急性脊髓损伤后48 h内外周血细胞因子的变化
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摘要
背景:急性脊髓损伤后微环境的改变是引起继发性损伤的主要因素,因此探讨急性脊髓损伤后微环境的改变对临床诊疗具有重要意义。目的:探讨急性脊髓损伤48h内患者的外周血白细胞介素6、脑源性神经营养因子、碱性成纤维细胞生长因子、神经营养因子3及神经营养因子4的表达水平及临床意义。方法:选择2016年10月至2018年6月广西医科大学第一附属医院脊柱骨病外科收治的急性脊髓损伤48 h内的患者29例,按照ASIA神经功能分级标准分为:完全性脊髓损伤11例;不完全性脊髓损伤18例;选取股骨头缺血性坏死患者13例作为对照组。采用酶联免疫吸附法测定42例患者外周血白细胞介素6、脑源性神经营养因子、碱性成纤维细胞生长因子、神经营养因子3及神经营养因子4的表达水平,并相互比较。结果与结论:酶联免疫吸附测定显示,脊髓损伤组外周血白细胞介素6、脑源性神经营养因子、碱性成纤维细胞生长因子、神经营养因子3及神经营养因子4表达水平明显高于对照组(P <0.05);其中完全性脊髓损伤组外周血中白细胞介素6、脑源性神经营养因子、碱性成纤维细胞生长因子、神经营养因子3及神经营养因子4表达水平明显高于不完全性脊髓损伤组(P<0.05)。结果证实,急性脊髓损伤后白细胞介素6、脑源性神经营养因子、碱性成纤维细胞生长因子、神经营养因子3及神经营养因子4表达水平升高,提示这些细胞因子可能参与急性脊髓损伤后重要的病理生理过程。
BACKGROUND: Change of microenvironment after acute spinal cord injury is the main factor causing secondary injury, so it is of great significance to investigate the changes of microenvironment after acute spinal cord injury for clinical diagnosis and treatment. OBJECTIVE: To investigate the expression levels and clinical significance of interleukin-6, brain derived neurotrophic factor, basic fibroblast growth factor, neurotrophin-3 and neurotrophin-4 in peripheral blood within 48 hours after acute spinal cord injury. METHODS: Twenty-nine patients with acute spinal cord injury admitted at the Department of Spinal Osteopathia, the First Affiliated Hospital of Guangxi Medical University from October 2016 to June 2018 were enrolled, and were divided into two groups according to American Spinal Injury Association impairment scale: complete spinal cord injury(n=11) and incomplete spinal cord injury(n=18). Thirteen patients with avascular necrosis of the femoral head were selected as controls. The expression levels of interleukin-6, brain derived neurotrophic factor, basic fibroblast growth factor, neurotrophin-3 and neurotrophin-4 in peripheral blood of 42 patients were determined by ELISA and compared. RESULTS AND CONCLUSION: The ELISA results showed that the expression levels of interleukin-6, brain derived neurotrophic factor, basic fibroblast growth factor, neurotrophin-3 and neurotrophin-4 in peripheral blood in the spinal cord injury group were significantly higher than those in the control group(P < 0.05). The expression levels of all above cytokines in the complete spinal cord injury group were significantly higher than those in the incomplete spinal cord injury group(P < 0.05). In summary, increased expression of interleukin-6, brain derived neurotrophic factor, basic fibroblast growth factor, neurotrophin-3, neurotrophin-4 after acute spinal cord injury indicates that it may participate in the important pathophysiological process after acute spinal cord injury.
