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1.
2.
Neural stem cell (NSC) transplantation is a major focus of current research for treatment of spinal cord injury (SCI). However, it is very important to promote the survival and differentiation of NSCs into myelinating oligodendrocytes (OLs). In this study, myelin basic protein-activated T (MBP-T) cells were passively immunized to improve the SCI microenvironment. Olig2-overexpressing NSCs were infected with a lentivirus carrying the enhanced green fluorescent protein (GFP) reporter gene to generate Olig2-GFP-NSCs that were transplanted into the injured site to differentiate into OLs. Transferred MBP-T cells infiltrated the injured spinal cord, produced neurotrophic factors, and induced the differentiation of resident microglia and/or infiltrating blood monocytes into an “alternatively activated” anti-inflammatory macrophage phenotype by producing interleukin-13. As a result, the survival of transplanted NSCs increased fivefold in MBP-T cell-transferred rats compared with that of the vehicle-treated control. In addition, the differentiation of MBP-positive OLs increased 12-fold in Olig2-GFP-NSC-transplanted rats compared with that of GFP-NSC-transplanted controls. In the MBP-T cell and Olig2-GFP-NSC combined group, the number of OL-remyelinated axons significantly increased compared with those of all other groups. However, a significant decrease in spinal cord lesion volume and an increase in spared myelin and behavioral recovery were observed in Olig2-NSC- and NSC-transplanted MBP-T cell groups. Collectively, these results suggest that MBP-T cell adoptive immunotherapy combined with NSC transplantation has a synergistic effect on histological and behavioral improvement after traumatic SCI. Although Olig2 overexpression enhances OL differentiation and myelination, the effect on functional recovery may be surpassed by MBP-T cells.  相似文献   

3.
The chemokine stromal-derived factor-1 (SDF-1, also known as CXCL12) and its receptor CXCR4 have been implicated in homing of stem cells to the bone marrow and the homing of bone marrow-derived cells to sites of injury. Bone marrow cells infiltrate brain and give rise to long-term resident cells following injury. Therefore, SDF-1 and CXCR4 expression patterns in 40 mice were examined relative to the homing of bone marrow-derived cells to sites of ischemic injury using a stroke model. Mice received bone marrow transplants from green fluorescent protein (GFP) transgenic donors and later underwent a temporary middle cerebral artery suture occlusion (MCAo). SDF-1 was associated with blood vessels and cellular profiles by 24 hours through at least 30 days post-MCAo. SDF-1 expression was principally localized to the ischemic penumbra. The majority of SDF-1 expression was associated with reactive astrocytes; much of this was perivascular. GFP+ cells were associated with SDF-1-positive vessels and were also found in the neuropil of regions with increased SDF-1 immunoreactivity. Most vessel-associated GFP+ cells resemble pericytes or perivascular microglia and the majority of the GFP+ cells in the parenchyma displayed characteristics of activated microglial cells. These findings suggest SDF-1 is important in the homing of bone marrow-derived cells, especially monocytes, to areas of ischemic injury.  相似文献   

4.
This review will focus on matrix metalloproteinases (MMPs) and their inhibitors in the context of spinal cord injury (SCI). MMPs have a specific cellular and temporal pattern of expression in the injured spinal cord. Here we consider their diverse functions in the acutely injured cord and during wound healing. Excessive activity of MMPs, and in particular gelatinase B (MMP-9), in the acutely injured cord contributes to disruption of the blood-spinal cord barrier, and the influx of leukocytes into the injured cord, as well as apoptosis. MMP-9 and MMP-2 regulate inflammation and neuropathic pain after peripheral nerve injury and may contribute to SCI-induced pain. Early pharmacologic inhibition of MMPs or the gelatinases (MMP-2 and MMP-9) results in an improvement in long-term neurological recovery and is associated with reduced glial scarring and neuropathic pain. During wound healing, gelatinase A (MMP-2) plays a critical role in limiting the formation of an inhibitory glial scar, and mice that are genetically deficient in this protease showed impaired recovery. Together, these findings illustrate complex, temporally distinct roles of MMPs in SCIs. As early gelatinase activity is detrimental, there is an emerging interest in developing gelatinase-targeted therapeutics that would be specifically tailored to the acute injured spinal cord. Thus, we focus this review on the development of selective gelatinase inhibitors.  相似文献   

