【《动脉粥样硬化与免疫细胞研究国内外文献综述》2500字】

动脉粥样硬化与免疫细胞研究国内外文献综述最近，各种免疫疗法和疫苗接种法在患有AS的动物模型中显示出了乐观的治疗前景，这与CANTOS试验提出的细胞因子抗体相比或许更有意义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]。免疫疗法和疫苗接种可以有效避免宿主防御。免疫细胞广泛参与AS发展过程。最初，单核/巨噬细胞与树突状细胞（DCs）存在于动脉外膜和新内膜中，由Toll样受体配体和清除剂受体激活，进而转入血管内膜，分泌炎性细胞因子维持和加剧AS，吸引更多的免疫细胞。在成熟的AS斑块中，T细胞分泌炎性因子，使炎症持续存在，同时肥大细胞大量聚集，在AS斑块核心形成免疫细胞浸润。由此可见，对免疫细胞进行有效的调节可能在一定程度上改善疾病的进程。1.2.1单核/巨噬细胞单核/巨噬细胞作为重要的免疫细胞之一，被认为最早进入动脉粥样硬化病变区域，并且它在动脉粥样硬化斑块的形成、发展及转归中均起到了至关重要的作用。在AS病变进展过程的早期阶段，多种风险因素如高脂血症、高血压、高血糖、吸烟等，引起血管内皮细胞受损，随后导致血管内皮细胞在其表面分泌大量的细胞趋化因子，这些趋化因子进而与单核细胞表面表达的同源相关受体结合后调控并激活相关信号通路，促进这些单核细胞向血管内皮进行定向迁移。在趋化作用下，单核细胞通过血小板和内皮细胞所分泌的P凝集素糖蛋白配体-1（PSGL-1）和内皮凝集素之间的相互作用，滚动至发炎的内皮区域。随后在多种蛋白如单核细胞整合蛋白（VLA-4）、血管细胞粘附分子（VCAM-1）、细胞间粘附分子（ICAM-1）等作用下，单核细胞可进入血管内膜，分化成巨噬细胞，其表面表达A型清道夫受体（SR-A）和B型家族成员CD36等，在这种作用下，巨噬细胞会吞噬过量的氧化型低密度脂蛋白（ox-LDL），同时由于相关受体不受到负反馈相关调节而导致胞内出现脂质的严重堆积，形成泡沫细胞并堆积形成动脉粥样硬化的起始标志——早期脂质条纹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]。随疾病进展，巨噬细胞活化并促进血管平滑肌细胞迁移和增殖ADDINEN.CITEADDINEN.CITE.DATA[5]。其合成分泌的胶原纤维，可在病变区形成纤维斑块。在炎症环境的持续作用下，干扰素γ（IFN-γ）降低胶原蛋白合成能力，同时基质金属蛋白酶（MMP）降解胶原，这些都削弱了帽子结构，使得其趋向不稳定ADDINEN.CITEADDINEN.CITE.DATA[6]。于是多种继发性病变如血栓、斑块破裂等易于发生，最终产生严重心血管疾病。1.2.2T淋巴细胞正常动脉的防御机制依赖于内皮细胞的先天免疫反应，这一过程始于单核/巨噬细胞的激活，而适应性免疫则依赖于T细胞和B细胞所介导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]。研究结果显示，在人和小鼠AS斑块中均有T细胞亚群存在ADDINEN.CITEADDINEN.CITE.DATA[8]。其中，CD4+T细胞常见于AS斑块部位，是适应性免疫应答的关键调节因子，能够分化为各种类型的辅助型T细胞，包括Th1、Th2、Th17或Treg细胞谱系。Th细胞和Treg细胞可以激活或抑制其他免疫细胞的反应，不仅能发挥促炎作用，还能发挥抗炎作用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]。数据显示，AS斑块中CD4+T细胞以Th1和Th2细胞为主，且Th1细胞占主要部分。IFN-γ作为Th1细胞的标志性细胞因子，不仅能促使炎症因子如趋化因子和粘附分子等分泌的上调，还能够提高巨噬细胞和内皮细胞的活化程度，促进AS斑块的病理进程ADDINEN.CITEADDINEN.CITE.DATA[10]。当重组的外源性IFN-γ经由腹腔给药注射到ApoE（-/-）小鼠30天时，与给予PBS对照组的小鼠相比，病变大小增加了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细胞也可分泌其他因子并激活单核/巨噬细胞、T细胞等免疫细胞，加速斑块部位的炎症反应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细胞与Th1不同，其分泌的IL-4可以抑制IFN-γ的产生，但其对于动脉粥样硬化是促进还是保护作用尚不清楚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]。与IL-4不同，大多研究表明IL-5、IL-13具有动脉粥样硬化保护作用。在高脂饮食喂养的LDLr（-/-）小鼠中，与PBS治疗的小鼠相比，IL-13上调了斑块中的胶原含量，同时下调了VCAM-1的表达，降低了斑块部位中巨噬细胞的浸润丰度ADDINEN.CITEADDINEN.CITE.DATA[14]。1.2.3树突状细胞DCs也在动脉粥样硬化的病理进展中起重要作用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参与内皮活化过程，通过促进炎症介质表达，加强AS的形成，导致斑块不稳定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]。较高的血流剪切力与较高数量的DCs聚集都常见于粥样硬化易发部位，两者可能存在关联性ADDINEN.CITEADDINEN.CITE.DATA[17,18]。颈动脉标本的免疫组化分析显示，在早期AS斑块中DCs较少，且著少于晚期斑块。与初始病变相比，晚期斑块中过半的DCs都表现出了成熟表型，例如CD83+，DC-LAMP+，这些结果表明DCs似乎参与了动脉粥样硬化发展的各阶段ADDINEN.CITEADDINEN.CITE.DATA[19]。泡沫细胞除源自巨噬细胞之外，亦有研究表明DCs也可能起到了重要的作用。虽然相关作用的机制仍有待进一步探究，但DCs来源的泡沫细胞，在AS进程中可能有关键作用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肥大细胞肥大细胞与动脉粥样硬化斑块病变进程有高度关联性ADDINEN.CITEADDINEN.CITE.DATA[21]。在正常的动脉内膜中，肥大细胞的数量极少，而在AS斑块区域，肥大细胞数量则明显增多，占比提高了9倍，表明两者存在相关性。肥大细胞活化并释放促炎因子、生长因子、血管活性物质以及蛋白水解酶等，例如TNF-α、类胰蛋白酶、胃蛋白酶、糜蛋白酶，导致其对所在血管壁周围环境产生不利影响，引发基质降解、细胞凋亡，促进粥样硬化的进展ADDINEN.CITEADDINEN.CITE.DATA[22,23]。在这些分泌的介质中，类胰蛋白酶和糜蛋白酶被认为是肥大细胞促进斑块不稳定的主要原因。在多数研究中，血浆类胰蛋白酶的水平与心血管疾病的严重程度相关，在颈动脉内膜异位症后出现继发性心血管疾病的患者中，其血浆胰蛋白酶水平显著增加ADDINEN.CITEADDINEN.CITE.DATA[24]。并且在最近的研究中显示类胰蛋白酶的过度表达会增加斑块出血的频率，而这个现象可以被类胰蛋白酶靶向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，降低胆固醇外排，使巨噬细胞、平滑肌细胞转化为泡沫细胞。载脂蛋白A-1（ApoA-1）是HDL的主要载脂蛋白，研究表明肥大细胞产生的糜蛋白酶可以引起脂肪降解并降低ApoA-1的水平，改变脂质代谢ADDINEN.CITEADDINEN