BACKGROUND: Change of microenvironment after acute spinal cord injury is the main factor causing secondary injury, so it is of great significance to investigate the changes of microenvironment after acute spinal cord injury for clinical diagnosis and treatment. OBJECTIVE: To investigate the expression levels and clinical significance of interleukin-6, brain derived neurotrophic factor, basic fibroblast growth factor, neurotrophin-3 and neurotrophin-4 in peripheral blood within 48 hours after acute spinal cord injury. METHODS: Twenty-nine patients with acute spinal cord injury admitted at the Department of Spinal Osteopathia, the First Affiliated Hospital of Guangxi Medical University from October 2016 to June 2018 were enrolled, and were divided into two groups according to American Spinal Injury Association impairment scale: complete spinal cord injury(n=11) and incomplete spinal cord injury(n=18). Thirteen patients with avascular necrosis of the femoral head were selected as controls. The expression levels of interleukin-6, brain derived neurotrophic factor, basic fibroblast growth factor, neurotrophin-3 and neurotrophin-4 in peripheral blood of 42 patients were determined by ELISA and compared. RESULTS AND CONCLUSION: The ELISA results showed that the expression levels of interleukin-6, brain derived neurotrophic factor, basic fibroblast growth factor, neurotrophin-3 and neurotrophin-4 in peripheral blood in the spinal cord injury group were significantly higher than those in the control group(P < 0.05). The expression levels of all above cytokines in the complete spinal cord injury group were significantly higher than those in the incomplete spinal cord injury group(P < 0.05). In summary, increased expression of interleukin-6, brain derived neurotrophic factor, basic fibroblast growth factor, neurotrophin-3, neurotrophin-4 after acute spinal cord injury indicates that it may participate in the important pathophysiological process after acute spinal cord injury.
引文
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[8]Lan WB,Lin JH,Chen XW,et al.Overexpressing neuroglobin improves functional recovery by inhibiting neuronal apoptosis after spinal cord injury.Brain Res.2014;1562:100-108.
[9]Zhou HL,Zhang XJ,Zhang MY,et al.Transplantation of human amniotic mesenchymal stem cells promotes functional recovery in a rat model of traumatic spinal cord injury.Neurochem Res.2016;475(2):1-11.
[10]Nakata N,Kato H,Kogure K.Protective effects of basic fibroblast growth factor against hippocampal neuronal damage following cerebral ischemia in the gerbil.Brain Res.1993;605(2):354-356.
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[13]Filli L,Engmann AK,Z?rner B,et al.Bridging the gap:a reticulo-propriospinal detour bypassing an incomplete spinal cord injury.J Neurosci.2014;34(40):13399-13410.
[14]Yuan Y,Su Z,Pu Y,et al.Ethyl pyruvate promotes spinal cord repair by ameliorating the glial microenvironment.Br JPharmacol.2012;166(2):749-763.
[15]宫德星,吕奎荣.急性脊髓损伤的MRI诊断[J].齐鲁医学杂志,2008,23(6):516-517.
[16]王方永,李建军.脊髓损伤神经学分类国际标准(ASIA 2011版)最新修订及标准解读[J].中国康复理论与实践,2012,18(8):797-800.
[17]Chhabra HS,Sarda K,Arora M,et al.Autologous bone marrow cell transplantation in acute spinal cord injury-an Indian pilot study.Spinal Cord.2015;54(1):57-64.
[18]Tuna M,Polat S,Erman T,et al.Effect of anti-rat interleukin-6antibody after spinal cord injury in the rat:inducible nitric oxide synthase expression,sodium-and potassium-activated,magnesium-dependent adenosine-5-triphosphatase and superoxide dismutase activation,and ultrastructural changes.J Neurosurg.2001;95(1):64-73.
[19]Park DY,Mayle RE,Smith RL,et al.Combined transplantation of human neuronal and mesenchymal stem cells following spinal cord injury.Global Spine J.2013;3(1):1-6.
[20]De Moraes JK,Wagner VP,Fonseca FP,et al.Uncovering the role of brain‐derived neurotrophic factor/tyrosine kinase receptor B signaling in head and neck malignancies.J Oral Pathol Med.2018;47(3):221-227.
[21]Yang JW,Liang Z,Deng SD,et al.Brain-derived neurotrophic factor promotes growth of neurons and neural stem cells possibly by triggering the phosphoinositide 3-kinase/AKT/glycogen synthase kinase-3β/β-catenin pathway.CNS Neurol Disord Drug Targets.2017;16(7):828-836.
[22]ang B,Qin J,Nie Y,et al.Brain-derived neurotrophic factor propeptide inhibits proliferation and induces apoptosis in C6glioma cells.Neuroreport.2017;28(12):726-730.
[23]Habtemariam S.The brain-derived neurotrophic factor in neuronal plasticity and neuroregeneration:new pharmacological concepts for old and new drugs.Neural Regen Res.2018;13(6):983-984.
[24]Marti?ón S,García-Vences E,Toscano-Tejeida D,et al.Long-term production of BDNF and NT-3 induced by A91-immunization after spinal cord injury.BMC Neurosci.2016;17(1):42.
[25]Alonso Vanegas MA,Fawcett JP,Causing CG,et al.Characterization of dopaminergic midbrain neurons in a DBH:BDNF transgenic mouse.J Comp Neurol.2015;413(3):449-462.
[26]Sharma HS,Nyberg F,Westman J,et al.Brain derived neurotrophic factor and insulin like growth factor-1 attenuate upregu-lation of nitric oxide synthase and cell injury following trauma to the spinal cord:an immunohistochemical study in the rat.Amino Acids.1998;14(1):121-129.
[27]Garraway SM,Anderson AJ,Mendell LM.BDNF-induced facilitation of afferent-evoked responses in lamina II neurons is reduced after neonatal spinal cord contusion injury.JNeurophysiol.2005;94(3):1798-804.
[28]Zhao YZ,Lin M,Lin Q,et al.Intranasal delivery of bFGF with nanoliposomes enhances in vivo,neuroprotection and neural injury recovery in a rodent stroke model.J Control Release.2016;224:165-175.
[29]Rabchevsky AG,Fugaccia I,Turner AF,et al.Basic fibroblast growth factor(bFGF)enhances functional recovery following severe spinal cord injury to the rat.Exp Neurol.2000;164(2):280-291.
[30]Chen B,He J,Yang H,et al.Repair of spinal cord injury by implantation of bFGF-incorporated HEMA-MOETACLhydrogel in rats.Sci Rep.2015;5:9017.
[31]蔡俊赢,董效禹,赖嘉新,等.bFGF通过抑制Nogo-A信号减少脊髓损伤后胶质瘢痕的形成[J].中国生物化学与分子生物学报,2017,33(7):681-686.
[32]Aoyagi A,Nishikawa K,Saito H,et al.Characterization of basic fibroblast growth factor-mediated acceleration of axonal branching in cultured rat hippocampal neurons.Brain Res.1994;661(1-2):117-126.
[33]Kojima A,Tator CH.Intrathecal administration of epidermal growth factor and fibroblast growth factor 2 promotes ependymal proliferation and functional recovery after spinal cord injury in adult rats.J Neurotrauma.2002;19(2):223-38.
[34]Li Y,Xia B,Li R,Yin D,et al.Expression of brain-derived neurotrophic factors,neurotrophin-3,and neurotrophin-4 in the nucleus accumbens during heroin dependency and withdrawal.Neuroreport.2017;28(11):654-660.
[35]Tseng PT,Chen YW,Tu KY,et al.State-dependent increase in the levels of neurotrophin-3 and neurotrophin-4/5 in patients with bipolar disorder:a meta-analysis.J Psychiatr Res.2016;79:86-92.
[36]Loch AA,Zanetti MV,de Sousa RT,et al.Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium.Prog Neuropsychopharmacol Biol Psychiatry.2015;56:243-246.
[37]Szczepankiewicz A,Rachel M,Sobkowiak P,et al.Serum neurotrophin-3 and neurotrophin-4 levels are associated with asthma severity in children.Eur Respir J.2012;39(4):1035-1037.
[38]Hechler D,Boato F,Nitsch R,et al.Differential regulation of axon outgrowth and reinnervation by neurotrophin-3 and neurotrophin-4 in the hippocampal formation.Exp Brain Res.2010;205(2):215-221.
[39]Nassenstein C,Braun A,Erpenbeck VJ,et al.The neurotrophins nerve growth factor,brain-derived neurotrophic factor,neurotrophin-3,and neurotrophin-4 are survival and activation factors for eosinophils in patients with allergic bronchial asthma.J Exp Med.2003;198(3):455-467.
[40]Guo Y,Ma Y,Pan YL,et al.Jisuikang,a Chinese herbal formula,increases neurotrophic factor expression and promotes the recovery of neurological function after spinal cord injury.Neural Regen Res.2017;12(9):1519-1528.
[41]Yang Z,Duan H,Mo L,et al.The effect of the dosage of NT-3/chitosan carriers on the proliferation and differentiation of neural stem cells.Biomaterials.2010;31(18):4846-4854.
[42]Schnell L,Schneider R,Kolbeck R,et al.Neurotrophin-3enhances sprouting of corticospinal tract duringdevelopment and after adult spinal cord lesion.Nature.1994;367(6459):170-173.
[43]Harvey AR,Lovett SJ,Majda BT,et al.Neurotrophic factors for spinal cord repair:Which,where,how and when to apply,and for what period of time?Brain Res.2015;1619:36-71.
[44]Tobias CA,Shumsky JM,Tuszynski MH,et al.Delayed grafting of BDNF and NT-3 producing fibroblasts into the injured spinal cord stimulates sprouting,partially rescues axotomized red nucleus neurons from loss and atrophy,and provides limited regeneration.Exp Neurol.2003;184(1):97-113.
[45]Junger H,Varon S.Neurotrophin-4(NT-4)and glial cell line-derived neurotrophic factor(GDNF)promote the survival of corticospinal motor neurons of neonatal rats in vitro.Brain Res.1997;762(1-2):56-60.
[2]Mcdonald JW,Sadowsky C.Spinal-cord injury.Lancet.2002;359(9304):417-425.
[3]李柯柯,宗少晖.脊髓损伤中的免疫炎性细胞因子[J].中国组织工程研究,2015,18(53):8646-8646.
[4]Hagg T,Oudega M.Degenerative and spontaneous regenerative processes after spinal cord injury.JNeurotrauma.2006;23(3-4):264-280.
[5]Dougherty KD,Dreyfus CF,Black IB.Brain-derived neurotrophic factor in astrocytes,oligodendrocytes,and microglia/macrophages after spinal cord injury.Neurobiol Dis.2000;7(6):574-585.
[6]Kaplin AI,Deshpande DM,Scott E,et al.IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis.J Clin Invest.2005;115(10):2731-41.
[7]郑晶晶,姚安会,刘芳芳,等.小鼠脊髓损伤早期不同炎症因子的表达变化[J].细胞与分子免疫学杂志,2012,28(4):391-394.
[8]Lan WB,Lin JH,Chen XW,et al.Overexpressing neuroglobin improves functional recovery by inhibiting neuronal apoptosis after spinal cord injury.Brain Res.2014;1562:100-108.
[9]Zhou HL,Zhang XJ,Zhang MY,et al.Transplantation of human amniotic mesenchymal stem cells promotes functional recovery in a rat model of traumatic spinal cord injury.Neurochem Res.2016;475(2):1-11.
[10]Nakata N,Kato H,Kogure K.Protective effects of basic fibroblast growth factor against hippocampal neuronal damage following cerebral ischemia in the gerbil.Brain Res.1993;605(2):354-356.
[11]Fahmy GH,Moftah MZ.FGF-2 in astroglial cells during vertebrate spinal cord recovery.Front Cell Neurosci.2010;4(1):129.
[12]Brown A,Ricci MJ,Weaver LC.NGF message and protein distribution in the injured rat spinal cord.Exp Neurol.2004;188(1):115-127.
