炎症反应在易损斑块中的作用及其机制研究进展
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摘要
炎症反应在易损斑块的形成和进展中发挥重要作用,同时调控血管局部病变及全身炎症状态。一些促炎性细胞和炎症因子使斑块纤维帽的抗张强度降低,坏死脂质内核增大,血管机械稳定性丧失和斑块破裂;另一方面,炎症反应的激活和代谢紊乱也会引起内皮功能不全、斑块侵蚀进而导致血栓形成。该过程主要由巨噬细胞和淋巴细胞等多种炎症细胞参与,并受到多种因素调控,包括胆固醇结晶和脂质递质、血管剪切力、血管新生及斑块内出血等。此外,机体还存在一些抑炎性分子,能避免易损斑块向破裂或侵蚀进展。促炎和抗炎反应的平衡影响急性冠状动脉事件的发生。因此,以炎症反应为靶点,筛选出有易损斑块的患者并干预,或可减少急性冠状动脉事件的发生和改善预后,具有重要临床价值。
Inflammatory response plays an important part in the formation and progression of vulnerable plaque. It regulates the lesions locally in the artery as well as the global inflammatory status. Some pro-inflammatory cells and cytokines can reduce the tensile strength of the collagen cap surrounding the plaque and enlarge the necrotic lipid core, thus causing the loss of mechanical stability and plaque rupture. On the other hand, activation of inflammatory response and metabolic disturbance can also instigate endothelial dysfunction, plaque erosion, and further thrombosis. Such process is mediated by several immune cells such as macrophages and lymphocytes, along with other regulatory factors consisting of cholesterol crystals and lipid mediators, shear stress as well as angiogenesis and intraplaque haemorrhage. Moreover, several anti-inflammatory factors are found able to protect the vulnerable plaque from rupture or erosion, highlighting the balance of inflammatory response is essential for the occurrence of acute coronary syndrome(ACS). Thus, targeting specific factors in the inflammatory response may be valuable in screening and treating patients with vulnerable plaque, preventing ACS and improving the prognosis.
Inflammatory response plays an important part in the formation and progression of vulnerable plaque. It regulates the lesions locally in the artery as well as the global inflammatory status. Some pro-inflammatory cells and cytokines can reduce the tensile strength of the collagen cap surrounding the plaque and enlarge the necrotic lipid core, thus causing the loss of mechanical stability and plaque rupture. On the other hand, activation of inflammatory response and metabolic disturbance can also instigate endothelial dysfunction, plaque erosion, and further thrombosis. Such process is mediated by several immune cells such as macrophages and lymphocytes, along with other regulatory factors consisting of cholesterol crystals and lipid mediators, shear stress as well as angiogenesis and intraplaque haemorrhage. Moreover, several anti-inflammatory factors are found able to protect the vulnerable plaque from rupture or erosion, highlighting the balance of inflammatory response is essential for the occurrence of acute coronary syndrome(ACS). Thus, targeting specific factors in the inflammatory response may be valuable in screening and treating patients with vulnerable plaque, preventing ACS and improving the prognosis.
引文
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[41] Koskinas KC,Feldman CL,Chatzizisis YS,et al.Natural history of experimental coronary atherosclerosis and vascular remodeling in relation to endothelial shear stress:a serial,in vivo intravascular ultrasound study[J].Circulation,2010,121(19):2092-2101.
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[43] Phinikaridou A,Hua N,Pham T,et al.Regions of low endothelial shear stress colocalize with positive vascular remodeling and atherosclerotic plaque disruption:an in vivo magnetic resonance imaging study[J].Circ Cardiovasc Imaging,2013,6(2):302-310.
[44] Kolodgie FD,Gold HK,Burke AP,et al.Intraplaque hemorrhage and progression of coronary atheroma[J].N Engl J Med,2003,349(24):2316-2325.
[45] Welsh P,Grassia G,Botha S,et al.Targeting inflammation to reduce cardiovascular disease risk:a realistic clinical prospect?[J].Br J Pharmacol,2017,174(22):3898-3913.
[46] Ridker PM,Everett BM,Thuren T,et al.Antiinflammatory therapy with canakinumab for atherosclerotic disease[J].N Engl J Med,2017,377(12):1119-1131.
