脑出血后血肿周围组织炎症反应的研究进展

脑出血是临床常见的血管性疾病,发病率、死亡率和致残率都较高,但目前尚缺乏能明显改善预后的治疗措施。脑出血后继发性脑损伤的机制较复杂,其中血肿周围组织炎症反应在继发性脑损伤中发挥重要作用。研究发现,炎症细胞的渗出及浸润、细胞因子的上调、基质金属蛋白酶的释放以及活性氧的过度产生等多种因素均参与血肿周围组织炎症反应。进一步深入研究脑出血后血肿周围组织炎症反应及其可调节性,对指导临床脑出血病人的治疗具有重大意义。     

炎症反应在脑出血后继发性脑损伤中作用机制的研究进展

正脑出血是第二大卒中类型,病死率和致残率高~([1])。目前,脑出血仍然没有统一规范的确切治疗方法。脑出血引起脑损伤的机制仍然不清楚,许多研究表明炎症反应在脑出血继发性脑损伤过程中有重要作用,调控炎症反应有助于减轻继发性脑损伤、脑水肿,改善神经功能障碍~([2,3])。本文就炎症反应在脑     

脑出血后炎症反应的研究进展

炎症是具有血管系统的活体组织对损伤因子所发生的防御反应.近年来的研究表明脑出血后血肿周围存在明显的炎症反应,炎症反应在脑出血继发性脑损伤中起着十分重要的作用[1].脑出血后炎症反应的研究已成为目前研究的热点,现综述如下.     

炎症反应与大鼠脑出血后脑损伤的相关性

为探讨炎症反应与大鼠脑出血后脑损伤的相关性，分别从血肿周围脑组织炎性细胞浸润、炎性因子释放、补体激活等几方面对炎症反应在脑出血后脑损伤中的作用进行研究。     

脑血管病与炎症因子

脑血管病后继发性脑损害是导致原有病情加重的主要原因.炎症反应在继发性脑损伤过程中发挥关键性作用,直接影响患者的预后.炎症反应始于炎症细胞黏附、迁移、浸润、活化以及炎症因子释放,其内在机制不明.深入了解炎症反应在脑血管病后的作用机制,将为了解炎症反应的发生、发展和治疗提供参考.……     

凝血酶在自发性脑出血后脑水肿形成中的作用

脑出血后脑水肿形成是导致继发性神经损害的一个重要因素。近年来，有关脑出血后脑水肿产生机制的研究表明，凝血时释放的凝血酶可能是引起脑出血后脑水肿的重要物质之一，凝血酶在脑出血后脑水肿形成、炎症反应等方面起着重要作用。本文对近年来凝血酶在自发性脑出血后脑水肿形成中的作用研究进展作一综述。     

脑出血后炎症反应的研究

<正>脑出血指原发性脑实质内出血,占全部脑卒中的10%～15%,急性期病死率高达30%～40%~([1])。脑出血后继发性脑损伤主要由血肿占位及压迫效应、脑水肿、血-脑脊液屏障(blood-brain barrier,BBB)的破坏、以及一系列炎症反应造成。其中炎症反应贯穿于脑出血损伤的各个阶段,在疾病进程中起至关重要的作用。脑出血后参与炎症反应的细胞     

出血性脑损伤细胞凋亡机制研究进展

近年研究认为 :出血性脑损伤以继发性损伤为主 ,细胞凋亡机制参与了脑出血继发性损伤。脑出血导致细胞凋亡可能与出血后凝血酶大量形成、红细胞分解产物聚集、兴奋性氨基酸受体激活、多种细胞因子释放及炎细胞浸润等因素有关。探讨脑出血细胞凋亡机制可能为防治出血性脑损伤寻找到新的靶点     

microRNAs在脑出血后病理生理机制中的作用

脑出血是一种高发病率和高死亡率的疾病,出血后的一系列继发性反应可以造成的严重的神经功能损伤.近年来,研究发现多个microRNA在脑出血后异常表达,参与了出血后的氧化损伤、炎症、水肿以及神经细胞凋亡等多个病理生理过程,从而加重了脑出血后继发性脑损伤.本文综述了目前microRNAs在脑出血后病理生理机制中作用的相关研究.     

