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戰(zhàn)爭(zhēng)中的孩子范文第1篇

戰(zhàn)爭(zhēng)中的孩子

1937年8月28日，一位記者來(lái)到上?；疖?chē)站南站，那里一片祥和，人們說(shuō)說(shuō)笑笑，臉上露著喜悅，有個(gè)一家三口正在那里，媽媽抱著一個(gè)男孩，好可愛(ài)的小男孩，穿著漂亮的衣服，手里還拿著一個(gè)小熊，大概是爸爸剛給他買(mǎi)的。

突然，天空中響起警報(bào)聲，大家喊：“鬼子來(lái)了！快跑??！”“轟”的一聲巨響，火車(chē)站的候車(chē)室瞬間倒塌了。日本戰(zhàn)斗機(jī)像兇惡的老鷹一樣在天空中飛來(lái)飛去。車(chē)站里成千上萬(wàn)的人們驚慌失措，逃得逃，叫的叫，哭的哭，亂成一片。頃刻之間，硝煙滾滾，血肉橫飛。日本戰(zhàn)斗機(jī)又放了一枚炸彈，正好落在天橋上，天橋頓時(shí)塌了一半。日本侵略者用惡狼般的眼睛盯著廢墟，繼續(xù)往下投炸彈，許多人都倒在了血泊之中。

這時(shí)，傳來(lái)一陣哭聲，聞聲過(guò)去，一個(gè)二三歲的男孩正在坐在鐵道中間，他在不停地哭嚎，他的哭聲令人揪心，他的衣服已經(jīng)破爛不堪了，手里抱著爸爸給他買(mǎi)的小熊，他干瘦干瘦的，他的周?chē)钦◤椝槠?，他身上也濺滿(mǎn)了血，滿(mǎn)臉都是灰塵，彈片劃傷了他。他的父母在哪兒？原來(lái)，炸彈落下時(shí)，男孩的父母用自己的身軀護(hù)住了他，同時(shí)，一枚炸彈不偏不正地落在了這對(duì)夫婦的身上……

幾分鐘前這個(gè)男孩還是媽媽?xiě)阎械膵蓛?，爸爸跟他逗?lè)，可是幾分鐘后這個(gè)孩子就成了無(wú)助的孤兒。這個(gè)孤獨(dú)，可憐的孩子，他以后的生活又會(huì)如何？相信他會(huì)記住這段歷史，發(fā)奮讀書(shū)，為振興中華而不懈努力。

戰(zhàn)爭(zhēng)中的孩子范文第2篇

你們好！

我的年齡與你們相差不幾，但你們卻被戰(zhàn)火這個(gè)惡魔困著，而我卻享受有愛(ài)、有幸福的生活。你們是不幸中不不幸，年齡那么小就被抓去充軍、打仗，讓你們那好沒(méi)有綻放的花朵枯萎。我不敢想象你們那惡魔般的生活，不知道那么是否害怕，是否悲傷，是否……

我同情你們，我憐憫你們。我與你們相比就好似天壤之別，好似一個(gè)生活在天上，一個(gè)生活在地獄一樣。我想為你們插上一對(duì)翅膀，讓你們逃離那戰(zhàn)爭(zhēng)飛上藍(lán)天，與我們一同享受被陽(yáng)光、被幸福、被愛(ài)包裹著的幸福。讓那凋謝的花朵重新綻放出美麗與光彩。

最后，希望在戰(zhàn)火中的孩子們堅(jiān)強(qiáng)，不要被那戰(zhàn)爭(zhēng)的惡魔嚇倒。———要打敗戰(zhàn)爭(zhēng)的惡魔，打敗戰(zhàn)爭(zhēng)的惡魔！

祝：

你們幸?？鞓?lè)！

戰(zhàn)爭(zhēng)中的孩子范文第3篇

我是一個(gè)孤獨(dú)的孩子，我沒(méi)有親人，沒(méi)有朋友，所有的一切的一切我都沒(méi)有。就連最?lèi)?ài)我爸爸媽媽也離我而去了，

1937年8月28日，我們一家走在上?；疖?chē)南站時(shí)。突然，天上出現(xiàn)幾個(gè)亮點(diǎn)，越來(lái)越近，才看清楚是導(dǎo)彈。頓時(shí)，人群慌亂?？墒菍?dǎo)彈還是向火車(chē)站炸了過(guò)來(lái)。在彌漫著硝煙的火車(chē)站內(nèi)，大概只有我一個(gè)人活了下來(lái)那時(shí)我覺(jué)得我被整個(gè)世界給遺棄了。無(wú)論我怎么哭怎么叫，都沒(méi)有人回應(yīng)我。映入我眼簾的卻是一滴滴鮮血和無(wú)數(shù)的生命，它聯(lián)系著一個(gè)字，是“殺”。當(dāng)時(shí)我的眼里只有仇恨，殺死日本人，為我的爸爸媽媽報(bào)仇血恨。彌漫著的硝煙伴隨著孤零零的我，哭喊聲在火車(chē)站內(nèi)蕩漾。就連天上的云也被染成血紅色了，沒(méi)有小鳥(niǎo)的歡叫，再也沒(méi)有往日那熱鬧的情景了。

