動(dòng)脈粥樣硬化與免疫細(xì)胞研究國內(nèi)外文獻(xiàn)綜述最近，各種免疫療法和疫苗接種法在患有AS的動(dòng)物模型中顯示出了樂觀的治療前景，這與CANTOS試驗(yàn)提出的細(xì)胞因子抗體相比或許更有意義ADDINEN.CITE<EndNote><Cite><Author>Kobiyama</Author><Year>2018</Year><RecNum>148</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>148</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619836678">148</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Kobiyama,K.</author><author>Ley,K.</author></authors></contributors><auth-address>LaJollaInstAllergy&Immunol,DivInflammatBiol,9420AthenaCirDr,LaJolla,CA92037USA UnivCalifSanDiego,DeptBioengn,SanDiego,CA92103USA</auth-address><titles><title>AtherosclerosisAChronicInflammatoryDiseaseWithanAutoimmuneComponent</title><secondary-title>CirculationResearch</secondary-title><alt-title>CircRes</alt-title></titles><alt-periodical><full-title>CircRes</full-title></alt-periodical><pages>1118-1120</pages><volume>123</volume><number>10</number><keywords><keyword>atherosclerosis</keyword><keyword>autoimmunity</keyword><keyword>interleukin-1</keyword><keyword>peripheralvasculardisease</keyword><keyword>stroke</keyword><keyword>vaccination</keyword><keyword>ldl</keyword></keywords><dates><year>2018</year><pub-dates><date>Oct26</date></pub-dates></dates><isbn>0009-7330</isbn><accession-num>WOS:000451350700009</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000451350700009</style></url></related-urls></urls><electronic-resource-num>10.1161/Circresaha.118.313816</electronic-resource-num><language>English</language></record></Cite></EndNote>[3]。免疫療法和疫苗接種可以有效避免宿主防御。免疫細(xì)胞廣泛參與AS發(fā)展過程。最初，單核/巨噬細(xì)胞與樹突狀細(xì)胞（DCs）存在于動(dòng)脈外膜和新內(nèi)膜中，由Toll樣受體配體和清除劑受體激活，進(jìn)而轉(zhuǎn)入血管內(nèi)膜，分泌炎性細(xì)胞因子維持和加劇AS，吸引更多的免疫細(xì)胞。在成熟的AS斑塊中，T細(xì)胞分泌炎性因子，使炎癥持續(xù)存在，同時(shí)肥大細(xì)胞大量聚集，在AS斑塊核心形成免疫細(xì)胞浸潤。由此可見，對免疫細(xì)胞進(jìn)行有效的調(diào)節(jié)可能在一定程度上改善疾病的進(jìn)程。1.2.1單核/巨噬細(xì)胞單核/巨噬細(xì)胞作為重要的免疫細(xì)胞之一，被認(rèn)為最早進(jìn)入動(dòng)脈粥樣硬化病變區(qū)域，并且它在動(dòng)脈粥樣硬化斑塊的形成、發(fā)展及轉(zhuǎn)歸中均起到了至關(guān)重要的作用。在AS病變進(jìn)展過程的早期階段，多種風(fēng)險(xiǎn)因素如高脂血癥、高血壓、高血糖、吸煙等，引起血管內(nèi)皮細(xì)胞受損，隨后導(dǎo)致血管內(nèi)皮細(xì)胞在其表面分泌大量的細(xì)胞趨化因子，這些趨化因子進(jìn)而與單核細(xì)胞表面表達(dá)的同源相關(guān)受體結(jié)合后調(diào)控并激活相關(guān)信號通路，促進(jìn)這些單核細(xì)胞向血管內(nèi)皮進(jìn)行定向遷移。在趨化作用下，單核細(xì)胞通過血小板和內(nèi)皮細(xì)胞所分泌的P凝集素糖蛋白配體-1（PSGL-1）和內(nèi)皮凝集素之間的相互作用，滾動(dòng)至發(fā)炎的內(nèi)皮區(qū)域。隨后在多種蛋白如單核細(xì)胞整合蛋白（VLA-4）、血管細(xì)胞粘附分子（VCAM-1）、細(xì)胞間粘附分子（ICAM-1）等作用下，單核細(xì)胞可進(jìn)入血管內(nèi)膜，分化成巨噬細(xì)胞，其表面表達(dá)A型清道夫受體（SR-A）和B型家族成員CD36等，在這種作用下，巨噬細(xì)胞會(huì)吞噬過量的氧化型低密度脂蛋白（ox-LDL），同時(shí)由于相關(guān)受體不受到負(fù)反饋相關(guān)調(diào)節(jié)而導(dǎo)致胞內(nèi)出現(xiàn)脂質(zhì)的嚴(yán)重堆積，形成泡沫細(xì)胞并堆積形成動(dòng)脈粥樣硬化的起始標(biāo)志——早期脂質(zhì)條紋ADDINEN.CITE<EndNote><Cite><Author>Moore</Author><Year>2011</Year><RecNum>93</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>93</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619832806">93</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Moore,K.J.</author><author>Tabas,I.