[13]Filli L,Engmann AK,Z?rner B,et al.Bridging the gap:a reticulo-propriospinal detour bypassing an incomplete spinal cord injury.J Neurosci.2014;34(40):13399-13410.
[14]Yuan Y,Su Z,Pu Y,et al.Ethyl pyruvate promotes spinal cord repair by ameliorating the glial microenvironment.Br JPharmacol.2012;166(2):749-763.
[15]宫德星,吕奎荣.急性脊髓损伤的MRI诊断[J].齐鲁医学杂志,2008,23(6):516-517.
[16]王方永,李建军.脊髓损伤神经学分类国际标准(ASIA 2011版)最新修订及标准解读[J].中国康复理论与实践,2012,18(8):797-800.
[17]Chhabra HS,Sarda K,Arora M,et al.Autologous bone marrow cell transplantation in acute spinal cord injury-an Indian pilot study.Spinal Cord.2015;54(1):57-64.
[18]Tuna M,Polat S,Erman T,et al.Effect of anti-rat interleukin-6antibody after spinal cord injury in the rat:inducible nitric oxide synthase expression,sodium-and potassium-activated,magnesium-dependent adenosine-5-triphosphatase and superoxide dismutase activation,and ultrastructural changes.J Neurosurg.2001;95(1):64-73.
[19]Park DY,Mayle RE,Smith RL,et al.Combined transplantation of human neuronal and mesenchymal stem cells following spinal cord injury.Global Spine J.2013;3(1):1-6.
[20]De Moraes JK,Wagner VP,Fonseca FP,et al.Uncovering the role of brain‐derived neurotrophic factor/tyrosine kinase receptor B signaling in head and neck malignancies.J Oral Pathol Med.2018;47(3):221-227.
[21]Yang JW,Liang Z,Deng SD,et al.Brain-derived neurotrophic factor promotes growth of neurons and neural stem cells possibly by triggering the phosphoinositide 3-kinase/AKT/glycogen synthase kinase-3β/β-catenin pathway.CNS Neurol Disord Drug Targets.2017;16(7):828-836.
[22]ang B,Qin J,Nie Y,et al.Brain-derived neurotrophic factor propeptide inhibits proliferation and induces apoptosis in C6glioma cells.Neuroreport.2017;28(12):726-730.
[23]Habtemariam S.The brain-derived neurotrophic factor in neuronal plasticity and neuroregeneration:new pharmacological concepts for old and new drugs.Neural Regen Res.2018;13(6):983-984.
[24]Marti?ón S,García-Vences E,Toscano-Tejeida D,et al.Long-term production of BDNF and NT-3 induced by A91-immunization after spinal cord injury.BMC Neurosci.2016;17(1):42.
[25]Alonso Vanegas MA,Fawcett JP,Causing CG,et al.Characterization of dopaminergic midbrain neurons in a DBH:BDNF transgenic mouse.J Comp Neurol.2015;413(3):449-462.
[26]Sharma HS,Nyberg F,Westman J,et al.Brain derived neurotrophic factor and insulin like growth factor-1 attenuate upregu-lation of nitric oxide synthase and cell injury following trauma to the spinal cord:an immunohistochemical study in the rat.Amino Acids.1998;14(1):121-129.
[27]Garraway SM,Anderson AJ,Mendell LM.BDNF-induced facilitation of afferent-evoked responses in lamina II neurons is reduced after neonatal spinal cord contusion injury.JNeurophysiol.2005;94(3):1798-804.
[28]Zhao YZ,Lin M,Lin Q,et al.Intranasal delivery of bFGF with nanoliposomes enhances in vivo,neuroprotection and neural injury recovery in a rodent stroke model.J Control Release.2016;224:165-175.
[29]Rabchevsky AG,Fugaccia I,Turner AF,et al.Basic fibroblast growth factor(bFGF)enhances functional recovery following severe spinal cord injury to the rat.Exp Neurol.2000;164(2):280-291.