罪惡滔天的日本人，這個(gè)仇我一定會(huì)報(bào)的。如果你們要悔改，那就不要再侵犯我們中國(guó)吧！讓我們向全世界呼吁：“要和平不要戰(zhàn)爭(zhēng)。”

北京石景山區(qū)西黃村小學(xué)四年級(jí):李?yuàn)?/p>

戰(zhàn)爭(zhēng)中的孩子范文第4篇

關(guān)鍵詞：趨化因子; 小膠質(zhì)細(xì)胞; 神經(jīng)炎癥; 阿爾茨海默病;

Progress in research on the role of chemokines and microglia in the neuroinflammation of Alzheimer’s disease

WANG Jia ZHANG Li WEI Heru ZHAI Yueyi LIU Shufeng ZHANG Lianfeng

Hebei Key Lab of Laboratory Animal science, Hebei Medical University Key Laboratory of Human Disease Comparative Medicine, National Health and Family Planning Commission of P.R.C, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medicine Center, Peking Union Medical College

Abstract：

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease characterized by dementia as the main symptom. The main neuropathologic features include senile plaques, neurofibrillary tangles, neuroinflammation, and neuron loss. Deposition of amyloid β-protein and misfolded tau protein in patients with AD induces the activation of microglia; this leads to the secretion of cytokines and chemokines, which jointly induce a neuroinflammatory response and affect the progression of AD. This review briefly summarizes the role of microglial activation and chemokine release in the neuroinflammation of AD and provides new insight into the treatment of AD.

Keyword：

chemokines; microglia; neuroinflammation; Alzheimer's disease;

阿爾茨海默?。ˋlzheimer disease，AD）是一種常見(jiàn)的慢性進(jìn)行性神經(jīng)退行性疾病，主要臨床表現(xiàn)為進(jìn)行性認(rèn)知功能障礙、精神和行為異常，逐漸發(fā)展為無(wú)法進(jìn)行日常生活的嚴(yán)重癡呆。AD主要病理學(xué)改變有大腦皮質(zhì)區(qū)和海馬區(qū)的細(xì)胞外β-淀粉樣蛋白（amyloid β-protein，Aβ）沉積形成的老年斑（senile plaques，SP）、神經(jīng)細(xì)胞內(nèi)過(guò)度磷酸化的Tau蛋白錯(cuò)誤折疊后聚集形成的神經(jīng)原纖維纏結(jié)（neurofibrillary tangles，NFTs）、神經(jīng)炎癥和神經(jīng)元丟失[1]。目前，AD的發(fā)病原因與發(fā)病機(jī)制尚不明確，經(jīng)典的病因假說(shuō)有Aβ級(jí)聯(lián)假說(shuō)和Tau蛋白假說(shuō)等。越來(lái)越多證據(jù)顯示神經(jīng)炎癥在AD發(fā)病中具重要作用，神經(jīng)炎癥是中樞神經(jīng)系統(tǒng)（central nervous system，CNS）針對(duì)各種有害刺激（如損傷或感染）發(fā)生的免疫反應(yīng)，由CNS的神經(jīng)膠質(zhì)細(xì)胞、內(nèi)皮細(xì)胞和外周的免疫細(xì)胞介導(dǎo)并產(chǎn)生細(xì)胞因子、趨化因子、活性氧等各種炎性介質(zhì)共同引起[2]。AD病理研究發(fā)現(xiàn)SP附近存在反應(yīng)性小膠質(zhì)細(xì)胞，同時(shí)檢測(cè)到AD病人腦實(shí)質(zhì)中炎性細(xì)胞因子和趨化因子（chemokine，CK）的水平升高，揭示AD中存在神經(jīng)炎癥，并參與AD的發(fā)病機(jī)制[1,3]。AD中的神經(jīng)炎癥主要以Aβ沉積和錯(cuò)誤折疊的Tau蛋白對(duì)小膠質(zhì)細(xì)胞的持續(xù)激活，導(dǎo)致細(xì)胞因子和趨化因子等炎性介質(zhì)的不斷釋放產(chǎn)生的慢性炎癥反應(yīng)，而釋放的趨化因子誘導(dǎo)小膠質(zhì)細(xì)胞向神經(jīng)炎癥區(qū)域遷移，發(fā)揮促炎或抗炎的作用，進(jìn)而影響AD的發(fā)展[4]。因此，本文將重點(diǎn)論述小膠質(zhì)細(xì)胞激活和趨化因子釋放在AD神經(jīng)炎癥中發(fā)揮的作用。