</author></authors></contributors><auth-address>ColumbiaUniv,DeptMed,NewYork,NY10032USA ColumbiaUniv,DeptPathol&CellBiol,NewYork,NY10032USA ColumbiaUniv,DeptPhysiol&CellularBiophys,NewYork,NY10032USA NYU,DeptMed,MedCtr,NewYork,NY10016USA NYU,DeptCellBiol,MedCtr,NewYork,NY10016USA</auth-address><titles><title>MacrophagesinthePathogenesisofAtherosclerosis</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title></periodical><alt-periodical><full-title>Cell</full-title></alt-periodical><pages>341-355</pages><volume>145</volume><number>3</number><keywords><keyword>low-density-lipoprotein</keyword><keyword>endoplasmic-reticulumstress</keyword><keyword>foamcell-formation</keyword><keyword>promotescollagenaccumulation</keyword><keyword>apoptoticcells</keyword><keyword>dendriticcells</keyword><keyword>acceleratedatherosclerosis</keyword><keyword>immune-responses</keyword><keyword>cholesterol</keyword><keyword>mice</keyword></keywords><dates><year>2011</year><pub-dates><date>Apr29</date></pub-dates></dates><isbn>0092-8674</isbn><accession-num>WOS:000290022900005</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000290022900005</style></url></related-urls></urls><electronic-resource-num>10.1016/j.cell.2011.04.005</electronic-resource-num><language>English</language></record></Cite></EndNote>[4]。隨疾病進(jìn)展，巨噬細(xì)胞活化并促進(jìn)血管平滑肌細(xì)胞遷移和增殖ADDINEN.CITEADDINEN.CITE.DATA[5]。其合成分泌的膠原纖維，可在病變區(qū)形成纖維斑塊。在炎癥環(huán)境的持續(xù)作用下，干擾素γ（IFN-γ）降低膠原蛋白合成能力，同時(shí)基質(zhì)金屬蛋白酶（MMP）降解膠原，這些都削弱了帽子結(jié)構(gòu)，使得其趨向不穩(wěn)定ADDINEN.CITEADDINEN.CITE.DATA[6]。于是多種繼發(fā)性病變?nèi)缪ā邏K破裂等易于發(fā)生，最終產(chǎn)生嚴(yán)重心血管疾病。1.2.2T淋巴細(xì)胞正常動(dòng)脈的防御機(jī)制依賴于內(nèi)皮細(xì)胞的先天免疫反應(yīng)，這一過程始于單核/巨噬細(xì)胞的激活，而適應(yīng)性免疫則依賴于T細(xì)胞和B細(xì)胞所介導(dǎo)ADDINEN.CITE<EndNote><Cite><Author>Hansson</Author><Year>2011</Year><RecNum>96</RecNum><DisplayText><styleface="superscript">[7]</style></DisplayText><record><rec-number>96</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619834710">96</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Hansson,G.K.</author><author>Hermansson,A.</author></authors></contributors><auth-address>KarolinskaInst,KarolinskaUnivHospSolna,CtrMolMed,DeptMed,Stockholm,Sweden</auth-address><titles><title>Theimmunesysteminatherosclerosis</title><secondary-title>NatureImmunology</secondary-title><alt-title>NatImmunol</alt-title></titles><alt-periodical><full-title>NatImmunol</full-title></alt-periodical><pages>204-212</pages><volume>12</volume><number>3</number><keywords><keyword>low-density-lipoprotein</keyword><keyword>regulatoryt-cells</keyword><keyword>aldehyde-modifiedpeptide</keyword><keyword>rheumatoid-arthritis</keyword><keyword>apolipoproteinb-100</keyword><keyword>interferon-gamma</keyword><keyword>oxidizedldl</keyword><keyword>aggravateatherosclerosis</keyword><keyword>enhancesatherosclerosis</keyword><keyword>reducedatherosclerosis</keyword></keywords><dates><year>2011</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1529-2908</isbn><accession-num>WOS:000287354400007</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000287354400007</style></url></related-urls></urls><electronic-resource-num>10.1038/ni.2001</electronic-resource-num><language>English</language></record></Cite></EndNote>[7]。研究結(jié)果顯示，在人和小鼠AS斑塊中均有T細(xì)胞亞群存在ADDINEN.CITEADDINEN.CITE.DATA[8]。