胥雪蓮 綜述 何川 審校

(1. 重慶醫(yī)科大學(xué)附屬大學(xué)城醫(yī)院心血管內(nèi)科，重慶401331； 2. 成都大學(xué)附屬醫(yī)院心血管內(nèi)科，四川 成都610081)

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炎癥與動(dòng)脈粥樣硬化

胥雪蓮1綜述 何川2審校

(1. 重慶醫(yī)科大學(xué)附屬大學(xué)城醫(yī)院心血管內(nèi)科，重慶401331； 2. 成都大學(xué)附屬醫(yī)院心血管內(nèi)科，四川 成都610081)

動(dòng)脈粥樣硬化是嚴(yán)重危害人類健康的重大疾病。近年來，越來越多的學(xué)者形成共識(shí)，慢性炎癥貫穿于動(dòng)脈粥樣硬化發(fā)生、發(fā)展的各個(gè)環(huán)節(jié)，動(dòng)脈粥樣硬化就是一種炎癥性疾病?，F(xiàn)就動(dòng)脈粥樣硬化發(fā)生、發(fā)展的炎癥過程以及動(dòng)脈粥樣硬化相關(guān)分子的研究進(jìn)展做一綜述。

炎癥;動(dòng)脈粥樣硬化;炎癥因子

動(dòng)脈粥樣硬化是嚴(yán)重危害人類健康的重大疾病。近年來，越來越多的學(xué)者形成共識(shí)，慢性炎癥貫穿于動(dòng)脈粥樣硬化發(fā)生、發(fā)展的各個(gè)環(huán)節(jié)，動(dòng)脈粥樣硬化就是一種炎癥性疾病?，F(xiàn)就動(dòng)脈粥樣硬化發(fā)生、發(fā)展的炎癥過程以及動(dòng)脈粥樣硬化相關(guān)分子的研究進(jìn)展做一綜述。

1 炎癥在動(dòng)脈粥樣硬化發(fā)生的各個(gè)階段的作用

正常的血管內(nèi)膜能阻止淋巴細(xì)胞的黏附，而當(dāng)各種危險(xiǎn)因素，如高膽固醇血癥、肥胖、胰島素抵抗、高血壓或吸煙等持續(xù)作用，造成內(nèi)皮損傷，觸發(fā)血管內(nèi)皮表達(dá)黏附分子，如P選擇素、血管細(xì)胞黏附分子-1(VCAM-1)等介導(dǎo)循環(huán)中的單核細(xì)胞和淋巴細(xì)胞的黏附[1]。動(dòng)脈粥樣硬化多發(fā)生在血管分叉處，由于該處血管內(nèi)皮受到血流切應(yīng)力作用，導(dǎo)致局部一氧化氮(NO)等內(nèi)皮保護(hù)因子的產(chǎn)生減少，VCAM-1產(chǎn)生增多[2]。

白細(xì)胞一旦黏附到內(nèi)皮，就會(huì)穿透內(nèi)皮，而這一作用是由于單核細(xì)胞趨化因子-1(MCP-1)直接趨化單核細(xì)胞[3]；而T細(xì)胞趨化因子直接趨化淋巴細(xì)胞[4]。當(dāng)這些血循環(huán)中的炎細(xì)胞定位于血管壁，就參與和擴(kuò)大了炎癥反應(yīng)。巨嗜細(xì)胞表達(dá)清道夫受體，大量攝取氧化修飾的低密度脂蛋白(ox-LDL)形成泡沫細(xì)胞。除了MCP-1，巨噬細(xì)胞集落刺激因子(M-CSF)促進(jìn)血中的單核細(xì)胞向巨噬細(xì)胞分化形成泡沫細(xì)胞[5]。T細(xì)胞也被激活，分泌細(xì)胞因子如γ-干擾素、腫瘤壞死因子(TNF)-α，又可以刺激巨嗜細(xì)胞、血管內(nèi)皮細(xì)胞和血管平滑肌細(xì)胞(SMCs)[6]。當(dāng)這個(gè)炎癥過程繼續(xù)，活化的淋巴細(xì)胞、血管內(nèi)皮和SMCs可以分泌成纖維介導(dǎo)因子，包括大量的蛋白肽生長因子，促進(jìn)SMCs的增殖及動(dòng)脈粥樣斑塊里周圍基質(zhì)的增生[7]。

炎癥過程不但加速動(dòng)脈粥樣硬化的發(fā)生和發(fā)展，并且也參與血栓形成和斑塊破裂。大多數(shù)的冠狀動(dòng)脈血栓由于斑塊的不穩(wěn)定導(dǎo)致致死性急性心肌梗死的發(fā)生增加。斑塊內(nèi)活化的巨噬細(xì)胞增多產(chǎn)生大量的蛋白水解酶，降解斑塊纖維帽的膠原使纖維帽變薄，更易于破裂。而斑塊中由活化T細(xì)胞分泌的γ-干擾素能抑制血管SMCs分泌膠原，導(dǎo)致斑塊缺乏膠原的加固而易破裂[8-9]。巨嗜細(xì)胞產(chǎn)生的組織因子是主要的促凝血因子，可觸發(fā)血栓形成。炎癥介質(zhì)通過斑塊中的巨嗜細(xì)胞調(diào)節(jié)組織因子的表達(dá)，說明炎癥和血栓形成的內(nèi)在聯(lián)系[10]。

2 ox-LDL和動(dòng)脈粥樣硬化

近年來“脂質(zhì)氧化修飾學(xué)說”在動(dòng)脈粥樣硬化發(fā)病過程中的作用被人們所接受。ox-LDL由NO、髓過氧化物酶及血漿銅藍(lán)蛋白誘導(dǎo)產(chǎn)生[11-12]。ox-LDL可誘導(dǎo)巨噬細(xì)胞、血管SMCs表達(dá)黏附分子、趨化因子、前炎癥因子和其他炎癥介質(zhì)，觸發(fā)動(dòng)脈粥樣硬化的炎癥反應(yīng)。ox-LDL也能上調(diào)內(nèi)皮細(xì)胞黏附因子的表達(dá)，誘導(dǎo)巨噬細(xì)胞化學(xué)趨化因子MCP-1、M-CSF的表達(dá)[13]。臨床研究中發(fā)現(xiàn)急性心肌梗死患者的ox-LDL水平高于心絞痛患者和正常對(duì)照，而不穩(wěn)定型心絞痛患者的ox-LDL水平高于穩(wěn)定型心絞痛患者[14]。

然而仍有很多證據(jù)顯示經(jīng)典的“氧化修飾學(xué)說”并不能解釋低密度脂蛋白(LDL)致動(dòng)脈粥樣硬化的全部。臨床上幾個(gè)大規(guī)模實(shí)驗(yàn)顯示維生素E、β胡蘿卜素等抗氧化劑的單獨(dú)或聯(lián)合應(yīng)用均不能降低冠心病的發(fā)病率和病死率[15]。體外ox-LDL與人單核細(xì)胞來源的巨噬細(xì)胞共同孵育時(shí)，并未見到細(xì)胞內(nèi)的脂質(zhì)積聚[16]。在小鼠上雙敲除A、B兩型清道夫受體，并不能降低高脂血癥誘導(dǎo)的泡沫細(xì)胞形成和粥樣斑塊的面積[17]。

3 清道夫受體和動(dòng)脈粥樣硬化

在動(dòng)脈粥樣硬化發(fā)病機(jī)制中，巨噬細(xì)胞清道夫受體大量攝取ox-LDL形成泡沫細(xì)胞，是早期的病理學(xué)標(biāo)志。在動(dòng)脈粥樣硬化中，主要的清道夫受體是清道夫受體A(SR-A)和CD36。

SR-A與ox-LDL結(jié)合，是動(dòng)脈粥樣硬化發(fā)生的主要受體。轉(zhuǎn)染SR-A的細(xì)胞同ox-LDL共孵育可加速脂質(zhì)負(fù)荷細(xì)胞(類似動(dòng)脈粥樣硬化斑塊中的泡沫細(xì)胞)形成[18]。并且在動(dòng)脈粥樣硬化斑塊中可檢測(cè)到SR-A的表達(dá)[19]。Suzuki等[20]研究顯示與SR-A和載脂蛋白E(ApoE)雙敲除小鼠相比，ApoE單敲除小鼠動(dòng)脈粥樣硬化斑塊減少50%。

CD36是清道夫受體B家族的一員，可結(jié)合ox-LDL。CD36和SR-A是主要的巨噬細(xì)胞結(jié)合和攝取ox-LDL的受體，有75%～90%的ox-LDL通過這兩個(gè)受體攝取和降解[21]。Febbraio等[22]研究顯示CD36和ApoE雙敲除小鼠比ApoE單敲除小鼠動(dòng)脈粥樣硬化斑塊減少76.5%，結(jié)合內(nèi)化ox-LDL的能力下降60%。

4 LDL受體和動(dòng)脈粥樣硬化

LDL受體在生理?xiàng)l件下調(diào)節(jié)膽固醇穩(wěn)態(tài)平衡。有研究表明LDL受體在動(dòng)脈粥樣硬化斑塊中高表達(dá)并且參與細(xì)胞脂質(zhì)攝取。在外周細(xì)胞血漿中高LDL濃度抑制LDL受體活性，對(duì)維持細(xì)胞膽固醇穩(wěn)態(tài)，防止發(fā)生動(dòng)脈粥樣硬化發(fā)揮重要作用。然而在肝細(xì)胞中引起減少LDL受體活性極為不利。例如在家族性高膽固醇血癥患者，就是肝細(xì)胞通過LDL受體途徑攝取和降解LDL缺陷，通常是由于LDL受體或載脂蛋白B的受體基因突變所致。家族性高膽固醇血癥患者血漿中的膽固醇水平升高，導(dǎo)致組織中膽固醇過多積聚，引起動(dòng)脈粥樣硬化和增加心血管病的發(fā)病率[23]。

LDL受體途徑在肝細(xì)胞和外周細(xì)胞的調(diào)節(jié)維持了血漿膽固醇的恒定水平。Ruan等[24]研究表明在炎癥因子[TNF-α、白介素(IL)-1β]作用下，打破血管SMCs和人腎小球系膜細(xì)胞(HMCs)的LDL受體的負(fù)反饋調(diào)節(jié)導(dǎo)致泡沫細(xì)胞的形成和動(dòng)脈粥樣硬化。Chen等[25]研究表明HMCs對(duì)炎癥比肝臟來源細(xì)胞系(HepG2細(xì)胞)更敏感是外周細(xì)胞在炎癥刺激下更容易形成泡沫細(xì)胞的一個(gè)原因。

5 動(dòng)脈粥樣硬化的炎性標(biāo)志物

C反應(yīng)蛋白(CRP)是預(yù)測(cè)心血管事件發(fā)生強(qiáng)有力的獨(dú)立的預(yù)測(cè)因子。 CRP是一個(gè)早期急性期反應(yīng)蛋白，主要是IL-6和TNF-α刺激肝細(xì)胞產(chǎn)生。有兩個(gè)假說來解釋CRP升高在動(dòng)脈粥樣硬化發(fā)病中的作用：一是由于ox-LDL刺激動(dòng)脈壁炎癥的發(fā)生，產(chǎn)生細(xì)胞因子誘導(dǎo)急性期反應(yīng)蛋白，如CRP的產(chǎn)生；二是急性期反應(yīng)物的慢性升高由于吸煙、慢性感染、年齡、肥胖、高脂血癥或糖尿病引起，所有的這些原因都導(dǎo)致動(dòng)脈粥樣硬化的發(fā)展。最近的研究表明，CRP不僅是發(fā)生心血管危險(xiǎn)的預(yù)測(cè)因子，也是直接致動(dòng)脈粥樣硬化因子。Paul等[26]研究發(fā)現(xiàn)CRP加快了ApoE-/-敲除小鼠動(dòng)脈粥樣斑塊形成的進(jìn)展。越來越多的體外實(shí)驗(yàn)證實(shí)CRP介導(dǎo)了多種動(dòng)脈粥樣硬化因子的活化和表達(dá)，是致動(dòng)脈粥樣硬化因子。Hein等[27]研究發(fā)現(xiàn)CRP下調(diào)內(nèi)皮型一氧化氮合酶，減少NO的釋放。Verma等研究表明CRP刺激內(nèi)皮細(xì)胞產(chǎn)生血管收縮因子內(nèi)皮素-1和炎癥因子IL-6。Pasceri等研究表明CRP能增加VCAM-1、ICAM-1、E-選擇素和MCP-1的表達(dá)，促進(jìn)白細(xì)胞的遷移[28]。CRP是潛在的巨噬細(xì)胞化學(xué)趨化因子，并促進(jìn)巨噬細(xì)胞攝取LDL[29]。CRP能通過上調(diào)核因子-κB刺激單核細(xì)胞產(chǎn)生組織因子和前炎癥因子[30]。在SMCs，CRP上調(diào)血管緊張素1型受體，刺激SMCs的增殖、遷移，新生內(nèi)膜形成和反應(yīng)性氧化物的產(chǎn)生。