1 小膠質(zhì)細(xì)胞的激活

小膠質(zhì)細(xì)胞是神經(jīng)膠質(zhì)細(xì)胞的一種，大約占大腦中神經(jīng)膠質(zhì)細(xì)胞的10%左右。研究表明小膠質(zhì)細(xì)胞起源于卵黃囊的原始巨噬細(xì)胞，相當(dāng)于腦和脊髓中的巨噬細(xì)胞[5]。靜息的小膠質(zhì)細(xì)胞以休眠模式監(jiān)視著周?chē)M織的免疫狀態(tài)，當(dāng)出現(xiàn)炎癥刺激時(shí)，小膠質(zhì)細(xì)胞迅速被激活，通過(guò)改變形態(tài)遷移至病變部位，清除壞死物質(zhì)，支持和保護(hù)神經(jīng)系統(tǒng)。激活后的小膠質(zhì)細(xì)胞可以極化為促炎或抗炎表型，分別稱(chēng)為經(jīng)典激活小膠質(zhì)細(xì)胞（M1型）和替代激活小膠質(zhì)細(xì)胞（M2型）[6]。M1型為促炎狀態(tài)，釋放大量促炎因子（如IL-1β、TNF-α、IFN-γ、CCL2）以及一氧化氮合酶iNOS，活性氧ROS等炎性成分，不斷加劇炎癥反應(yīng)，引起神經(jīng)元變性及腦組織損傷。M2型為抗炎狀態(tài)，能夠釋放抗炎因子（如IL-4、IL-10、IL-13、YM-1）以及神經(jīng)營(yíng)養(yǎng)因子促進(jìn)炎癥消退，吞噬細(xì)胞碎片，促進(jìn)組織修復(fù)并重建體內(nèi)穩(wěn)態(tài)[6,7,8]。

AD產(chǎn)生的Aβ沉積、錯(cuò)誤折疊的Tau蛋白及損傷的神經(jīng)元會(huì)吸引小膠質(zhì)細(xì)胞的聚集并引起其激活，同時(shí)引起細(xì)胞因子和趨化因子的釋放，這些因素與Aβ持續(xù)相互作用形成AD中的神經(jīng)炎癥[9,10]。AD病理研究中發(fā)現(xiàn)Aβ可以誘導(dǎo)小膠質(zhì)細(xì)胞的聚集并浸潤(rùn)在淀粉樣斑塊周?chē)珹β可以作為危險(xiǎn)相關(guān)分子模式激活小膠質(zhì)細(xì)胞表面模式識(shí)別受體如Toll樣受體（Toll-like receptors，TLR），髓樣細(xì)胞觸發(fā)受體2（triggering receptor expressed on myeloid cells，TREM2），清道夫受體（scavenger receptor，SR-AI/II），補(bǔ)體受體，受體晚期糖基化終產(chǎn)物（receptor advanced glycosylation end product，RAGE）等，引起小膠質(zhì)細(xì)胞的活化、分泌、吞噬等作用[11,12]。Aβ還可以直接以濃度依賴(lài)的方式與淀粉樣前體蛋白（amyloid precursor protein，APP）相互作用，共同誘導(dǎo)小膠質(zhì)細(xì)胞的激活并分泌炎性因子TNF-α[13]。Nussbaum等[14]發(fā)現(xiàn)Aβ還能誘導(dǎo)Tau蛋白異常聚集，并在細(xì)胞內(nèi)形成NFTs而引發(fā)慢性神經(jīng)炎癥。相關(guān)研究報(bào)道在AD患者海馬體的NFTs和帶有纏結(jié)的神經(jīng)元附近，以及Tau蛋白轉(zhuǎn)基因動(dòng)物模型（TAUSHR72轉(zhuǎn)基因大鼠和TauR406W轉(zhuǎn)基因小鼠）中，常出現(xiàn)小膠質(zhì)細(xì)胞的激活，可能的原因是當(dāng)Tau蛋白發(fā)生錯(cuò)誤折疊后，不斷聚集并在神經(jīng)元中形成NFTs，破壞神經(jīng)元的功能并導(dǎo)致細(xì)胞最后死亡，引發(fā)的炎癥激活小膠質(zhì)細(xì)胞。這些均表明炎癥反應(yīng)與NFTs之間存在密切關(guān)系[10,15,16]。同時(shí)激活的小膠質(zhì)細(xì)胞釋放的TNF-α?xí)隗w外誘導(dǎo)Tau蛋白的聚集[17]。因此，Aβ沉積和錯(cuò)誤折疊的Tau蛋白可以通過(guò)多種途徑激活小膠質(zhì)細(xì)胞炎癥反應(yīng)路徑，并進(jìn)一步影響AD的發(fā)生、發(fā)展。