5.
Spinal cord injuries disrupt central autonomic pathways that regulate immune function, and increasing evidence suggests that this may cause deficiencies in immune responses in people with spinal cord injuries. Here we analyze the consequences of spinal cord injury (SCI) on immune responses following experimental viral infection of mice. Female C57BL/6 mice received complete crush injuries at either thoracic level 3 (T3) or 9 (T9), and 1 week post-injury, injured mice and un-injured controls were infected with different dosages of mouse hepatitis virus (MHV, a positive-strand RNA virus). Following MHV infection, T3- and T9-injured mice exhibited increased mortality in comparison to un-injured and laminectomy controls. Infection at all dosages resulted in significantly higher viral titer in both T3- and T9-injured mice compared to un-injured controls. Investigation of anti-viral immune responses revealed impairment of cellular infiltration and effector functions in mice with SCI. Specifically, cell-mediated responses were diminished in T3-injured mice, as seen by reduction in virus-specific CD4+ T lymphocyte proliferation and IFN-γ production and decreased numbers of activated antigen presenting cells compared to infected un-injured mice. Collectively, these data indicate that the inability to control viral replication following SCI is not level dependent and that increased susceptibility to infection is due to suppression of both innate and adaptive immune responses.  相似文献   

6.
Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes involved in inflammation, wound healing and other pathological processes after neurological disorders. MMP-2 promotes functional recovery after spinal cord injury (SCI) by regulating the formation of a glial scar. In the present study, we aimed to investigate the expression and/or activity of several MMPs, after SCI and human umbilical cord blood mesenchymal stem cell (hUCB) treatment in rats with a special emphasis on MMP-2. Treatment with hUCB after SCI altered the expression of several MMPs in rats. MMP-2 is upregulated after hUCB treatment in spinal cord injured rats and in spinal neurons injured either with staurosporine or hydrogen peroxide. Further, hUCB induced upregulation of MMP-2 reduced formation of the glial scar at the site of injury along with reduced immunoreactivity to chondroitin sulfate proteoglycans. Blockade of MMP-2 activity in hUCB cocultured injured spinal neurons reduced the protection offered by hUCB which indicated the involvement of MMP-2 in the neuroprotection offered by hUCB. Based on these results, we conclude that hUCB treatment after SCI upregulates MMP-2 levels and reduces the formation of the glial scar thereby creating an environment suitable for endogenous repair mechanisms.  相似文献   

7.
Neuronal cell death and the failure of axonal regeneration cause a permanent functional deficit following spinal cord injury (SCI). Administration of recombinant glial cell line-derived neurotrophic factor (GDNF) has previously been reported to rescue neurons following severe SCI, resulting in improved hindlimb locomotion in rats. In this study, thus, GDNF gene therapy using an adenoviral vector (rAd-GDNF) was examined in rats following SCI induced by dropping the NYU weight-drop impactor from a height of 25 mm onto spinal segment T9-T10. To evaluate the efficacy of intraspinal injection of recombinant adenovirus into the injured spinal cord, we observed green fluorescent protein (GFP) gene transfer in the contused spinal cord. GFP was effectively expressed in the injured spinal cord, and the most prominently transduced cells were astrocytes. The expression of GDNF was detected only in rats receiving rAd-GDNF, not the controls, and remained detectable around the injured site for at least 8 days. Open-field locomotion analysis revealed that rats receiving rAd-GDNF exhibited improved locomotor function and hindlimb weight support compared to the control groups. Immunohistochemical examination for the neuronal marker, calcitonin gene-related peptide (CGRP), showed an increase in CGRP+ neuronal fibers in the injured spinal cord in rats receiving rAd-GDNF treatment. Collectively, the results suggest that adenoviral gene transfer of GDNF can preserve neuronal fibers and promote hindlimb locomotor recovery from spinal cord contusion. This research should provide information for developing a clinical strategy for GDNF gene therapy.  相似文献   

8.