脑出血后炎症反应中小胶质细胞及其相关炎症介质的作用研究进展

脑出血(ICH)继发脑损伤发生机制较为复杂,其中血肿周围组织的炎症反应在继发性脑损伤中至关重要.多种细胞及与其相关的炎症介质在ICH后炎症反应中发挥作用.本文主要就小胶质细胞及与其相关的肿瘤坏死因子(TNF)、白细胞介素(IL)、转化生长因子-β(TGF-β)、基质金属蛋白酶(MMPs)等在炎症反应中的主要作用及临床应...     

Activation of P2X4 receptor exacerbates acute brain injury after intracerebral hemorrhage

IntroductionIntracerebral hemorrhage (ICH) accounts for 10%–15% of all strokes and culminates in high mortality and disability. After ICH, brain injury is initiated by the mass effect of hematoma, followed by secondary cytotoxic injury from dying brain cells, hematoma disintegration, and cascading brain immune response. However, the molecular mechanism of secondary cytotoxic brain injury in ICH is not completely understood. The sensitive purinergic receptor, P2X4 receptor (P2X4R), was known to recognize extracellular free ATP released by dying cells during tissue injury.AimsIn this study, we aim to understand the role of P2X4R in acute brain injury triggered by ICH.ResultsIn this study, we found that the sensitive purinergic receptor, P2X4R, was upregulated in the brain of patients with ICH as well as in a mouse model of ICH induced by collagenase injection. P2X4R blockage with the specific inhibitor 5‐BDBD attenuated brain injury in ICH mice by significantly reducing brain edema, blood–brain barrier leakage, neural death, and ultimately acute neurodeficits. Further study indicated that the protective effect of P2X4R inhibition is related to decreased pro‐inflammatory activity of microglia and recruitment of peripheral immune cells into the hemorrhagic brain.ConclusionsThese results suggest that the P2X4 receptor is activated by ICH stimuli which worsen brain injury following ICH.     

Acute inflammatory reaction following experimental intracerebral hemorrhage in rat

Previous studies on intracerebral hemorrhage (ICH) indicate that brain edema increases progressively in the first 24 h and remains elevated for several days. The cause of secondary brain injury and edema formation is uncertain. We hypothesized that inflammatory mediators released from the blood after cerebral hemorrhage might cause secondary brain injury and edema formation. This study investigates if, when and where inflammation occurs after ICH in rat. Immunocytochemistry for polymorphonuclear leukocyte marker (myeloperoxidase, MPO), microglia marker (OX42) and intracellular adhesion molecule-1 (ICAM-1) was performed in control, and 1, 3, 7 and 10 days after the injection of 100 microliter autologous blood in the right basal ganglia. Double labeling immunohistochemistry was used to identify ICAM-1 positive cells. The results show that an inflammatory response occurred in and around the blood clot after ICH, characterized by the infiltration of neutrophils and macrophages as well as activation of microglia. ICAM-1 immunoreactivity was observed in blood vessels adjacent to the clot, as well as in activated microglia and neurons in the ipsilateral hemisphere. The present study demonstrates there is an inflammatory response in the brain after ICH. Infiltrating leukocytes and activated microglia may release cytotoxic mediators contributing to secondary brain injury.     

Enhanced electrical responsiveness in the cerebral cortex with oral melatonin administration after a small hemorrhage near the internal capsule in rats

