loss of normal or gain of abnormal astrocyte activities. A rapidly growing understanding of the mechanisms underlying astrocyte signaling and reactive astrogliosis has the potential to open doors to identifying many molecules that might serve as novel therapeutic targets for a wide range of neurological disorders. This review considers general principles and examines selected examples regarding the potential of targeting specific molecular aspects of reactive astrogliosis for therapeutic manipulations, including regulation of glutamate, reactive oxygen species, and cytokines.     

Modulating astrogliosis after neurotrauma

Traumatic injury to the adult central nervous system (CNS) results in a rapid response from resident astrocytes, a process often referred to as reactive astrogliosis or glial scarring. The robust formation of the glial scar and its associated extracellular matrix (ECM) molecules have been suggested to interfere with any subsequent neural repair or CNS axonal regeneration. A series of recent in vivo experiments has demonstrated a distinct inhibitory influence of the glial scar on axonal regeneration. Here we review several experimental strategies designed to elucidate the roles of astrocytes and their associated ECM molecules after CNS damage, including astrocyte ablation techniques, transgenic approaches, and alterations in the deposition of the ECM. In the short term, mediators that modulate the inflammatory mechanisms responsible for eliciting astrogliotic scarring hold strong potential for establishing a favorable environment for neuronal repair. In the future, the conditional (inducible) genetic manipulation of astrocytes holds promise for further increasing our understanding of the functional biology of astrocytes as well as opening new therapeutic windows. Nevertheless, it is most likely that, to obtain long distance axonal regeneration within the injured adult CNS, a combinatorial approach involving different repair strategies, including but not limited to astrogliosis modulation, will be required.     

Expression of vascular endothelial growth factor by reactive astrocytes and associated neoangiogenesis

Injury to the central nervous system (CNS) invokes a reparative response known as astrogliosis, characterized largely by hypertrophy, proliferation and increased expression of glial fibrillary acidic protein (GFAP), resulting in reactive astrocytosis. Based on our prior observation that peritumoral reactive astrocytes express Vascular Endothelial Growth Factor (VEGF), a highly potent and specific angiogenic growth factor, we have hypothesized that reactive astrocytosis also contributes to the neovascularization associated with astrogliosis. To evaluate this hypothesis we evaluated human surgical/autopsy specimens from a variety of CNS disorders that induce astrogliosis and an experimental CNS needle injury model in wild type and GFAP:Green Fluorescent Protein (GFP) transgenic mice. Using computer image semi-quantitative analysis we evaluated the number of GFAP-positive reactive astrocytes, degree of VEGF expression by these astrocytes, associated Factor VIII-positive microvascular density (MVD) and Ki-67 proliferating endothelial cells. The degree of reactive astrocytosis correlated to levels of VEGF immunoreactivity and MVD in the neuropathological specimens. The mouse-needle-stick brain injury model demonstrated this correlation was temporally and spatially related and maximal after 1 week. These results, involving both human pathology specimens augmented by experimental animal data, supports our hypothesis that the neoangiogenesis associated with reactive astrogliosis is correlated to increased reactive astrocytosis and associated VEGF expression.     

ERK/MAP kinase is chronically activated in human reactive astrocytes

Reactive astrogliosis is the most prominent macroglial response to diverse forms of CNS injury. We assessed a potential role for the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway because it represents a common effector for several major families of transmembrane receptors implicated in astrogliosis. Immunohistochemical detection of activated ERK/MAPK in a series of human neurosurgical specimens utilizing phosphorylation state-dependent antibodies consistently revealed intense immunoreactivity in reactive astrocytes in both subacute and chronic lesions, including infarct, mechanical trauma, chronic epilepsy, and progressive multifocal leukoencephalopathy. Neurons, oligodendroglia, and most inflammatory cells showed little or no detectable activation. These observations suggest a testable hypothesis: activation of the ERK/MAPK pathway is an obligatory step for the triggering and/or persistence of reactive astrogliosis.     