靜息的小膠質(zhì)細(xì)胞在AD產(chǎn)生的病理中可以誘導(dǎo)激活為M1型和M2型。目前的研究認(rèn)為在AD的早期，Aβ沉積將靜止的小膠質(zhì)細(xì)胞激活為M2型，M2型極化的小膠質(zhì)細(xì)胞表現(xiàn)表現(xiàn)出神經(jīng)保護(hù)和抗炎作用，分泌抗炎因子，吞噬、降解、去除Aβ和Tau，抑制炎癥反應(yīng)。隨著AD病理發(fā)展，Aβ和Aβ誘導(dǎo)的促炎因子持續(xù)相互作用使小膠質(zhì)細(xì)胞過(guò)度活化轉(zhuǎn)變?yōu)镸1型，M1型的小膠質(zhì)細(xì)胞表現(xiàn)出神經(jīng)毒性和促炎作用，釋放大量促炎因子，運(yùn)動(dòng)能力下降，吞噬、降解能力減弱，加劇炎癥反應(yīng)[18,19]。圖1為小膠質(zhì)細(xì)胞在AD中的激活。從圖中發(fā)現(xiàn)，AD中激活的M1型小膠質(zhì)細(xì)胞可以引起促炎性趨化因子（CCL2、CCL3、CCL4、CCL5、CXCL1、CXCL8、CXCL9、CXCL10）的分泌，M2型小膠質(zhì)細(xì)胞引起抗炎性趨化因子（CCL22、CXCL8、CXCL12、CX3CL1）的分泌[20,21,22,23]。由此可見(jiàn)，小膠質(zhì)細(xì)胞的極化過(guò)程中會(huì)引起大量趨化因子的分泌，這些趨化因子與小膠質(zhì)細(xì)胞相互作用，共同影響AD的進(jìn)程。因此，下文將對(duì)趨化因子分類(lèi)總結(jié)并分別展開(kāi)論述。

圖1 小膠質(zhì)細(xì)胞在AD中的激活過(guò)程

2 趨化因子的分泌

趨化因子是一類(lèi)促使細(xì)胞分化、遷移和運(yùn)輸功能的多肽，能夠激活趨化因子受體，在炎癥過(guò)程中誘導(dǎo)趨化、組織外滲以及調(diào)節(jié)白細(xì)胞的功能[24]。趨化因子及其受體在大腦中以低水平表達(dá)，受到炎癥刺激才會(huì)發(fā)生調(diào)節(jié)作用，其表達(dá)主要來(lái)源于小膠質(zhì)細(xì)胞及其他神經(jīng)細(xì)胞 [25]。趨化因子根據(jù)分子中N-末端半胱氨酸的不同位置分為四個(gè)亞家族，包括CXC、CC、C和CX3C。其中CXC趨化因子亞族17個(gè)成員，C趨化因子亞族2個(gè)成員，CX3C趨化因子亞族1個(gè)成員。而CC趨化因子則是趨化因子家族中最大的亞類(lèi)，包括28個(gè)成員，分別為CCL1~CCL28。CXC趨化因子家族成員中CXCL1、CXCL9、CXCL10在AD中上調(diào)，參與促炎反應(yīng)[22,23]。CX3C家族的唯一成員CX3CL1發(fā)現(xiàn)具有抑制Tau蛋白病理改變，增加神經(jīng)信號(hào)傳導(dǎo)和神經(jīng)保護(hù)作用[26]。更多的研究發(fā)現(xiàn)大量的CC趨化因子在AD中上調(diào)，少量因子存在下調(diào)或者不變[27]，且其受體CCR3，CCR5陽(yáng)性反應(yīng)的小膠質(zhì)細(xì)胞與Aβ沉積密切相關(guān)[28]。提示了CC趨化因子在AD中可能的重要作用和未來(lái)研究方向。因此，本文重點(diǎn)論述CC趨化因子在AD神經(jīng)炎癥和小膠質(zhì)細(xì)胞的激活中的重要作用。28個(gè)CC趨化因子的受體、功能和在AD中的表達(dá)變化總結(jié)見(jiàn)表1。根據(jù)28個(gè)CC趨化因子目前已發(fā)現(xiàn)的炎癥調(diào)節(jié)作用將其分為三類(lèi)：促炎性、抗炎性和雙重功能的趨化因子。分述見(jiàn)表1。