其中，CD4+T細(xì)胞常見于AS斑塊部位，是適應(yīng)性免疫應(yīng)答的關(guān)鍵調(diào)節(jié)因子，能夠分化為各種類型的輔助型T細(xì)胞，包括Th1、Th2、Th17或Treg細(xì)胞譜系。Th細(xì)胞和Treg細(xì)胞可以激活或抑制其他免疫細(xì)胞的反應(yīng)，不僅能發(fā)揮促炎作用，還能發(fā)揮抗炎作用ADDINEN.CITE<EndNote><Cite><Author>Zhu</Author><Year>2008</Year><RecNum>98</RecNum><DisplayText><styleface="superscript">[9]</style></DisplayText><record><rec-number>98</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619834710">98</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zhu,J.F.</author><author>Paul,W.E.</author></authors></contributors><auth-address>NIAID,ImmunolLab,NIH,Bethesda,MD20892USA</auth-address><titles><title>CD4Tcells:fates,functions,andfaults</title><secondary-title>Blood</secondary-title><alt-title>Blood</alt-title></titles><periodical><full-title>Blood</full-title><abbr-1>Blood</abbr-1></periodical><alt-periodical><full-title>Blood</full-title><abbr-1>Blood</abbr-1></alt-periodical><pages>1557-1569</pages><volume>112</volume><number>5</number><keywords><keyword>growth-factor-beta</keyword><keyword>interferon-regulatoryfactor-4</keyword><keyword>locus-controlregion</keyword><keyword>hyper-igesyndrome</keyword><keyword>ror-gamma-t</keyword><keyword>allergicdisregulationsyndrome</keyword><keyword>immunologicalself-tolerance</keyword><keyword>transcriptionfactorgata-3</keyword><keyword>developingth1cells</keyword><keyword>helpertype-1cells</keyword></keywords><dates><year>2008</year><pub-dates><date>Sep1</date></pub-dates></dates><isbn>0006-4971</isbn><accession-num>WOS:000258956200009</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000258956200009</style></url></related-urls></urls><electronic-resource-num>10.1182/blood-2008-05-078154</electronic-resource-num><language>English</language></record></Cite></EndNote>[9]。數(shù)據(jù)顯示，AS斑塊中CD4+T細(xì)胞以Th1和Th2細(xì)胞為主，且Th1細(xì)胞占主要部分。IFN-γ作為Th1細(xì)胞的標(biāo)志性細(xì)胞因子，不僅能促使炎癥因子如趨化因子和粘附分子等分泌的上調(diào)，還能夠提高巨噬細(xì)胞和內(nèi)皮細(xì)胞的活化程度，促進(jìn)AS斑塊的病理進(jìn)程ADDINEN.CITEADDINEN.CITE.DATA[10]。當(dāng)重組的外源性IFN-γ經(jīng)由腹腔給藥注射到ApoE（-/-）小鼠30天時(shí)，與給予PBS對照組的小鼠相比，病變大小增加了15%ADDINEN.CITE<EndNote><Cite><Author>Whitman</Author><Year>2000</Year><RecNum>100</RecNum><DisplayText><styleface="superscript">[11]</style></DisplayText><record><rec-number>100</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619834710">100</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Whitman,S.C.</author><author>Ravisankar,P.</author><author>Elam,H.</author><author>Daugherty,A.</author></authors></contributors><auth-address>UnivKentucky,GillHeartInst,AtherosclerosisResGrp,DivCardiovascMed,Lexington,KY40536USA</auth-address><titles><title>Exogenousinterferon-gammaenhancesatherosclerosisinapolipoproteinE-/-mice</title><secondary-title>AmericanJournalofPathology</secondary-title><alt-title>AmJPathol</alt-title></titles><periodical><full-title>AmericanJournalofPathology</full-title><abbr-1>AmJPathol</abbr-1></periodical><alt-periodical><full-title>AmericanJournalofPathology</full-title><abbr-1>AmJPathol</abbr-1></alt-periodical><pages>1819-1824</pages><volume>157</volume><number>6</number><keywords><keyword>low-density-lipoprotein</keyword><keyword>monocyte-derivedmacrophages</keyword><keyword>receptor-relatedprotein</keyword><keyword>cholesterol-fedrabbits</keyword><keyword>e-deficientmice</keyword><keyword>lymphocytes-t</keyword><keyword>lesions</keyword><keyword>cells</keyword><keyword>expression</keyword><keyword>hypercholesterolemia</keyword></keywords><dates><year>2000</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0002-9440</isbn><accession-num>WOS:000165668300009</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000165668300009</style></url></related-urls></urls><electronic-resource-num>Doi10.1016/S0002-9440(10)64820-1</electronic-resource-num><language>English</language></record></Cite></EndNote>[11]。此外，Th1細(xì)胞也可分泌其他因子并激活單核/巨噬細(xì)胞、T細(xì)胞等免疫細(xì)胞，加速斑塊部位的炎癥反應(yīng)ADDINEN.CITE<EndNote><Cite><Author>Saigusa</Author><Year>2020</Year><RecNum>101</RecNum><DisplayText><styleface="superscript">[12]</style></DisplayText><record><rec-number>101</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619834710">101</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Saigusa,R.</author><author>Winkels,H.</author><author>Ley,K.</author></authors></contributors><auth-address>LaJollaInstImmunol,DivInflammatBiol,LaJolla,CA92037USA UnivCalifSanDiego,DeptBioengn,LaJolla,CA92093USA</auth-address><titles><title>Tcellsubsetsandfunctionsinatherosclerosis</title><secondary-title>NatureReviewsCardiology</secondary-title><alt-title>NatRevCardiol</alt-title></titles><alt-periodical><full-title>NatRevCardiol</full-title></alt-periodical><pages>387-401</pages><volume>17</volume><number>7</number><keywords><keyword>low-density-lipoprotein</keyword><keyword>deficiencyreducesatherosclerosis</keyword><keyword>diet-inducedatherosclerosis</keyword><keyword>chemokinereceptorccr7</keyword><keyword>interferon-gamma</keyword><keyword>dendriticcells</keyword><keyword>myocardial-infarction</keyword><keyword>scavengerreceptor</keyword><keyword>lesiondevelopment</keyword><keyword>plaque-formation</keyword></keywords><dates><year>2020</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1759-5002</isbn><accession-num>WOS:000519843100001</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000519843100001</style></url></related-urls></urls><electronic-resource-num>10.1038/s41569-020-0352-5</electronic-resource-num><language>English</language></record></Cite></EndNote>[12]。Th2細(xì)胞與Th1不同，其分泌的IL-4可以抑制IFN-γ的產(chǎn)生，但其對于動(dòng)脈粥樣硬化是促進(jìn)還是保護(hù)作用尚不清楚ADDINEN.CITE<EndNote><Cite><Author>Wurtz</Author><Year>2004</Year><RecNum>102</RecNum><DisplayText><styleface="superscript">[13]</style></DisplayText><record><rec-number>102</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619834710">102</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wurtz,O.</author><author>Bajenoff,M.</author><author>Guerder,S.