Background

Immediately after spinal trauma, immune cells, and proinflammatory cytokines infiltrate the spinal cord and disrupt the focal microenvironment, which impedes axon regeneration and functional recovery. Previous studies have reported that regulatory T cells (Tregs) enter the central nervous system and exert immunosuppressive effects on microglia during multiple sclerosis and stroke. However, whether and how Tregs interact with microglia and modulate injured microenvironments after spinal cord injury (SCI) remains unknown.

Method

Regulatory T cells spatiotemporal characteristics were analyzed in a mouse contusion SCI model. Microglia activation status was evaluated by immunostaining and RNA sequencing. Cytokine production in injured spinal cord was examined using Luminex. The role of STAT3 in Treg–microglia crosstalk was investigated in a transwell system with isolated Tregs and primary microglia.

Results

Regulatory T cells infiltration of the spinal cord peaked on day 7 after SCI. Treg depletion promoted microglia switch to a proinflammatory phenotype. Inflammation-related genes, such as ApoD, as well as downstream cytokines IL-6 and TNF-α were upregulated in microglia in Treg-depleted mice. STAT3 inhibition was involved in Treg–microglia crosstalk, and STAT3 chemical blockade improved function recovery in Treg-depleted mice.

Conclusion

Our results suggest that Tregs promote functional recovery after SCI by alleviating microglia inflammatory reaction via STAT3.  相似文献   

9.
Spinal cord injury (SCI) results in substantial oligodendrocyte death and subsequent demyelination leading to white-matter defects. Cell replacement strategies to promote remyelination are under intense investigation; however, the optimal cell for transplantation remains to be determined. We previously isolated a platelet-derived growth factor (PDGF)-responsive neural precursor (PRP) from the ventral forebrain of fetal mice that primarily generates oligodendrocytes, but also astrocytes and neurons. Importantly, human PRPs were found to possess a greater capacity for oligodendrogenesis than human epidermal growth factor- and/or fibroblast growth factor-responsive neural stem cells. Therefore, we tested the potential of PRPs isolated from green fluorescent protein (GFP)-expressing transgenic mice to remyelinate axons in the injured rat spinal cord. PRPs were transplanted 1 week after a moderate thoracic (T9) spinal cord contusion in adult male rats. After initial losses, PRP numbers remained stable from 2 weeks posttransplantation onward and those surviving cells integrated into host tissue. Approximately one-third of the surviving cells developed the typical branched phenotype of mature oligodendrocytes, expressing the marker APC-CC1. The close association of GFP cells with myelin basic protein as well as with Kv1.2 and Caspr in the paranodal and juxtaparanodal regions of nodes of Ranvier indicated that the transplanted cells successfully formed mature myelin sheaths. Transplantation of PRPs into dysmyelinated Shiverer mice confirmed the ability of PRP-derived cells to produce compact myelin sheaths with normal periodicity. These findings indicate that PRPs are a novel candidate for CNS myelin repair, although PRP-derived myelinating oligodendrocytes were insufficient to produce behavioral improvements in our model of SCI.  相似文献   