Intracerebral hemorrhage (ICH) can cause direct brain injury at the insult site and indirect damage in remote brain areas. Although a protective effect of melatonin (ML) has been reported for ICH, its detailed mechanisms and effects on remote brain injury remain unclear. To clarify the mechanism of indirect neuroprotection after ICH, we first investigated whether ML improved motor function after ICH and then examined the underlying mechanisms. The ICH model rat was made by collagenase injection into the left globus pallidus, adjacent to the internal capsule. ML oral administration (15 mg/kg) for 7 days after ICH resulted in significant recovery of motor function. Retrograde labeling of the corticospinal tract by Fluoro‐Gold revealed a significant increase in numbers of positive neurons in the cerebral cortex. Immunohistological analysis showed that ML treatment induced no difference in OX41‐positive activated microglia/macrophage at day 1 (D1) but a significant reduction in 8‐hydroxydeoxyguanosin‐positive cells at D7. Neutral red assay revealed that ML significantly prevented H₂O₂‐induced cell death in cultured oligodendrocytes and astrocytes but not in neurons. Electrophysiological response in the cerebral cortex area where the number of Fluoro‐Gold‐positive cells was increased was significantly improved in ML‐treated rats. These data suggest that ML improves motor abilities after ICH by protecting oligodendrocytes and astrocytes in the vicinity of the lesion in the corticospinal tract from oxidative stress and causes enhanced electrical responsiveness in the cerebral cortex remote to the ICH pathology. © 2014 Wiley Periodicals, Inc.     

Transplantation of neural stem cells that overexpress SOD1 enhances amelioration of intracerebral hemorrhage in mice

Previous studies have shown that intraparenchymal transplantation of neural stem cells (NSCs) ameliorates neurologic deficits in animals with intracerebral hemorrhage (ICH). However, massive grafted cell death after transplantation, possibly caused by a hostile host brain environment, lessens the effectiveness of this approach. We focused on the effect of oxidative stress against grafted NSCs and hypothesized that conferring antioxidant properties to transplanted NSCs may overcome their death and enhance neuroprotection after ICH. Copper/zinc-superoxide dismutase (SOD1) is a specific antioxidant enzyme that counteracts superoxide anions. We investigated whether genetic manipulation to overexpress SOD1 enhances survival of grafted NSCs and accelerates amelioration of ICH. Neural stem cells that overexpress SOD1 were administered intracerebrally 3 days after ICH in a mouse model. Histologic and behavioral tests were examined after ICH. Copper/zinc-superoxide dismutase overexpression protected the grafted NSCs via a decrease in production of reactive oxygen species. This resulted in an increase in paracrine factors released by the NSCs, and an increase in surviving neurons in the striatum and a reduction in striatal atrophy. In addition, SOD1 overexpression showed progressive improvement in behavioral recovery. Our results suggest that enhanced antioxidative activity in NSCs improves efficacy of stem cell therapy for ICH.     

Lack of Aquaporin 9 Reduces Brain Angiogenesis and Exaggerates Neuronal Loss in the Hippocampus Following Intracranial Hemorrhage in Mice

Intracranial hemorrhage (ICH) is a common subtype of stroke with high morbidity and mortality. However, few clinical therapies that can reduce ICH-induced brain injury and promote the recovery outcome in ICH patients are available to improve the recovery from ICH. Given that aquaporin 9 (AQP9) plays a critical role in brain edema after ischemic stroke and traumatic brain injury and is involved in the regulation of angiogenesis, we examined the role of AQP9 in preventing neuronal loss and in neovascularization in the dorsal hippocampus (DH) after ICH. We found that intra-DH collagenase-induced ICH increased AQP9 protein levels in the hippocampus, which was associated with behavioral deficits in wild-type mice. However, ICH robustly enhanced behavioral deficits in the AQP9-null mice, as compared with the wild-type mice. Furthermore, neovascularization and proliferation of brain microvascular endothelial cells following ICH were severely impaired in the AQP9-null mice, as compared with the wild-type mice. Finally, hippocampal neuronal loss following ICH became severer in the AQP9-null mice, relative to the wild-type mice. Taken together, our findings indicated that AQP9 in the brain may play a compensatory role in response to ICH, promote brain angiogenesis, and prevent subsequent neuronal death, thus preventing the deterioration of neurological outcome of ICH.     