表1 CC趨化因子的功能及其受體

2.1促炎性趨化因子

促炎因子對(duì)炎癥的發(fā)展有促進(jìn)作用。大多數(shù)表現(xiàn)出促炎作用的趨化因子在AD及其產(chǎn)生的神經(jīng)炎癥中是上調(diào)的，如表1中CCL2、CCL3、CCL4、CCL5、CCL6、CCL9、CCL11、CCL12、CCL15，這些趨化因子不單表現(xiàn)參與炎癥反應(yīng)，也在AD的病理機(jī)制中發(fā)揮特有的作用，并且和其本身的氨基酸序列同源性密切相關(guān)。

CCL2，又稱(chēng)為單核細(xì)胞趨化蛋白（monocyte chemoattractant protein，MCP-1），由淀粉樣斑塊相關(guān)的小膠質(zhì)細(xì)胞產(chǎn)生，Kiyota等[75]的研究發(fā)現(xiàn)CCL2過(guò)表達(dá)的Tg2576（APPswe）/CCL2轉(zhuǎn)基因小鼠表現(xiàn)出小膠質(zhì)細(xì)胞的聚集和促進(jìn)Aβ沉積和淀粉樣斑塊形成，并加速了認(rèn)知障礙。CCL2過(guò)表達(dá)使rTg4510（tauP301L）轉(zhuǎn)基因小鼠模型的Tau蛋白病理惡化，表現(xiàn)以NFTs和磷酸化Tau陽(yáng)性包涵體的大量增加，并伴有膠質(zhì)細(xì)胞增生和明顯的炎癥反應(yīng)[76]。另一研究表明CCL2在遺忘性輕度認(rèn)知障礙（amnestic mild cognitive impairment，aMCI）、AD及同樣具有癡呆、腦萎縮特征的額顳葉型失智癥（Frontotemporal dementia，F(xiàn)TLD）患者的腦脊液（cerebrospinal fluid，CSF）中均明顯升高[77,78]。CCL12（MCP-5）是與CCL2（MCP-1）同源的單核細(xì)胞趨化因子，具有66％的氨基酸同一性。CCL2與CCL12都是Tau病理相關(guān)神經(jīng)炎癥的壓力應(yīng)激反應(yīng)基因[46]。CCL2和CCL12還可以同時(shí)與CCR2受體結(jié)合，CCR2在小膠質(zhì)細(xì)胞上具有迅速促進(jìn)嘌呤能受體（purinergic receptor，P2RX4）轉(zhuǎn)運(yùn)到細(xì)胞表面的能力，進(jìn)而促進(jìn)小膠質(zhì)細(xì)胞的胞吐作用[79]。脊髓中星形膠質(zhì)細(xì)胞表達(dá)的CCL7（MCP-3）和CCL2（MCP-1）具有大于60%的氨基酸同一性，也可以通過(guò)CCR2激活小膠質(zhì)細(xì)胞，產(chǎn)生更多炎性介質(zhì)引起神經(jīng)性疼痛[37,80]。根據(jù)以上證據(jù)說(shuō)明具有同源性基因的趨化因子可以與同一種受體結(jié)合，對(duì)炎癥刺激發(fā)揮同樣的促炎功能。

然而這一現(xiàn)象并不是完全一致的，有研究報(bào)道在212名FTLD患者與203名年齡匹配的對(duì)照人群觀(guān)察CCL2（MCP-1）A-2518G的單核苷酸多態(tài)性（single nucleotide polymorphism，SNP），F(xiàn)TLD患者腦脊液中MCP-1水平顯著高于對(duì)照組，MCP-1 A-2518G SNP可能通過(guò)影響MCP-1的產(chǎn)生而成為FTLD的保護(hù)因子[81]。CCL2和CCL8（MCP-2）同樣具有相似序列的趨化因子，其氨基酸序列同源性為62%，均會(huì)在神經(jīng)退行性疾病中升高[80]。在CCL8中發(fā)現(xiàn)SNP與CCL2都位于同一連鎖區(qū)，其中rs1163763會(huì)導(dǎo)致氨基酸的取代，對(duì)蛋白質(zhì)功能產(chǎn)生潛在的影響，對(duì)219名AD患者和209名FTLD患者進(jìn)行了rs1133763關(guān)聯(lián)測(cè)試，并與231名年齡相匹配的對(duì)照組進(jìn)行比較，發(fā)現(xiàn)CCL8 rs1133763的分布在患者和對(duì)照組之間沒(méi)有顯著差異。這種SNP相關(guān)的連鎖不平衡基因變異對(duì)神經(jīng)退行性疾病并無(wú)明顯作用[40]。因此，即使是具有同源性基因的趨化因子在神經(jīng)疾病中也會(huì)發(fā)揮各自不同的功能。

CCL3/巨噬細(xì)胞炎性蛋白-1α（Macrophage inflammatory protein，MIP-1α）和CCL4/巨噬細(xì)胞炎性蛋白-1β（Macrophage inflammatory protein，MIP-1β）是巨噬細(xì)胞炎性蛋白（MIP-1）的兩種形式，二者相互作用，共用同一受體CCR5，其功能與炎癥反應(yīng)有關(guān)[82]。5XFAD轉(zhuǎn)基因小鼠中淀粉樣斑塊相關(guān)的小膠質(zhì)細(xì)胞表現(xiàn)出免疫反應(yīng)過(guò)度和炎癥的高反應(yīng)性，同時(shí)發(fā)現(xiàn)促炎因子CCL3、CCL4、CCL6的表達(dá)[9]。Passos等[83]的研究也發(fā)現(xiàn)在小鼠側(cè)腦室注射Aβ1–40后，CCL3及其受體CCR5的表達(dá)水平升高，小膠質(zhì)細(xì)胞的數(shù)量也顯著增加。遺傳方面CCL3/MIP-1α的基因多態(tài)性影響中國(guó)人對(duì)AD的敏感性，其中MIP-1α-906（TA）6/（TA）6基因可能是AD的遺傳危險(xiǎn)因素[84]。研究發(fā)現(xiàn)AD患者的外周血單核細(xì)胞控制著CCL4的產(chǎn)生[85]，AD的APPswe/PS1dE9轉(zhuǎn)基因小鼠大腦的CCL4水平升高與大腦Aβ沉積呈年齡依賴(lài)性相關(guān)，并增加淀粉樣斑塊周?chē)切文z質(zhì)細(xì)胞的活化，放大了炎癥反應(yīng)[86]。

2.2抗炎性趨化因子

抗炎因子被認(rèn)為可以減輕炎癥反應(yīng)。目前明確具有抗炎作用的趨化因子CCL17、CCL18、CCL22在有關(guān)AD疾病中的研究較少，但在影響大腦認(rèn)知、神經(jīng)炎癥、小膠質(zhì)細(xì)胞的激活等神經(jīng)系統(tǒng)相關(guān)研究中發(fā)現(xiàn)了很多可能會(huì)影響AD疾病發(fā)展的抗炎作用。

CCL17，即胸腺和激活調(diào)節(jié)趨化因子（thymus and activation-regulated chemokine，TARC），是M2型巨噬細(xì)胞的標(biāo)志物，IL-4可以誘導(dǎo)其在巨噬細(xì)胞中形成和上調(diào)，激活的M2型巨噬細(xì)胞參與吞噬細(xì)胞碎片以及抑制炎癥反應(yīng)[55]。維生素D3可選擇性地增強(qiáng)小膠質(zhì)細(xì)胞HMO6中細(xì)胞因子IL-10和CCL17的表達(dá)，使小膠質(zhì)細(xì)胞具有抗炎活性，保護(hù)神經(jīng)進(jìn)行免疫修復(fù)[56]。在應(yīng)對(duì)LPS誘導(dǎo)的急性炎癥刺激時(shí)，與記憶認(rèn)知有關(guān)的海馬CA1區(qū)小膠質(zhì)細(xì)胞的CCL17上調(diào)，CCL17可以維持小膠質(zhì)細(xì)胞的靜息狀態(tài)，CCL17基因敲除小鼠（CCL17-/-）的小膠質(zhì)細(xì)胞體積減少，并呈現(xiàn)出分枝減少、極性增強(qiáng)的反應(yīng)形態(tài)[87]。一項(xiàng)針對(duì)高罹患AD疾病風(fēng)險(xiǎn)的墨西哥裔美國(guó)人關(guān)于遺忘性輕度認(rèn)知障礙的生物標(biāo)記物檢測(cè)發(fā)現(xiàn)在aMCI病例中血液生物標(biāo)記物以炎性因子為主，排列前三的標(biāo)記物分別為T(mén)NFα，IL-10和TARC，這些發(fā)現(xiàn)提示了炎性因子和aMCI發(fā)展至AD的代謝過(guò)程可能存在相互作用，還需要對(duì)上述炎性因子進(jìn)一步研究[88]。