[30]Chen B,He J,Yang H,et al.Repair of spinal cord injury by implantation of bFGF-incorporated HEMA-MOETACLhydrogel in rats.Sci Rep.2015;5:9017.
[31]蔡俊赢,董效禹,赖嘉新,等.bFGF通过抑制Nogo-A信号减少脊髓损伤后胶质瘢痕的形成[J].中国生物化学与分子生物学报,2017,33(7):681-686.
[32]Aoyagi A,Nishikawa K,Saito H,et al.Characterization of basic fibroblast growth factor-mediated acceleration of axonal branching in cultured rat hippocampal neurons.Brain Res.1994;661(1-2):117-126.
[33]Kojima A,Tator CH.Intrathecal administration of epidermal growth factor and fibroblast growth factor 2 promotes ependymal proliferation and functional recovery after spinal cord injury in adult rats.J Neurotrauma.2002;19(2):223-38.
[34]Li Y,Xia B,Li R,Yin D,et al.Expression of brain-derived neurotrophic factors,neurotrophin-3,and neurotrophin-4 in the nucleus accumbens during heroin dependency and withdrawal.Neuroreport.2017;28(11):654-660.
[35]Tseng PT,Chen YW,Tu KY,et al.State-dependent increase in the levels of neurotrophin-3 and neurotrophin-4/5 in patients with bipolar disorder:a meta-analysis.J Psychiatr Res.2016;79:86-92.
[36]Loch AA,Zanetti MV,de Sousa RT,et al.Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium.Prog Neuropsychopharmacol Biol Psychiatry.2015;56:243-246.
[37]Szczepankiewicz A,Rachel M,Sobkowiak P,et al.Serum neurotrophin-3 and neurotrophin-4 levels are associated with asthma severity in children.Eur Respir J.2012;39(4):1035-1037.
[38]Hechler D,Boato F,Nitsch R,et al.Differential regulation of axon outgrowth and reinnervation by neurotrophin-3 and neurotrophin-4 in the hippocampal formation.Exp Brain Res.2010;205(2):215-221.
[39]Nassenstein C,Braun A,Erpenbeck VJ,et al.The neurotrophins nerve growth factor,brain-derived neurotrophic factor,neurotrophin-3,and neurotrophin-4 are survival and activation factors for eosinophils in patients with allergic bronchial asthma.J Exp Med.2003;198(3):455-467.
[40]Guo Y,Ma Y,Pan YL,et al.Jisuikang,a Chinese herbal formula,increases neurotrophic factor expression and promotes the recovery of neurological function after spinal cord injury.Neural Regen Res.2017;12(9):1519-1528.
[41]Yang Z,Duan H,Mo L,et al.The effect of the dosage of NT-3/chitosan carriers on the proliferation and differentiation of neural stem cells.Biomaterials.2010;31(18):4846-4854.
[42]Schnell L,Schneider R,Kolbeck R,et al.Neurotrophin-3enhances sprouting of corticospinal tract duringdevelopment and after adult spinal cord lesion.Nature.1994;367(6459):170-173.
[43]Harvey AR,Lovett SJ,Majda BT,et al.Neurotrophic factors for spinal cord repair:Which,where,how and when to apply,and for what period of time?Brain Res.2015;1619:36-71.
[44]Tobias CA,Shumsky JM,Tuszynski MH,et al.Delayed grafting of BDNF and NT-3 producing fibroblasts into the injured spinal cord stimulates sprouting,partially rescues axotomized red nucleus neurons from loss and atrophy,and provides limited regeneration.Exp Neurol.2003;184(1):97-113.
[45]Junger H,Varon S.Neurotrophin-4(NT-4)and glial cell line-derived neurotrophic factor(GDNF)promote the survival of corticospinal motor neurons of neonatal rats in vitro.Brain Res.1997;762(1-2):56-60.
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