Glial responses, neuron death and lesion resolution after intracerebral hemorrhage in young vs. aged rats

Intracerebral hemorrhage (ICH) usually affects older humans but almost no experimental studies have assessed aged animals. We address how aging alters inflammation, neuron death and lesion resolution after a hemorrhage in the rat striatum. In the normal aged brain, microglia displayed a 'dystrophic' phenotype, with shorter cellular processes and large gaps between adjacent cells, and there was more astrocyte reactivity. The ICH injury was monitored as hematoma volume and number of dying neurons at 1 and 3 days, and the volume of the residual lesion, ventricles and lost tissue at 28 days. Inflammation at 1 and 3 days was assessed from densities of microglia with resting vs. activated morphologies, or expressing the lysosomal marker ED1. Despite an initial delay in neuron death in aged animals, by 28 days, there was no difference in neuron density or volume of tissue lost. However, lesion resolution was impaired in aged animals and there was less compensatory ventricular expansion. At 1 day after ICH, there were fewer activated microglia/macrophages in the aged brain, but by 3 days there were more of these cells at the edge of the hematoma and in the surrounding parenchyma. In both age groups a glial limitans had developed by 3 days, but astrocyte reactivity and the spread of activated microglia/macrophages into the surrounding parenchyma was greater in the aged. These findings have important implications for efforts to reduce secondary injury after ICH and to develop anti-inflammatory therapies to treat ICH in aged humans.     

Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury

Thrombin is thought to play an important role in brain damage associated with intracerebral hemorrhage (ICH). We previously showed that activation of mitogen-activated protein (MAP) kinases and recruitment of microglia are crucial for thrombin-induced shrinkage of the striatal tissue in vitro and thrombin-induced striatal damage in vivo. Here we investigated whether the same mechanisms are involved in ICH-induced brain injury. A substantial loss of neurons was observed in the center and the peripheral region of hematoma at 3 days after ICH induced by intrastriatal injection of collagenase in adult rats. Intracerebroventricular injection of argatroban or cycloheximide, both of which prevent thrombin cytotoxicity in vitro, exhibited a significant neuroprotective effect against ICH-induced injury. ICH-induced neuron loss was also prevented by a MAP kinase kinase inhibitor (PD98059) and a c-Jun N-terminal kinase inhibitor (SP600125). These drugs had no effect on hematoma size or ICH-induced brain edema. Activation of extracellular signal-regulated kinase in response to ICH was observed in both neurons and microglia. Despite their neuroprotective effects, MAP kinase inhibitors did not decrease the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells appearing after ICH. Identification of cell types revealed that TUNEL staining occurred prominently in neurons but not in microglia, whereas inhibition of MAP kinases resulted in appearance of TUNEL staining in microglia. These results suggest that thrombin and the activation of MAP kinases are involved in ICH-induced neuronal injury, and that neuroprotective effects of MAP kinases are in part mediated by arrestment of microglial activities.     

Vascular adhesion protein-1 inhibition provides antiinflammatory protection after an intracerebral hemorrhagic stroke in mice

The systemic immune response has a vital role in propagating the damage of an intracerebral hemorrhage (ICH). Vascular adhesion protein-1 (VAP-1), a semicarbazide (SCZ)-sensitive-amine-oxidase, was found in previous studies to have a role in migration of immune cells. In this study, we hypothesize that VAP-1 inhibition may decrease brain injury by attenuating the transmigration of immune cells to the injury site, and by doing so, reduce cerebral edema and improve neurobehavioral function in mice. Two VAP-1 inhibitors, LJP1586 and SCZ were given 1 hour after ICH induction by either collagenase or autologous blood injection. The VAP-1 siRNA, a VAP-1 gene silencer, and human recombinant AOC3 protein, a VAP-1 analogue, were delivered by intracerebroventricular injection. Postassessment included neurobehavioral testing, brain edema measurement, quantification of neutrophil infiltration and microglia/macrophage activation, and measurement of intercellular adhesion molecule-1 (ICAM-1), P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) expression 24 hours after ICH. We found that LJP1586 and SCZ reduced brain edema and neurobehavioral deficits 24 hours after ICH induction. These two drugs were also found to decrease levels of ICAM-1, MCP-1, TNF-α, and inhibit neutrophilic infiltration and microglia/macrophage activation. We conclude that VAP-1 inhibition provided antiinflammation effect by reducing adhesion molecule expression and immune cell infiltration after ICH.     

Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice

Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E₂ receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle-aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase-induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E₂ EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH.