炎症如何促进动脉粥样硬化发生？关键是这5步

脂质堆积和高血压被认为是动脉粥样硬化心血管疾病（ASCVD）的主要危险因素，降胆固醇和降压药物有望有效预防和消除ASCVD。但由于慢性血管炎症被排除在外，基于高胆固醇血症和高血压的干预方案未能产生理想的结果。

残余炎症风险被认为是影响ASCVD的关键协调因素。炎症驱动动脉粥样硬化启动，脂蛋白进入、滞留和氧化修饰导致内皮损伤，引发先天和适应性免疫反应。募集的免疫细胞通过释放促炎细胞因子、加速泡沫细胞形成、斑块内出血、基质降解酶的分泌和病变进展来协调早期动脉粥样硬化病变，最终通过各种炎症级联反应促进冠状动脉综合征。

动脉粥样硬化斑块的形成

动脉粥样硬化是由多个细胞及其分泌产物的渐进参与、脂肪条转化为纤维脂质斑块发展而来，从而导致斑块破裂和动脉粥样硬化血栓形成。动脉粥样硬化斑块的发展分为六个阶段：病变前（I期、II期和III期）和动脉粥样硬化斑块形成（IV期、V期和VI期）。

由于C反应蛋白（CRP）、低密度脂蛋白（LDL）和肿瘤坏死因子（TNF）-α水平升高，内皮细胞（EC）活性在I期发生改变。这种修饰导致LDL在内膜中被捕获，易发生基于氧化和糖基化的修饰。该机制将LDL转化为修饰的脂蛋白，导致EC功能失调，趋化因子（CD）和新型细胞粘附分子的出现证明了这一点。该过程伴随着炎症级联反应（III期），允许血浆单核细胞与血小板、T淋巴细胞和树突状细胞一起穿透动脉内膜。单核细胞吸收修饰的脂蛋白并将其转化为巨噬细胞衍生的泡沫细胞。平滑肌进入内膜导致IV期产生纤维帽。胆固醇晶体、细胞外基质和大量钙化核心的产生标志着进展到V期。VI期时，随着细胞因子的过度释放，纤维帽的衰弱表现出复杂的斑块，其中EC损伤和坏死代表动脉粥样硬化斑块形成的最后阶段。

白细胞募集和泡沫细胞形成

通常，内皮维持血管舒张、血管收缩、促凝血和抗凝事件之间的平衡。然而，内皮细胞可通过上调核因子κB（NF-κB）对损伤性刺激做出反应，增加白细胞的血管细胞粘附分子-1（VCAM-1）、细胞间粘附分子1（ICAM-1）、内皮素（ET-1）、血管紧张素（Ang）II和促凝血因子的表达。

上调受体表达增强了中性粒细胞和单核细胞从外周向皮下空间的渗漏。选择素依赖性粘附分子，包括E-选择素和P-选择素，可诱导白细胞和内皮细胞之间的低亲和力相互作用。这种短暂的相互作用导致白细胞活化，极晚期抗原-4（VLA-4）及其互补配体在活化的内皮细胞VCAM-1和ICAM-1上牢固粘附。巨噬细胞集落刺激因子（M-CSF）通过增强单核细胞分化，增加巨噬细胞数量、氧化低密度脂蛋白（ox-LDL）摄取和泡沫细胞形成，使情况恶化。

斑块堆积通常被观察为黄色的“脂肪条纹”，代表血管壁中的泡沫细胞堆积。清除剂受体（SR）CD36和SR-A1主要负责单核细胞衍生的巨噬细胞摄取ox-LDL。ox-LDL和SRs复合物促进修饰脂蛋白内化为细胞质脂滴。巨噬细胞、泡沫细胞的形成最初被认为是有利的，因为其ox-LDL螯合潜力。然而，随着时间的推移，泡沫细胞失去了消化脂蛋白的能力。内质网应激产生的活性氧（ROS）增加是细胞凋亡级联反应的触发因素。

接下来，泡沫细胞激活CD36和TLRs，它们促进细胞因子和趋化因子的产生，并通过向病变募集更多循环免疫成分来放大局部炎症反应。在这里，炎症检测有害刺激并将前IL-1β和IL-18切割到其活性状态。同时，激活清道夫受体促进IL-1α的分泌，IL-1α在动脉粥样硬化形成中比IL-1β发挥更重要的作用。IL-1α、IL-1β和IL-18与相应受体的相互作用导致T细胞活化，ROS和基质金属蛋白酶（MMP）的产生增加。免疫细胞灌注促进了促炎细胞因子的释放和动脉粥样硬化的恶化。另一方面，泡沫细胞增多症是一个从体内清除死细胞成分的过程，它被破坏，导致碎片和脂质在细胞室中积聚，为形成具有血栓形成特性的富含脂质的坏死核心铺平了道路。

脂蛋白进入、滞留和修饰动脉粥样硬化疾病的早期机制

脂蛋白进入、滞留和修饰动脉粥样硬化疾病的早期机制与LDL在动脉内膜中积聚引发的炎症反应有关。内皮膜通透性的变化、渗漏细胞与清除剂受体B1（SR-BI）和激活素受体样激酶-1（ALK-1）介导的LDL转运之间的细胞旁转运与低密度脂素的积累有关。内皮屏障的破坏迫使血管将更多的含有载脂蛋白B的循环LDL吸收到内膜中。随后，LDL被积累并保留在通过与细胞外基质中的内皮下蛋白聚糖结合形成动脉壁。此外，LDL通过与内皮细胞、平滑肌细胞和巨噬细胞产生的ROS和促氧化酶相互作用而进行氧化修饰。

这种氧化应激导致内皮细胞和巨噬细胞的细胞损伤和正常功能破坏。Nguyen等人发表的综述显示，ox-LDL可以抑制一氧化氮（NO）的产生，从而调节静息血小板和白细胞的粘附特性、血管张力、纤维蛋白完整性和血栓形成阻力。此外，NO对血管平滑肌细胞（VSMC）的异常增殖起着制衡作用。在不存在NO的情况下，单核细胞趋化蛋白-1（MCP-1）/CCR2和VCAM-1的表达上调，增强单核细胞和淋巴细胞的内皮结合。ox-LDL对血管组织的损伤，间接促进斑块中的血管生成和形成，这为动脉血管壁中的白细胞募集和增殖铺平了道路。

斑块进展

这种迁移使平滑肌细胞增殖并在内膜内分泌细胞外基质大分子。此外，泡沫细胞产生的IL-1β和IL-6、TNF-α和血小板衍生生长因子（PDGF）增加了平滑肌细胞和白细胞的迁移和增殖，同时加剧了动脉粥样硬化和血管炎症。泡沫细胞释放的PDGF和肝素酶促进病变中的凝血和微血栓形成。细胞外基质代谢削弱了预先形成的纤维帽，并促进脂肪条纹过渡到斑块形成阶段。代谢由平滑肌细胞介导的MMPs合成和分解细胞外基质来提供。在存在干扰素（IFN）-γ的情况下，胶原合成受到抑制，而PDGF和转化生长因子β（TGF-β）刺激胶原的间质产生。此外，TGF-β增强纤连蛋白和蛋白聚糖的形成，触发蛋白酶抑制剂的表达，并抑制蛋白水解酶的释放。炎性细胞因子刺激泡沫细胞分泌MMP，降解泡沫帽中的胶原蛋白和弹性蛋白。营养不良和不健康的生活方式也会在增厚内膜的深层传播坏死。

斑块破裂与完整性

斑块破裂的关键因素是灌注区域的范围、脂质核心大小、纤维帽厚度、平滑肌细胞凋亡以及蛋白水解酶和斑块钙化之间平衡的破坏。斑块的完整性在很大程度上受到细胞外基质代谢的影响，其通过激活细胞凋亡途径加快平滑肌和泡沫细胞的分解。细胞死亡，随后细胞内容物的释放，使更多的脂质和碎片被吸收，有助于脂质核心尺寸的扩大。此外，血管平滑肌（VSM）的凋亡和细胞外基质的加速降解进一步削弱了纤维帽，增加了易受斑块破裂的易感性。与较厚的斑块相比，缺乏平滑肌细胞的斑块更容易破裂，有可能引发血栓形成。血管往往容易破裂，从而增加斑块内出血的机会。此外，斑块内出血通过壁内血肿增强了对纤维帽和血管闭塞的破坏。

斑块钙化将张力转移到纤维帽和血管管腔之间的界面，导致斑块破裂。一旦斑块破裂，坏死核心中的血栓形成因子直接暴露于外周的单核细胞。活化的血小板通过血小板聚集开始血栓形成。另一方面，血栓形成和动脉粥样硬化斑块环境破坏了凝血和溶解之间的平衡，最终增加了闭塞性血栓形成的可能性。

小结

冠状动脉灌注不足促进单核细胞和T淋巴细胞的募集和活化。这些免疫细胞释放促炎性IL-1、IL-6、TNF-α和hs-CRP，有助于动脉粥样硬化病变、泡沫细胞形成、内皮功能障碍、增强血管通透性和募集平滑肌细胞。平滑肌细胞的排出促进了冠状动脉斑块中斑块生长和扩张帽发育。不稳定斑块的特点是有一个薄纤维帽和一个富含脂质的坏死核心，特别容易破裂，从而引发急性血栓事件。因此，这些效应分子在临床环境中被积极用作预测冠心病患者心血管风险和治疗反应的标志物。了解炎症传播、动脉粥样硬化形成和冠心病的相互作用，对于重新计算风险因素和阐明治疗干预的新靶点是非常有必要的。认识到个体之间的炎症过程和反应的异质性，可能有助于针对个体患者制定治疗策略。

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