IL-6是一個(gè)血循環(huán)中的細(xì)胞因子，是預(yù)測(cè)冠狀動(dòng)脈粥樣斑塊的炎性標(biāo)志物。在急性心肌梗死、不穩(wěn)定型心絞痛、經(jīng)皮冠狀動(dòng)脈介入術(shù)和再狹窄的患者中，血漿中的IL-6水平升高。IL-6可刺激血小板聚集，促進(jìn)組織因子、巨嗜細(xì)胞LDL受體、CRP和纖維蛋白素原的表達(dá)。IL-6同時(shí)也調(diào)節(jié)其他炎癥因子的表達(dá)，如IL-1和TNF-α[31]。

IL-1家族由幾個(gè)不同的與動(dòng)脈粥樣硬化相關(guān)的前炎癥因子組成。IL-1β主要由單核細(xì)胞和巨噬細(xì)胞產(chǎn)生，其次由血管SMCs、內(nèi)皮細(xì)胞和活化的血小板產(chǎn)生。IL-1β和IL-6、TNF-α有許多相似的作用。IL-1β可以提高內(nèi)皮黏附分子的表達(dá)，從而增加炎癥細(xì)胞的活化和內(nèi)皮細(xì)胞的黏附。同時(shí)IL-1β和TNF-α刺激血管SMCs產(chǎn)生IL-6，增加巨噬細(xì)胞表達(dá)集落刺激因子、血小板衍生生長因子和成纖維細(xì)胞生長因子，參與動(dòng)脈粥樣硬化的炎癥過程[32]。此外在冠心病患者中IL-1β水平增高[33]。

TNF-α是另一個(gè)有多種生物學(xué)效應(yīng)的多效炎癥因子，在炎癥反應(yīng)級(jí)聯(lián)中有重要作用，能刺激其他炎癥因子的合成。TNF-α由活化的巨噬細(xì)胞、內(nèi)皮細(xì)胞和血管SMCs產(chǎn)生。有研究表明TNF-α也在脂肪細(xì)胞和骨骼肌細(xì)胞表達(dá)。脂肪細(xì)胞表達(dá)TNF-α與肥胖引起的胰島素抵抗發(fā)病相關(guān)[34]。臨床研究顯示TNF-α是再發(fā)心肌梗死和經(jīng)皮冠狀動(dòng)脈介入術(shù)后再狹窄的一個(gè)獨(dú)立標(biāo)志物[35]。

TNF-α的細(xì)胞作用由TNF受體超家族介導(dǎo)。健康人群循環(huán)中的TNF-α常不能被檢測(cè)到或變異很大。相反，可溶性的TNF受體是更穩(wěn)定的蛋白，在血液循環(huán)中持續(xù)增高的時(shí)間長，是標(biāo)志TNF-α系統(tǒng)活化比TNF-α本身更好的標(biāo)志物[36]。

6 結(jié)語

炎癥過程貫穿于動(dòng)脈粥樣硬化的各個(gè)階段。炎癥標(biāo)志物不僅可預(yù)測(cè)心血管疾病的危險(xiǎn)程度，也促進(jìn)動(dòng)脈粥樣硬化的發(fā)生、發(fā)展。希望在不久的將來，抗炎治療可成為臨床治療動(dòng)脈粥樣硬化新的靶點(diǎn)。

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Inflammation and Atherosclerosis

XU Xuelian1, HE Chuan2

(1.Department of Cardiology,University-Town Hospital of Chongqing Medical University,Chongqing 401331,China;2.DepartmentofCardiology,AffiliatedHospital/ClinicalMedicalCollegeofChengduUniversity,Chengdu610081,Sichuan,China)

Atherosclerosis is a serious disease which is harmful to human health. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. Atherosclerosis is an inflammatory disease. This review provides important links between inflammation, inflammatory factors and the mechanisms of atherogenesis.

inflammation; atherosclerosis; inflammatory factors

胥雪蓮(1978—)，主治醫(yī)師，博士，主要從事動(dòng)脈粥樣硬化研究。Email：2480074@qq.com

1004-3934(2015)05-0634-04

R543.5

A

10.3969/j.issn.1004-3934.2015.05.029

2015-07-13