CCR4是CCL17和CCL22/巨噬細(xì)胞來(lái)源的趨化因子（macrophage-derived chemokine，MDC）的共同受體，CCR4的基因敲除小鼠（CCR4-/-）表現(xiàn)出運(yùn)動(dòng)和探索行為受損，此時(shí)的CCR4與其配體CCL22可能參與了神經(jīng)元和神經(jīng)膠質(zhì)細(xì)胞的功能調(diào)節(jié)[89]。CCL22在實(shí)驗(yàn)性自身免疫性腦脊髓炎（experimental autoimmune encephalomyelitis，EAE）小鼠的大腦中由小膠質(zhì)細(xì)胞產(chǎn)生，通過(guò)誘導(dǎo)TH2細(xì)胞的歸巢來(lái)調(diào)節(jié)Th1細(xì)胞介導(dǎo)的神經(jīng)炎癥[90]。CCL22同樣具有抗炎活性，在神經(jīng)系統(tǒng)疾病的脫髓鞘、神經(jīng)元損傷中，都檢測(cè)到了M2型小膠質(zhì)細(xì)胞標(biāo)志物IL-10、CCL18、CCL22，激活的M2型小膠質(zhì)細(xì)胞有助于免疫抑制，促進(jìn)神經(jīng)修復(fù)和髓鞘的再生[91]。Movsesyan等的研究團(tuán)隊(duì)[92,93]設(shè)計(jì)以CCL22作為分子佐劑的AD疫苗PMDC-3Aβ 1-11-PADRE，通過(guò)誘發(fā)細(xì)胞免疫及體液免疫，產(chǎn)生抗炎作用，減輕炎癥反應(yīng)，協(xié)同疫苗產(chǎn)生的抗Aβ抗體共同促進(jìn)APPSwe/PS1M146V/tauP301L轉(zhuǎn)基因小鼠大腦中Aβ沉積物的清除，抑制Aβ病理學(xué)的積累。

CCL18也稱(chēng)為替代巨噬細(xì)胞活化相關(guān)趨化因子-1（alternative macrophage activation associated chemokine，AMAC-1）和巨噬細(xì)胞炎性蛋白-4（MIP-4），它與CCL3關(guān)系最密切，共享64％的序列同一性，卻沒(méi)有激活與CCL3相同的受體，因?yàn)镃CL18具有獨(dú)特的四級(jí)結(jié)構(gòu)，可以和CCR8、PITPNM3、GPR30三種受體結(jié)合，表現(xiàn)出抗炎性趨化因子的作用。CCL18作為人和靈長(zhǎng)類(lèi)動(dòng)物獨(dú)有的趨化因子，從死亡后人腦組織分離出來(lái)的小膠質(zhì)細(xì)胞在IL-4刺激下培養(yǎng)，發(fā)現(xiàn)了CCL18上調(diào)[94]。在沒(méi)有IL-4的刺激，CCL18也可以誘導(dǎo)單核細(xì)胞成為M2型巨噬細(xì)胞，上調(diào)抗炎因子IL-10，并增強(qiáng)巨噬細(xì)胞的吞噬能力，清除細(xì)胞碎片[57]。

2.3 雙重功能趨化因子

有學(xué)者在炎癥相關(guān)研究中發(fā)現(xiàn)個(gè)別趨化因子具有促炎和抗炎的雙重作用，即在不同的炎癥環(huán)境中可以表現(xiàn)出促炎狀態(tài)也可以表現(xiàn)出抗炎狀態(tài)，如CCL1、CCL2、CCL7、CCL13、CCL14、CCL23、CCL24、CCL26。CCL1、CCL2、CCL7在神經(jīng)炎癥中表現(xiàn)出以促炎作用為主，而另外一些具有雙重功能的趨化因子在AD和神經(jīng)炎癥中的作用并不十分明確。

CCL23是具有促炎和抗炎雙重功能的趨化因子，在單核細(xì)胞中既能被IL-1β和IFN-γ誘導(dǎo)表達(dá)，也能由IL-4和IL-13誘導(dǎo)表達(dá)，在樹(shù)突狀細(xì)胞由IL-10誘導(dǎo)使其表達(dá)[65]。臨床研究表明AD患者血液中的CCL23高于健康對(duì)照者，從輕度認(rèn)知障礙（mild cognitive impaired，MCI）發(fā)展到AD患者的血液及腦脊液檢測(cè)數(shù)據(jù)中發(fā)現(xiàn)CCL23呈高進(jìn)展性，并且在AD遺傳易感因素ApoE ?4等位基因攜帶者血液中檢測(cè)到高水平的CCL23，可能與血漿中的炎癥反應(yīng)有關(guān)，預(yù)測(cè)CCL23可能是輕度認(rèn)知障礙發(fā)展到AD的血液生物炎性標(biāo)志物[66]。CCL23的受體CCR1，只在與Aβ42陽(yáng)性的神經(jīng)炎斑和營(yíng)養(yǎng)不良性神經(jīng)元中表達(dá)，并且隨臨床疾病的嚴(yán)重程度而增加，因此成為AD特有的神經(jīng)炎性標(biāo)志物[95]。

CCL26又稱(chēng)嗜酸性粒細(xì)胞趨化因子（Eotaxin-3），已證明IL-4和IL-13可通過(guò)JAK1-STAT6途徑上調(diào)CCL26的表達(dá)，表現(xiàn)出抗炎作用，但同時(shí)TNF-α對(duì)IL-4增強(qiáng)的CCL26產(chǎn)生協(xié)同作用[96]。在EAE大鼠的神經(jīng)炎癥反應(yīng)中，CCL26結(jié)合CCR3發(fā)揮促炎作用，加重腦組織損傷[70]。在輕度認(rèn)知障礙發(fā)展至AD的臨床隨訪(fǎng)研究中發(fā)現(xiàn)前驅(qū)性AD患者腦脊液中的CCL26顯著高于健康對(duì)照者[31]。

3 小結(jié)與展望

無(wú)論是衰老、遺傳或者環(huán)境因素造成的癡呆，都會(huì)在AD病理形成的過(guò)程中產(chǎn)生神經(jīng)炎癥。小膠質(zhì)細(xì)胞是大腦中免疫監(jiān)視器，也是神經(jīng)炎癥反應(yīng)的核心。小膠質(zhì)細(xì)胞作為AD清除Aβ的主要途徑，可以抑制淀粉樣蛋白的沉積延緩AD的發(fā)展；但炎性持續(xù)激活的小膠質(zhì)細(xì)胞會(huì)分泌更多的促炎因子，引起神經(jīng)元的損傷，加速AD的進(jìn)展。小膠質(zhì)細(xì)胞是AD的疾病發(fā)展的一把雙刃劍，如何抑制M1型小膠質(zhì)細(xì)胞的炎性激活，減輕炎癥反應(yīng)，增加M2型小膠質(zhì)細(xì)胞的神經(jīng)保護(hù)作用，維持穩(wěn)態(tài)的正性平衡成為治療AD疾病的方向。

趨化因子在AD的神經(jīng)炎癥反應(yīng)中具有雙向調(diào)節(jié)的作用，一方面具有促炎作用的趨化因子可以持續(xù)激活M1型小膠質(zhì)細(xì)胞分泌更多炎性因子及毒性物質(zhì)，使小膠質(zhì)細(xì)胞失控，加重炎癥反應(yīng)，形成惡性循環(huán)；另一方具有抗炎作用的趨化因子可以維持M2型小膠質(zhì)細(xì)胞的穩(wěn)態(tài)，增加Aβ內(nèi)化及降解，減輕炎癥的活躍程度。這是一個(gè)高度動(dòng)態(tài)的過(guò)程，神經(jīng)炎癥中的促炎和抗炎因子對(duì)于正常細(xì)胞組織代謝的動(dòng)態(tài)平衡至關(guān)重要，如何維持穩(wěn)態(tài)平衡決定了炎癥反應(yīng)的發(fā)展。AD疾病中的神經(jīng)炎癥活躍程度由趨化因子、細(xì)胞因子等炎性介質(zhì)所反應(yīng)，抗炎因子和促炎因子的平衡影響著AD的預(yù)后。很多研究將促炎性趨化因子CCL2、CCL3作為MCI發(fā)展到AD早期的炎性因子標(biāo)志物，也有將具有抗炎作用的CCL22作為分子佐劑的AD疫苗，但更多關(guān)于趨化因子的研究只是檢測(cè)其在AD中的水平變化，并沒(méi)有深入探索這些趨化因子對(duì)于小膠質(zhì)細(xì)胞或者Aβ誘導(dǎo)神經(jīng)炎癥的作用機(jī)制研究。因此需要明確抗炎性趨化因子控制小膠質(zhì)細(xì)胞表型轉(zhuǎn)換的機(jī)制，進(jìn)而可以通過(guò)增加抗炎性趨化因子的正向作用和減少促炎性趨化因子的負(fù)向作用來(lái)改善AD的神經(jīng)炎癥程度，為AD的治療提供新的思路。

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戰(zhàn)爭(zhēng)中的孩子范文第5篇

把手榴彈不變成甜蜜的棒棒糖，

因?yàn)橐粋€(gè)個(gè)手榴彈

正在摧殘孩子們幼小的心靈。

讓孩子們快樂(lè)吧！

把坦克變成奔跑的玩具汽車(chē)，

因?yàn)橐蛔箍?/p>

正在摧毀孩子們的家園。

讓孩子們快樂(lè)吧！

把炸彈變成跳動(dòng)的小皮球

因?yàn)橐粋€(gè)個(gè)炸彈

正在殺害孩子們的親人。

讓孩子們快樂(lè)吧！

把地雷變成滾動(dòng)的足球，

因?yàn)橐粋€(gè)個(gè)地雷

正在阻擋孩子們奔跑的腳步。

我們希望，我們祈盼，

讓?xiě)?zhàn)爭(zhēng)中的孩子有一個(gè)家，

溫馨的家；

讓?xiě)?zhàn)爭(zhēng)中的孩子有一個(gè)健康的身體，

完好無(wú)損的身體；

讓他們離開(kāi)“寒冷的冬天”，