10.
After spinal cord injury (SCI), white matter tracts are characterized by demyelination and increased sensitivity to the K(+) channel blocker 4-aminopyridine (4-AP). These effects appear to contribute to neurological impairment after SCI, although the molecular changes in K(+) channel subunit expression remain poorly understood. We examined changes in gene expression of the 4-AP-sensitive voltage-gated K(+) channel Kv 1.4 after chronic SCI in the rat. Quantitative immunoblotting showed that Kv 1.4 protein was significantly increased at 6 weeks, but not at 1 week, after SCI in spinal cord white matter. Kv 1.4 was localized to astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells but not to axons in both the normal and the injured spinal cord white matter. Because glial cells proliferate after SCI, we used immunogold electron microscopy to quantify Kv 1.4 protein in individual glial cells and found a sixfold increase of Kv 1.4 in cells of the oligodendrocyte lineage after chronic injury. Finally, quantitative in situ hybridization showed that Kv 1.4 mRNA was significantly upregulated in spinal cord white matter, but not gray matter, after SCI. In summary, we show that Kv 1.4 is expressed in glial cells and not in axons in the rat spinal cord white matter and that its expression is markedly increased in cells of the oligodendrocyte lineage after chronic SCI. Given that K(+) channels play a role in glial cell proliferation, cells exhibiting changes in Kv 1.4 expression may represent proliferating oligodendroglia in the chronically injured spinal cord.  相似文献   

11.
基质细胞衍生因子-1对间质干细胞迁移的影响   总被引:7,自引:0,他引:7  
目的:观察基质细胞衍生因子-1(SDF-1)在体内外对大鼠骨髓间质干细胞(rMSCs)的趋化诱导作用,探讨SDF-1对rMSCs迁移影响的可能机制。方法:应用体外细胞迁移实验及大鼠脑梗死模型体内移植,观察SDF-1对rMSCs的迁移影响。流式细胞术与RT-PCR检测rMSCs的CXC趋化因子受体4(CXCchemokinereceptor4,CXCR4)表达。结果:在SDF-1存在时,rMSCs迁移活跃,应用抗体封闭CXCR4后,这种迁移显著减弱。体内移植的rMSCs主要聚集在脑梗死灶周围,但在封闭CXCR4后,这种聚集现象大大减弱。流式细胞术示仅小部分rMSCs表面表达CXCR4,但经TritonX-100处理后,表达CXCR4的rMSCs增加。结论:SDF-1可通过CXCR4对rMSCs起趋化作用,针对这种作用可望调控干细胞向靶组织的趋化聚集量,达到治疗目的。  相似文献   

12.
Delayed transplantation of neural stem/progenitor cells (NS/PCs) into the injured spinal cord can promote functional recovery in adult rats and monkeys. To enhance the functional recovery after NS/PC transplantation, we focused on galectin‐1, a carbohydrate‐binding protein with pleiotropic roles in cell growth, differentiation, apoptosis, and neurite outgrowth. Here, to determine the combined therapeutic effect of NS/PC transplantation and galectin‐1 on spinal cord injury (SCI), human NS/PCs were transfected by lentivirus with galectin‐1 and green fluorescent protein (GFP), (Gal‐NS/PCs) or GFP alone (GFP‐NS/PCs), expanded in vitro, and then transplanted into the spinal cord of adult common marmosets, 9 days after contusive cervical SCI. The animals' motor function was evaluated by their spontaneous motor activity, bar grip power, and performance on a treadmill test. Histological analyses revealed that the grafted human NS/PCs survived and differentiated into neurons, astrocytes, and oligodendrocytes. There were significant differences in the myelinated area, corticospinal fibers, and serotonergic fibers among the Gal‐NS/PC, GFP‐NS/PC, vehicle‐control, and sham‐operated groups. The Gal‐NS/PC‐grafted animals showed a better performance on all the behavioral tests compared with the other groups. These findings suggest that Gal‐NS/PCs have better therapeutic potential than NS/PCs for SCI in nonhuman primates and that human Gal‐NS/PC transplantation might be a feasible treatment for human SCI. © 2010 Wiley‐Liss, Inc.  相似文献   

