免疫炎症与脑卒中的基础及临床研究
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摘要
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。
Stroke has become a major disease endangering human health due to its high morbidity, high disability rate and high mortality. After the acute ischemic stroke, the blood-brain barrier is destroyed. A large number of immune cells enter the central nervous system and interact with the central immune cells, which is able to further amplify the inflammatory response and aggravate ischemic brain damage. The immune inflammatory response runs through the process of injury and repair of ischemic stroke, in which microglia plays an important role. This paper summarizes the mechanism of inflammatory injury in acute ischemic stroke, introduces the current clinical trials of interventions in stroke patients with immunomodulators, presents the problems faced by clinical trials of stroke, as well as looks forward to the future of stroke immunotherapy.
Stroke has become a major disease endangering human health due to its high morbidity, high disability rate and high mortality. After the acute ischemic stroke, the blood-brain barrier is destroyed. A large number of immune cells enter the central nervous system and interact with the central immune cells, which is able to further amplify the inflammatory response and aggravate ischemic brain damage. The immune inflammatory response runs through the process of injury and repair of ischemic stroke, in which microglia plays an important role. This paper summarizes the mechanism of inflammatory injury in acute ischemic stroke, introduces the current clinical trials of interventions in stroke patients with immunomodulators, presents the problems faced by clinical trials of stroke, as well as looks forward to the future of stroke immunotherapy.
引文
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[2]FU Y,LIU Q,ANRATHER J,et al.Immune interventions in stroke[J].Nat Rev Neurol,2015,11(9):524-535.
[3]ORR AG,ORR AL,LI XJ,et al.Adenosine A(2A)receptor mediates microglial process retraction[J].Nat Neurosci,2009,12(7):872-878.
[4]STEPHENSON J,NUTMA E,VAN DERVALK P,et al.Inflammation in CNSneurodegenerative diseases[J].Immunology,2018,154(2):204-219.
[5]WANG J.Preclinical and clinical research on inflammation after intracerebral hemorrhage[J].Prog Neurobiol,2010,92(4):463-477.
[6]ZHOU Y,WANG Y,WANG J,et al.Inflammation in intracerebral hemorrhage:from mechanisms to clinical translation[J].Prog Neurobiol,2014,115:25-44.
[7]CHAMORROú,DIRNAGL U,URRA X,et al.Neuroprotection in acute stroke:targeting excitotoxicity,oxidative and nitrosative stress,and inflammation[J].Lancet Neurol,2016,15(8):869-881.
[8]GELDERBLOM M,LEYPOLDT F,STEINBACHK,et al.Temporal and spatial dynamics of cerebral immune cell accumulation in stroke[J].Stroke,2009,40(5):1849-1857.
[9]GAN Y,LIU Q,WU W,et al.Ischemic neurons recruit natural killer cells that accelerate brain infarction[J].Proc Natl Acad Sci USA,2014,111(7):2704-2709.
[10]LI M,LI Z,YAO Y,et al.Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity[J/OL].Proc Natl Acad Sci USA,2017,114(3):E396-E405(2016-12-19)[2018-11-19].https://www.pnas.org/content/114/3/E396.long.doi:10.1073/pnas.1612930114.
[11]LI D,LANG W,ZHOU C,et al.Upregulation of microglial ZEB1 ameliorates brain damage after acute ischemic stroke[J].Cell Rep,2018,22(13):3574-3586.
[12]PATYAR S,PRAKASH A,MODI M,et al.Role of vinpocetine in cerebrovascular diseases[J].Pharmacol Rep,2011,63(3):618-628.
[13]JEON KI,XU X,AIZAWA T,et al.Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism[J].Proc Natl Acad Sci U S A,2010,107(21):9795-9800.
[14]WANG H,ZHANG K,ZHAO L,et al.Antiinflammatory effects of vinpocetine on the functional expression of nuclear factorkappa B and tumor necrosis factor-alpha in a rat model of cerebral ischemia-reperfusion injury[J].Neurosci Lett,2014,566:247-251.
[15]ZHANG F,YAN C,WEI C,et al.Vinpocetine inhibits NF-kappaB-dependent inflammation in acute ischemic stroke patients[J].Transl Stroke Res,2018,9(2):174-184.
[16]CHUN J,BRINKMANN V.A mechanistically novel,first oral therapy for multiple sclerosis:the development of fingolimod(FTY720,Gilenya)[J].Discov Med,2011,12(64):213-228.
[17]FU Y,ZHANG N,REN L,et al.Impact of an immune modulator fingolimod on acute ischemic stroke[J].Proc Natl Acad Sci U S A,2014,111(51):18315-18320.
[18]ZHU Z,FU Y,TIAN D,et al.Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke:a pilot trial[J].Circulation,2015,132(12):1104-1112.
[19]RUDICK RA,SANDROCK A.Natalizumab:alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS[J].Expert Rev Neurother,2004,4(4):571-580.
[20]POLMAN CH,O’CONNOR PW,HAVRDOVAE,et al.A randomized,placebo-controlled trial of natalizumab for relapsing multiple sclerosis[J].N Engl J Med,2006,354(9):899-910.
[21]ELKINS J,VELTKAMP R,MONTANER J,et al.Safety and efficacy of natalizumab in patients with acute ischaemic stroke(ACTION):a randomised,placebo-controlled,double-blind phase 2 trial[J].Lancet Neurol,2017,16(3):217-226.
[22]SANMAMED MF,CHEN L.A paradigm shift in cancer immunotherapy:from enhancement to normalization[J].Cell,2018,175(2):313-326.