</author></authors></contributors><auth-address>UnivMediterranee,CNRS,INSERM,CtrImmunolMarseilleLuminy,F-13288Marseille09,France</auth-address><titles><title>IL-4-mediatedinhibitionofIFN-gammaproductionbyCD4(+)Tcellsproceedsbyseveraldevelopmentallyregulatedmechanisms</title><secondary-title>InternationalImmunology</secondary-title><alt-title>IntImmunol</alt-title></titles><alt-periodical><full-title>IntImmunol</full-title></alt-periodical><pages>501-508</pages><volume>16</volume><number>3</number><keywords><keyword>cellulardifferentiation</keyword><keyword>generegulation</keyword><keyword>t(h)1/t(h)2</keyword><keyword>transcriptionfactor</keyword><keyword>cytokinegene-expression</keyword><keyword>developingth1cells</keyword><keyword>lymph-nodes</keyword><keyword>transcriptionfactor</keyword><keyword>lineagecommitment</keyword><keyword>bet</keyword><keyword>gata-3</keyword><keyword>differentiation</keyword><keyword>stat6</keyword><keyword>responses</keyword></keywords><dates><year>2004</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0953-8178</isbn><accession-num>WOS:000220074400012</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000220074400012</style></url></related-urls></urls><electronic-resource-num>10.1093/intimm/dxh050</electronic-resource-num><language>English</language></record></Cite></EndNote>[13]。與IL-4不同，大多研究表明IL-5、IL-13具有動(dòng)脈粥樣硬化保護(hù)作用。在高脂飲食喂養(yǎng)的LDLr（-/-）小鼠中，與PBS治療的小鼠相比，IL-13上調(diào)了斑塊中的膠原含量，同時(shí)下調(diào)了VCAM-1的表達(dá)，降低了斑塊部位中巨噬細(xì)胞的浸潤豐度ADDINEN.CITEADDINEN.CITE.DATA[14]。1.2.3樹突狀細(xì)胞DCs也在動(dòng)脈粥樣硬化的病理進(jìn)展中起重要作用ADDINEN.CITE<EndNote><Cite><Author>Keaney</Author><Year>2011</Year><RecNum>104</RecNum><DisplayText><styleface="superscript">[15]</style></DisplayText><record><rec-number>104</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619834710">104</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Keaney,J.F.</author></authors></contributors><auth-address>UnivMassachusetts,SchMed,DeptMed,DivCardiovascMed,Worcester,MAUSA</auth-address><titles><title>ImmuneModulationofAtherosclerosis</title><secondary-title>Circulation</secondary-title><alt-title>Circulation</alt-title></titles><periodical><full-title>Circulation</full-title></periodical><alt-periodical><full-title>Circulation</full-title></alt-periodical><pages>E559-E560</pages><volume>124</volume><number>22</number><keywords><keyword>atherosclerosis</keyword><keyword>dendriticcells</keyword><keyword>t-cells</keyword><keyword>deficiency</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov29</date></pub-dates></dates><isbn>0009-7322</isbn><accession-num>WOS:000298130700002</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000298130700002</style></url></related-urls></urls><electronic-resource-num>10.1161/Circulationaha.111.074096</electronic-resource-num><language>English</language></record></Cite></EndNote>[15]。DCs參與內(nèi)皮活化過程，通過促進(jìn)炎癥介質(zhì)表達(dá)，加強(qiáng)AS的形成，導(dǎo)致斑塊不穩(wěn)定ADDINEN.CITE<EndNote><Cite><Author>Broder</Author><Year>2013</Year><RecNum>105</RecNum><DisplayText><styleface="superscript">[16]</style></DisplayText><record><rec-number>105</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619834710">105</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Broder,A.</author><author>Chan,J.J.</author><author>Putterman,C.