[47] Mitroulis I,Ruppova K,Wang B,et al.Modulation of myelopoiesis progenitors is an integral component of trained immunity[J].Cell,2018,172(1-2):147-161.
[2] Falk E,Nakano M,Bentzon JF,et al.Update on acute coronary syndromes:the pathologists' view[J].Eur Heart J,2013,34(10):719-728.
[3] 周小林,杨淑华,郭志明,等.易损斑块的研究进展[J].中国动脉硬化杂志,2011,19(3):279.
[4] Kasikara C,Doran AC,Cai B,et al.The role of non-resolving inflammation in atherosclerosis[J].J Clin Invest,2018,128(7):2713-2723.
[5] Hansson GK,Libby P,Tabas I.Inflammation and plaque vulnerability[J].J Intern Med,2015,278(5):483-493.
[6] Falk E,Shah PK,Fuster V.Coronary plaque disruption[J].Circulation,1995,92(3):657-671.
[7] Arbab-Zadeh A,Fuster V.The myth of the “vulnerable plaque”:transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment[J].J Am Coll Cardiol,2015,65(8):846-855.
[8] Libby P,Ridker PM,Hansson GK.Progress and challenges in translating the biology of atherosclerosis[J].Nature,2011,473(7347):317-325.
[9] Tabas I,Garcia-Cardena G,Owens GK.Recent insights into the cellular biology of atherosclerosis[J].J Cell Biol,2015,209(1):13-22.
[10] Hansson GK,Hermansson A.The immune system in atherosclerosis[J].Nat Immunol,2011,12(3):204-212.
[11] Libby P,Tabas I,Fredman G,et al.Inflammation and its resolution as determinants of acute coronary syndromes[J].Circ Res,2014,114(12):1867-1879.
[12] Toutouzas K,Benetos G,Drakopoulou M,et al.Incremental predictive value of carotid inflammation in acute ischemic stroke[J].Stroke,2015,46(1):272-274.
[13] Teng N,Maghzal GJ,Talib J,et al.The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture[J].Redox Rep,2017,22(2):51-73.
[14] Bentzon JF,Otsuka F,Virmani R,et al.Mechanisms of plaque formation and rupture[J].Circ Res,2014,114(12):1852-1866.
[15] Lievens D,Eijgelaar WJ,Biessen EA,et al.The multi-functionality of CD40L and its receptor CD40 in atherosclerosis[J].Thromb Haemost,2009,102(2):206-214.
[16] Edfeldt K,Swedenborg J,Hansson GK,et al.Expression of toll-like receptors in human atherosclerotic lesions:a possible pathway for plaque activation[J].Circulation,2002,105(10):1158-1161.
[17] Leeka J,Schwartz BG,Kloner RA.Sporting events affect spectators' cardiovascular mortality:it is not just a game[J].Am J Med,2010,123(11):972-977.
[18] Vergallo R,Ren X,Yonetsu T,et al.Pancoronary plaque vulnerability in patients with acute coronary syndrome and ruptured culprit plaque:a 3-vessel optical coherence tomography study[J].Am Heart J,2014,167(1):59-67.
[19] Myers KS,Rudd JH,Hailman EP,et al.Correlation between arterial FDG uptake and biomarkers in peripheral artery disease[J].JACC Cardiovasc Imaging,2012,5(1):38-45.
[20] Toutouzas K,Benetos G,Drakopoulou M,et al.Morphological and functional assessment of carotid plaques have similar predictive accuracy for coronary artery disease[J].Stroke,2013,44(9):2607-2609.
[21] Cimmino G,Loffredo FS,Morello A,et al.Immune-inflammatory activation in acute coronary syndromes:A look into the heart of unstable coronary plaque[J].Curr Cardiol Rev,2017,13(2):110-117.
[22] Libby P.Inflammation in atherosclerosis[J].Arterioscler Thromb Vasc Biol,2012,32(9):2045-2051.
[23] Miller YI,Choi SH,Wiesner P,et al.Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity[J].Circ Res,2011,108(2):235-248.
[24] Cai B,Thorp EB,Doran AC,et al.MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis[J].J Clin Invest,2017,127(2):564-568.
[25] De Paoli F,Staels B,Chinetti-Gbaguidi G.Macrophage phenotypes and their modulation in atherosclerosis[J].Circ J,2014,78(8):1775-1781.
[26] Boyle JJ,Harrington HA,Piper E,et al.Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype[J].Am J Pathol,2009,174(3):1097-1108.
[27] New SE,Goettsch C,Aikawa M,et al.Macrophage-derived matrix vesicles:an alternative novel mechanism for microcalcification in atherosclerotic plaques[J].Circ Res,2013,113(1):72-77.
[28] Motoyama S,Kondo T,Sarai M,et al.Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes[J].J Am Coll Cardiol,2007,50(4):319-326.
[29] Flego D,Severino A,Trotta F,et al.Increased PTPN22 expression and defective CREB activation impair regulatory T-cell differentiation in non-ST-segment elevation acute coronary syndromes[J].J Am Coll Cardiol,2015,65(12):1175-1186.
[30] Weber C,Zernecke A,Libby P.The multifaceted contributions of leukocyte subsets to atherosclerosis:lessons from mouse models[J].Nat Rev Immunol,2008,8(10):802-815.
[31] van Dijk RA,Duinisveld AJ,Schaapherder AF,et al.A change in inflammatory footprint precedes plaque instability:a systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis[J].J Am Heart Assoc,2015,4(4):e001403.
[32] Hermansson A,Ketelhuth DF,Strodthoff D,et al.Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis[J].J Exp Med,2010,207(5):1081-1093.
[33] Klingenberg R,Gerdes N,Badeau RM,et al.Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis[J].J Clin Invest,2013,123(3):1323-1334.
[34] Duewell P,Kono H,Rayner KJ,et al.NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals[J].Nature,2010,464(7293):1357-1361.
[35] Samuelsson B.Role of basic science in the development of new medicines:examples from the eicosanoid field[J].J Biol Chem,2012,287(13):10070-10080.
[36] Fredman G,Hellmann J,Proto JD,et al.An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques[J].Nat Commun,2016,7:12859.
[37] Vedre A,Pathak DR,Crimp M,et al.Physical factors that trigger cholesterol crystallization leading to plaque rupture[J].Atherosclerosis,2009,203(1):89-96.
[38] Raitoharju E,Oksala N,Lehtimaki T.MicroRNAs in the atherosclerotic plaque[J].Clin Chem,2013,59(12):1708-1721.
[39] 刘静,王媚媚,何文智,等.受剪切应力调控的microRNAs在动脉粥样硬化中作用机制的研究进展[J].中国动脉硬化杂志,2017,25(12):1287-1290.
[40] Chatzizisis YS,Baker AB,Sukhova GK,et al.Augmented expression and activity of extracellular matrix-degrading enzymes in regions of low endothelial shear stress colocalize with coronary atheromata with thin fibrous caps in pigs[J].Circulation,2011,123(6):621-630.
[41] Koskinas KC,Feldman CL,Chatzizisis YS,et al.Natural history of experimental coronary atherosclerosis and vascular remodeling in relation to endothelial shear stress:a serial,in vivo intravascular ultrasound study[J].Circulation,2010,121(19):2092-2101.
[42] Koskinas KC,Sukhova GK,Baker AB,et al.Thin-capped atheromata with reduced collagen content in pigs develop in coronary arterial regions exposed to persistently low endothelial shear stress[J].Arterioscler Thromb Vasc Biol,2013,33(7):1494-1504.
[43] Phinikaridou A,Hua N,Pham T,et al.Regions of low endothelial shear stress colocalize with positive vascular remodeling and atherosclerotic plaque disruption:an in vivo magnetic resonance imaging study[J].Circ Cardiovasc Imaging,2013,6(2):302-310.
[44] Kolodgie FD,Gold HK,Burke AP,et al.Intraplaque hemorrhage and progression of coronary atheroma[J].N Engl J Med,2003,349(24):2316-2325.
[45] Welsh P,Grassia G,Botha S,et al.Targeting inflammation to reduce cardiovascular disease risk:a realistic clinical prospect?[J].Br J Pharmacol,2017,174(22):3898-3913.
[46] Ridker PM,Everett BM,Thuren T,et al.Antiinflammatory therapy with canakinumab for atherosclerotic disease[J].N Engl J Med,2017,377(12):1119-1131.
[47] Mitroulis I,Ruppova K,Wang B,et al.Modulation of myelopoiesis progenitors is an integral component of trained immunity[J].Cell,2018,172(1-2):147-161.