13.
Traumatic spinal cord injury (SCI) affects the activation, migration, and function of microglia, neutrophils and monocyte/macrophages. Because these myeloid cells can positively and negatively affect survival of neurons and glia, they are among the most commonly studied immune cells. However, the mechanisms that regulate myeloid cell activation and recruitment after SCI have not been adequately defined. In general, the dynamics and composition of myeloid cell recruitment to the injured spinal cord are consistent between mammalian species; only the onset, duration, and magnitude of the response vary. Emerging data, mostly from rat and mouse SCI models, indicate that resident and recruited myeloid cells are derived from multiple sources, including the yolk sac during development and the bone marrow and spleen in adulthood. After SCI, a complex array of chemokines and cytokines regulate myelopoiesis and intraspinal trafficking of myeloid cells. As these cells accumulate in the injured spinal cord, the collective actions of diverse cues in the lesion environment help to create an inflammatory response marked by tremendous phenotypic and functional heterogeneity. Indeed, it is difficult to attribute specific reparative or injurious functions to one or more myeloid cells because of convergence of cell function and difficulties in using specific molecular markers to distinguish between subsets of myeloid cell populations. Here we review each of these concepts and include a discussion of future challenges that will need to be overcome to develop newer and improved immune modulatory therapies for the injured brain or spinal cord.  相似文献   

14.
目的 研究腹腔注射丹酚酸B(Sal B)对大鼠急性脊髓损伤(SCI)模型的神经保护作用和促功能恢复作用,探讨Sal B在急性SCI治疗的应用价值,并探讨其量效关系. 方法参照Allen法制作SD大鼠T9脊髓节段急性损伤模型,腹腔注射Sal B或PBS液,按照注射液的不同分为4组:Sal B高剂量组(20 mg/kg组),Sal B中剂量组(10 mg/kg组),Sal B低剂量组(2 mg/kg组)和对照组(注射PBS液),每组12只.用比色法检测髓过氧化物酶活性;用免疫组织化学染色法检测损伤脊髓节段MMP-1、c-Fos抗体表达情况,用干湿重法评价的水肿程度,并采用后肢功能评分(BBB)评分评价10 d内大鼠的运动功能恢复情况. 结果损伤后4 h Sal B治疗组髓过氧化物酶活性下降,损伤后1 dHE染色切片显示SalB组治疗后局部组织损伤减轻,炎性细胞浸润数量减少,损伤后1d免疫组化染色结果显示,Sal B治疗组比对照组MMP-1表达减少,c-Fos表达下调;Sal B治疗组水肿程度轻于对照组,从SCI后第7天起,SalB组高剂量组(20 mg/kg组)和对照组之间的BBB评分有显著性差异(P<0.05).各指标改善情况与Sal B剂量呈正相关性. 结论 Sal B可减轻大鼠SCI后的组织损伤,下调损伤相关因子MMP-1和c-Fos的表达,降低损伤局部髓过氧化物酶活性,减轻组织水肿,并能促进损伤大鼠的功能恢复.  相似文献   

15.
丹酚酸B促进大鼠急性脊髓损伤修复及量效关系探讨   总被引:1,自引:0,他引:1  
目的 研究腹腔注射丹酚酸B(Sal B)对大鼠急性脊髓损伤(SCI)模型的神经保护作用和促功能恢复作用,探讨Sal B在急性SCI治疗的应用价值,并探讨其量效关系. 方法参照Allen法制作SD大鼠T9脊髓节段急性损伤模型,腹腔注射Sal B或PBS液,按照注射液的不同分为4组:Sal B高剂量组(20 mg/kg组),Sal B中剂量组(10 mg/kg组),Sal B低剂量组(2 mg/kg组)和对照组(注射PBS液),每组12只.用比色法检测髓过氧化物酶活性;用免疫组织化学染色法检测损伤脊髓节段MMP-1、c-Fos抗体表达情况,用干湿重法评价的水肿程度,并采用后肢功能评分(BBB)评分评价10 d内大鼠的运动功能恢复情况. 结果损伤后4 h Sal B治疗组髓过氧化物酶活性下降,损伤后1 dHE染色切片显示SalB组治疗后局部组织损伤减轻,炎性细胞浸润数量减少,损伤后1d免疫组化染色结果显示,Sal B治疗组比对照组MMP-1表达减少,c-Fos表达下调;Sal B治疗组水肿程度轻于对照组,从SCI后第7天起,SalB组高剂量组(20 mg/kg组)和对照组之间的BBB评分有显著性差异(P<0.05).各指标改善情况与Sal B剂量呈正相关性. 结论 Sal B可减轻大鼠SCI后的组织损伤,下调损伤相关因子MMP-1和c-Fos的表达,降低损伤局部髓过氧化物酶活性,减轻组织水肿,并能促进损伤大鼠的功能恢复.  相似文献   