</author></authors></contributors><auth-address>MontefioreMedCtr,AlbertEinsteinCollMed,DivRheumatol,Bronx,NY10461USA AlbertEinsteinCollMed,Bronx,NY10461USA</auth-address><titles><title>Dendriticcells:Animportantlinkbetweenantiphospholipidantibodies,endothelialdysfunction,andatherosclerosisinautoimmuneandnon-autoimmunediseases</title><secondary-title>ClinicalImmunology</secondary-title><alt-title>ClinImmunol</alt-title></titles><alt-periodical><full-title>ClinImmunol</full-title></alt-periodical><pages>197-206</pages><volume>146</volume><number>3</number><keywords><keyword>dendriticcells</keyword><keyword>antiphospholipidantibodies</keyword><keyword>atherosclerosis</keyword><keyword>antiphospholipidsyndrome</keyword><keyword>systemic-lupus-erythematosus</keyword><keyword>low-density-lipoprotein</keyword><keyword>beta(2)-glycoproteini</keyword><keyword>cardiovascular-diseases</keyword><keyword>beta2-glycoproteini</keyword><keyword>rheumatic-diseases</keyword><keyword>immune-mechanisms</keyword><keyword>vascular-disease</keyword><keyword>apoptoticcells</keyword><keyword>t-cells</keyword></keywords><dates><year>2013</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1521-6616</isbn><accession-num>WOS:000316241700005</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000316241700005</style></url></related-urls></urls><electronic-resource-num>10.1016/j.clim.2012.12.002</electronic-resource-num><language>English</language></record></Cite></EndNote>[16]。較高的血流剪切力與較高數(shù)量的DCs聚集都常見于粥樣硬化易發(fā)部位，兩者可能存在關(guān)聯(lián)性ADDINEN.CITEADDINEN.CITE.DATA[17,18]。頸動(dòng)脈標(biāo)本的免疫組化分析顯示，在早期AS斑塊中DCs較少，且著少于晚期斑塊。與初始病變相比，晚期斑塊中過半的DCs都表現(xiàn)出了成熟表型，例如CD83+，DC-LAMP+，這些結(jié)果表明DCs似乎參與了動(dòng)脈粥樣硬化發(fā)展的各階段ADDINEN.CITEADDINEN.CITE.DATA[19]。泡沫細(xì)胞除源自巨噬細(xì)胞之外，亦有研究表明DCs也可能起到了重要的作用。雖然相關(guān)作用的機(jī)制仍有待進(jìn)一步探究，但DCs來源的泡沫細(xì)胞，在AS進(jìn)程中可能有關(guān)鍵作用ADDINEN.CITE<EndNote><Cite><Author>Subramanian</Author><Year>2014</Year><RecNum>109</RecNum><DisplayText><styleface="superscript">[20]</style></DisplayText><record><rec-number>109</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619834710">109</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Subramanian,M.</author><author>Tabas,I.</author></authors></contributors><auth-address>ColumbiaUniv,DeptMed,NewYork,NY10032USA ColumbiaUniv,DeptPathol&CellBiol,NewYork,NY10032USA ColumbiaUniv,DeptPhysiol,NewYork,NY10032USA</auth-address><titles><title>Dendriticcellsinatherosclerosis</title><secondary-title>SeminarsinImmunopathology</secondary-title><alt-title>SeminImmunopathol</alt-title></titles><alt-periodical><full-title>SeminImmunopathol</full-title></alt-periodical><pages>93-102</pages><volume>36</volume><number>1</number><keywords><keyword>dendriticcells</keyword><keyword>atherosclerosis</keyword><keyword>tregs</keyword><keyword>efferocytosis</keyword><keyword>regulatoryt-cells</keyword><keyword>low-density-lipoprotein</keyword><keyword>receptor-deficientmice</keyword><keyword>arterialintima</keyword><keyword>acceleratesatherosclerosis</keyword><keyword>promotesatherosclerosis</keyword><keyword>reducesatherosclerosis</keyword><keyword>chronicinflammation</keyword><keyword>interferon-alpha</keyword><keyword>apoptoticcells</keyword></keywords><dates><year>2014</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1863-2297</isbn><accession-num>WOS:000330959700007</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000330959700007</style></url></related-urls></urls><electronic-resource-num>10.1007/s00281-013-0400-x</electronic-resource-num><language>English</language></record></Cite></EndNote>[20]。