The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain

We monitor cellular responses to a penetrating wound in the cerebral cortex of adult rat during the first weeks after injury. Two classes of activated mononuclear phagocytes containing acetylated low-density lipoprotein (ac-LDL) receptors appear within hours at the wound site. One type of cell surrounding the lesion edge had thin, delicate processes and is identical in appearance to ramified microglia found in developing brain. Within the lesion, round cells are recognized as blood-borne macrophages when labeled by intravenous injection of carbon particles. Thus, both process-bearing reactive microglia and invading macrophages respond to brain trauma. The greatest number of ac-LDL(+) or nonspecific esterase(+) mononuclear phagocytes appears 2 days after injury within the wound site and are associated with a peak production of the cytokine interleukin-1 (IL-1). Because intracerebral infusion of IL-1 is known to stimulate astrogliosis and neovascularization (Giulian et al., 1988), we examine the time course of injury-induced reactive astrogliosis and angiogenesis. A 5-fold increase in the number of reactive astroglia is found at 3 d and a marked neovascularization at 5 d after injury. During the first week, mononuclear phagocytes engulf particles and clear them from the wound site either by migrating to the brain surface or by entering newly formed brain vasculature. To investigate further the role of reactive brain mononuclear phagocytes in CNS injury, we use drugs to inhibit trauma-induced inflammation. When applied in vivo, chloroquine or colchicine reduce the number of mononuclear phagocytes in damaged brain, help to block reactive astrogliosis and neovascularization, and slow the rate of debris clearance from sites of traumatic injury. In contrast, the glucocorticoid dexamethasone neither reduces the number of brain inflammatory cells nor hampers such responses as phagocytosis, astrogliosis, neovascularization, or debris clearance in vivo. Our observations show that mononuclear phagocytes play a major role in wound healing after CNS trauma with some events controlled by secretion of cytokines. Moreover, certain classes of immunosuppressive drugs may be useful in the treatment of acute brain injury.     

Proinflammatory cytokines in injured rat brain following perinatal asphyxia

In contrast to astrogliosis, which is common to injuries of the adult CNS, in the developing brain this process is minimal. Reasons postulated for this include the relative immaturity of the immune system and the consequent insufficient production of cytokines to evoke astrogliosis. To explore this hypothesis, the study was undertaken to detect the presence of some proinflammatory cytokines in the injured rat brain following perinatal asphyxia (ischaemia/hypoxia). The localisation of TNF-alpha, IL-15, IL-17 and IL-17 receptors was visualised by means of immunohistochemistry. In numerous neurones of the rat brain, the IL-17 appeared to be constitutively expressed. In the early period of inflammation the IL-15 was produced mainly by the blood cells penetrating the injured brain but later it was synthesised also by reactive astrocytes surrounding brain cysts and forming dense astrogliosis around necrotic brain regions. The direct effect on astrogliosis of other estimated cytokines seems to be negligible. All the results lead to the conclusion that from all cytokines identified in the injured immature rat brain the IL-15 plays the most important role during inflammatory response and participates in the gliosis of reactive astrocytes.     

Astrocyte immune responses in epilepsy

Astrocytes, the major glial cell type of the central nervous system (CNS), are known to play a major role in the regulation of the immune/inflammatory response in several human CNS diseases. In epilepsy-associated pathologies, the presence of astrogliosis has stimulated extensive research focused on the role of reactive astrocytes in the pathophysiological processes that underlie the development of epilepsy. In brain tissue from patients with epilepsy, astrocytes undergo significant changes in their physiological properties, including the activation of inflammatory pathways. Accumulating experimental evidence suggests that proinflammatory molecules can alter glio-neuronal communications contributing to the generation of seizures and seizure-related neuronal damage. In particular, both in vitro and in vivo data point to the role of astrocytes as both major source and target of epileptogenic inflammatory signaling. In this context, understanding the astroglial inflammatory response occurring in epileptic brain tissue may provide new strategies for targeting astrocyte-mediated epileptogenesis. This article reviews current evidence regarding the role of astrocytes in the regulation of the innate immune responses in epilepsy. Both clinical observations in drug-resistant human epilepsies and experimental findings in clinically relevant models will be discussed and elaborated, highlighting specific inflammatory pathways (such as interleukin-1β/toll-like receptor 4) that could be potential targets for antiepileptic, disease-modifying therapeutic strategies.