16.
We have demonstrated that overcoming matrix metalloproteinase (MMP)-mediated suppression of glial proliferation stimulates axonal regeneration in the peripheral nervous system. The regenerative capacity of the adult CNS in response to injury and demyelination depends on the ability of multipotent glial NG2+ progenitor cells to proliferate and mature, mainly into oligodendrocytes. Herein, we have established the important role of MMPs, specifically MMP-9, in regulation of NG2+ cell proliferation in injured spinal cord. Targeting transiently induced MMP-9 using acute MMP-9/2 inhibitor (SB-3CT) therapy for two days after T9-10 spinal cord dorsal hemisection produced a significant increase in mitosis (assessed by bromodeoxyuridine incorporation) of NG2+ cells but not GFAP + astrocytes and Iba-1+ microglia and/or macrophages. Acute MMP-9/2 blockade reduced the shedding of the NG2 proteoglycan and of the NR1 subunit of the N-methyl D-aspartate (NMDA) receptor, whose decline is believed to accompany NG2+ cell maturation into OLs. Increase in post-mitotic oligodendrocytes during remyelination and improved myelin neuropathology in the hemisected spinal cord were accompanied by locomotion and somatosensory recovery after acute MMP-9/2 inhibition. Collectively, these data establish a novel role for MMPs in regulation of NG2+ cell proliferation in the damaged CNS, and a long-term benefit of acute MMP-9 block after SCI.  相似文献   

17.
Impaired axonal regeneration is a common observation after central nervous system (CNS) injury. The stromal cell-derived factor-1, SDF-1/CXCL12, has previously been shown to promote axonal growth in the presence of potent chemorepellent molecules known to be important in nervous system development. Here, we report that treatment with SDF-1α is sufficient to overcome neurite outgrowth inhibition mediated by CNS myelin towards cultured postnatal dorsal root ganglion neurons. While we found both cognate SDF-1 receptors, CXCR4 and CXCR7/RDC1, to be coexpressed on myelin-sensitive dorsal root ganglion neurons, the distinct expression pattern of CXCR4 on growth cones and branching points of neurites suggests a function of this receptor in chemokine-mediated growth promotion and/or arborization. These in vitro findings were further corroborated as local intrathecal infusion of SDF-1 into spinal cord injury following thoracic dorsal hemisection resulted in enhanced sprouting of corticospinal tract axons into white and grey matter. Our findings indicate that SDF-1 receptor activation might constitute a novel therapeutic approach to promote axonal growth in the injured CNS.  相似文献   