1.2.4肥大細(xì)胞肥大細(xì)胞與動(dòng)脈粥樣硬化斑塊病變進(jìn)程有高度關(guān)聯(lián)性ADDINEN.CITEADDINEN.CITE.DATA[21]。在正常的動(dòng)脈內(nèi)膜中，肥大細(xì)胞的數(shù)量極少，而在AS斑塊區(qū)域，肥大細(xì)胞數(shù)量則明顯增多，占比提高了9倍，表明兩者存在相關(guān)性。肥大細(xì)胞活化并釋放促炎因子、生長因子、血管活性物質(zhì)以及蛋白水解酶等，例如TNF-α、類胰蛋白酶、胃蛋白酶、糜蛋白酶，導(dǎo)致其對所在血管壁周圍環(huán)境產(chǎn)生不利影響，引發(fā)基質(zhì)降解、細(xì)胞凋亡，促進(jìn)粥樣硬化的進(jìn)展ADDINEN.CITEADDINEN.CITE.DATA[22,23]。在這些分泌的介質(zhì)中，類胰蛋白酶和糜蛋白酶被認(rèn)為是肥大細(xì)胞促進(jìn)斑塊不穩(wěn)定的主要原因。在多數(shù)研究中，血漿類胰蛋白酶的水平與心血管疾病的嚴(yán)重程度相關(guān)，在頸動(dòng)脈內(nèi)膜異位癥后出現(xiàn)繼發(fā)性心血管疾病的患者中，其血漿胰蛋白酶水平顯著增加ADDINEN.CITEADDINEN.CITE.DATA[24]。并且在最近的研究中顯示類胰蛋白酶的過度表達(dá)會(huì)增加斑塊出血的頻率，而這個(gè)現(xiàn)象可以被類胰蛋白酶靶向si-RNA抑制ADDINEN.CITE<EndNote><Cite><Author>Zhi</Author><Year>2013</Year><RecNum>115</RecNum><DisplayText><styleface="superscript">[25]</style></DisplayText><record><rec-number>115</rec-number><foreign-keys><keyapp="EN"db-id="zavwxwewazep9tefwx55dftp9w2f99f9wpz2"timestamp="1619834710">115</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zhi,X.L.</author><author>Xu,C.</author><author>Zhang,H.</author><author>Tian,D.</author><author>Li,X.B.</author><author>Ning,Y.X.</author><author>Yin,L.H.</author></authors></contributors><auth-address>FudanUniv,ShanghaiMedColl,TeachingCtrExptMed,LabMedMolBiol,Shanghai200433,PeoplesRChina FudanUniv,ZhongshanHosp,DeptPathol,Shanghai200433,PeoplesRChina FudanUniv,ShanghaiMedColl,DeptPhysiol&Pathophysiol,Shanghai200433,PeoplesRChina</auth-address><titles><title>TryptasePromotesAtheroscleroticPlaqueHaemorrhageinApoE-/-Mice</title><secondary-title>PlosOne</secondary-title><alt-title>PlosOne</alt-title></titles><periodical><full-title>PLoSOne</full-title></periodical><alt-periodical><full-title>PLoSOne</full-title></alt-periodical><volume>8</volume><number>4</number><keywords><keyword>mast-celltryptase</keyword><keyword>plasminogen-activatorinhibitor-1</keyword><keyword>humancarotidarteries</keyword><keyword>endothelial-cells</keyword><keyword>intraplaquehemorrhage</keyword><keyword>angiogenesis</keyword><keyword>cancer</keyword><keyword>growth</keyword><keyword>cholesterol</keyword><keyword>progression</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr3</date></pub-dates></dates><isbn>1932-6203</isbn><accession-num>WOS:000318840100110</accession-num><urls><related-urls><url><styleface="underline"font="default"size="100%"><GotoISI>://WOS:000318840100110</style></url></related-urls></urls><electronic-resource-num>ARTNe60960 10.1371/journal.pone.0060960</electronic-resource-num><language>English</language></record></Cite></EndNote>[25]。糜蛋白酶作用于高密度脂蛋白HDL并起到抑制作用，降低膽固醇外排，使巨噬細(xì)胞、平滑肌細(xì)胞轉(zhuǎn)化為泡沫細(xì)胞。載脂蛋白A-1（ApoA-1）是HDL的主要載脂蛋白，研究表明肥大細(xì)胞產(chǎn)生的糜蛋白酶可以引起脂肪降解并降低ApoA-1的水平，改變脂質(zhì)代謝ADDINEN.CITEADDINEN