18.
The chemokine CCL21 is released from injured neurons and acts as a ligand of the chemokine receptor, CXCR3, which likely contributes to pro-inflammatory adaptations and secondary neuronal damage. CCL21-CXCR3 signalling may therefore impact on the development of neuropathic pain. By using the respective knockout mice we show that deficiency of CCL19/21 in plt/plt mice attenuates nerve injury evoked pain but not the hyperalgesia evoked by autoimmune encephalomyelitis (EAE). Oppositely, CXCR3-deficiency had no protective effect after traumatic nerve injury but reduced EAE-evoked hyperalgesia and was associated with reduced clinical EAE scores, a reduction of the pro-inflammatory cell infiltration and reduced upregulation of interferon gamma and interleukin-17 in the spinal cord. In contrast, microglia activation in the spinal cord after traumatic sciatic nerve injury was neither attenuated in CXCR3−/− nor plt/plt mice, nor in double knockouts. However, the severity of EAE, but not the hyperalgesia, was also reduced in plt/plt mice, which was associated with reduced infiltration of the spinal cord with CCR7+ T-cells, an increase of CD25+ T-cells and reduced upregulation of CXCL9 and 10, CCL11 and 12. The data show that CCL21 and CXCR3 have dichotomous functions in traumatic and EAE-evoked neuropathic pain suggesting diverse mechanisms likely requiring diverse treatments although both types of neuropathic pain are mediated in part through the immune activation.  相似文献   

19.

Objective

Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9 have been known to play an important role in secondary inflammatory reaction after spinal cord injury (SCI). The aim of this study was to investigate the expression and activity of MMP-2 and MMP-9 and to determine their relationship with disruption of endothelial blood-barrier after photochemically induced SCI in rats.

Methods

Female Sprague-Dawley rats, weighing between 250 and 300 g (aged 8 weeks) received focal spinal cord ischemia by photothrombosis using Rose Bengal. Expressions and activities of MMP-2 and MMP-9 were assessed by Western blot and gelatin zymography at various times from 6 h to 7 days. Endothelial blood-barrier integrity was assessed indirectly using spinal cord water content.

Results

Zymography and Western blot analysis demonstrated rapid up-regulation of MMP-9 protein levels in spinal cord after ischemic onset. Expressions and activities of MMP-9 showed a significant increased at 6 h after the photothrombotic ischemic event, and reached a maximum level at 24 h after the insult. By contrast, activated MMP-2 was not detected at any time point in either the experimental or the control groups. When compared with the control group, a significant increase in spinal cord water content was detected in rats at 24 h after photothrombotic SCI.

Conclusion

Early up-regulation of MMP-9 might be correlated with increased water content in the spinal cord at 24 h after SCI in rats. Results of this study suggest that MMP-9 is the key factor involved in disruption of the endothelial blood-barrier of the spinal cord and subsequent secondary damage after photothrombotic SCI in rats.  相似文献   

20.
CNS injury stimulates the expression of several proinflammatory cytokines and chemokines, some of which including MCP-1 (also known as CCL2), KC (CXCL1), and MIP-2 (CXCL2) act to recruit Gr-1+ leukocytes at lesion sites. While earlier studies have reported that neutrophils and monocytes/macrophages contribute to secondary tissue loss after spinal cord injury (SCI), recent work has shown that depletion of Gr-1+ leukocytes compromised tissue healing and worsened functional recovery. Here, we demonstrate that astrocytes distributed throughout the spinal cord initially contribute to early neuroinflammation by rapidly synthesizing MCP-1, KC, and MIP-2, from 3 up to 12 h post-SCI. Chemokine expression by astrocytes was followed by the infiltration of blood-derived immune cells, such as type I “inflammatory” monocytes and neutrophils, into the lesion site and nearby damaged areas. Interestingly, astrocytes from mice deficient in MyD88 signaling produced significantly less MCP-1 and MIP-2 and were unable to synthesize KC. Analysis of the contribution of MyD88-dependent receptors revealed that the astrocytic expression of MCP-1, KC, and MIP-2 was mediated by the IL-1 receptor (IL-1R1), and not by TLR2 or TLR4. Flow cytometry analysis of cells recovered from the spinal cord of MyD88- and IL-1R1-knockout mice confirmed the presence of significantly fewer type I “inflammatory” monocytes and the almost complete absence of neutrophils at 12 h and 4 days post-SCI. Together, these results indicate that MyD88/IL-1R1 signals regulate the entry of neutrophils and, to a lesser extent, type I “inflammatory” monocytes at sites of SCI.  相似文献   

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