高致病性冠状病毒感染与免疫血栓形成的机制研究进展

doi:10.19803/j.1672-8629.20230464

摘要/Abstract

摘要： 目的综述高致病性冠状病毒感染时免疫血栓形成机制,为临床防治提供参考。方法查阅国内外文献,从凝血功能紊乱,免疫/炎症反应失调,内皮细胞损伤/功能障碍、血小板障碍等方面综述高致病性冠状病毒导致宿主免疫血栓的致病机制。结果高致病性冠状病毒感染导致失控的免疫血栓形成与细胞因子风暴、中性粒细胞胞外陷阱形成、补体系统和肾素血管紧张素系统过度激活,内皮细胞氧化应激及糖萼损伤等有关,是造成患者重症及死亡的关键原因。结论深入研究高致病性冠状病毒感染引起免疫血栓的发病机制,开发并评估潜在的治疗干预措施,不仅可以减轻该病的急性和远期后果,对未来应对其他新发、突发感染性疾病也具有重大意义。

关键词: 高致病性, 冠状病毒感染, 免疫血栓形成, 过度炎症, 内皮损伤, 凝血系统激活

Abstract: Objective To review the mechanism of immunethrombosis in highly pathogenic coronavirus（HPCoVs）infections and provide reference for clinical prevention and treatment. Methods Domestic and foreign literature was reviewed to outline the pathogenic mechanism of host immunethrombosis caused by Hcov in terms of coagulation disorders, immune/inflammatory disorders, endothelial cell injury/dysfunction, and platelet disorders. Results The uncontrolled immunethrombosis caused by Hcov infections was related to cytokine storm, formation of neutrophil extracellular traps, excessive activation of the complement system and renin-angiotensin system, oxidative stress of endothelial cells and glycocalyx damage, which were the leading causes of critical illness and death of patients. Conclusion An in-depth study of the pathogenesis of immunethrombosis due to highly pathogenic coronavirus infections and the development and evaluation of potential therapeutic interventions could not only mitigate the acute and long-term consequences of the disease, but also have significant implications for future responses to other emerging and emergent infectious diseases.

Key words: highly pathogenic, coronavirus infection, immune thrombosis, hyperinflammation, endothelial damage, coagulation system activation

中图分类号:

孙绮悦, 郭姗姗, 赵荣华, 包蕾, 耿子涵, 李舒冉, 徐英莉, 张敬升, 崔晓兰, 孙静. 高致病性冠状病毒感染与免疫血栓形成的机制研究进展[J]. 中国药物警戒, 2024, 21(3): 246-252.

SUN Qiyue, GUO Shanshan, ZHAO Ronghua, BAO Lei, GENG Zihan, LI Shuran, XU Yingli, ZHANG Jingsheng, CUI Xiaolan, SUN Jing. Highly pathogenic coronavirus infection and immunothrombosis: research advances[J]. Chinese Journal of Pharmacovigilance, 2024, 21(3): 246-252.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://www.zgywjj.com/CN/10.19803/j.1672-8629.20230464

https://www.zgywjj.com/CN/Y2024/V21/I3/246

参考文献

[1] WEISS SR, LEIBOWITZ JL.Coronavirus pathogenesis[J]. Adv Virus Res, 2011, 59(81): 85-164.
[2] LUO YB, WU Y, LU M, et al.Thoughts on the strategy and mechanism of normalized prevention and control of COVID-19[J]. Public Health and Preventive Medicine(公共卫生与预防医学), 2020, 31(6): 1-5.
[3] GIANNIS D, ZIOGAS IA, GIANNI P.Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past[J]. J Clin Virol, 2020, 23(4): 104362.
[4] ACKERMANN M, VERLEDEN SE, KUEHNEL M, et al.Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19[J]. N Engl J Med, 2020, 383(2): 120-128.
[5] PELLICORI P, DOOLUB G, WONG CM, et al.Novel coronavirus pneumonia and its cardiovascular effects: a systematic review of epidemiological studies[J]. Chinese Journal of Hypertension(中华高血压杂志), 2021, 29(5): 499.
[6] GUAN WJ, Ni ZY, HU Y, et al.Clinical characteristics of coronavirus disease 2019 in China[J]. N Engl J Med, 2020, 382(18): 1708-1720.
[7] DI MINNO A, AMBROSINO P, CALCATERRA I, et al.COVID-19 and venous thromboembolism: a meta-analysis of literature studies[J]. Semin Thromb Hemost, 2020, 46(7): 763-771.
[8] LI Y, LI M, WANG M, et al.Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study[J].Stroke Vasc Neurol, 2020, 5(3): 279-284.
[9] UMAPATHI T, KOR AC, VENKETASUBRAMANIAN N, et al.Large artery ischaemic stroke in severe acute respiratory syndrome (SARS)[J]. J Neurol, 2004, 251(10): 1227-1231.
[10] ASSIRI A, ALTAWFIQ JA, ALRABEEAH AA, et al.Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study[J]. Lancet Infect Dis, 2013, 13(9): 752-761.
[11] CAMPOROTA L, CRONIN JN, BUSANA M, et al.Pathophysiology of coronavirus-19 disease acute lung injury[J]. Curr Opin Crit Care, 2022, 28(1): 9-16.
[12] LIM MS, MCRAE S.COVID-19 and immunothrombosis: Pathophysiology and therapeutic implications[J]. Crit Rev Oncol Hematol, 2021, 168: 103529.
[13] MARUHASHI T, HIGASHI Y.Pathophysiological association of endothelial dysfunction with fatal outcome in COVID-19[J]. Int J Mol Sci, 2021, 22(10): 5131.
[14] BOSCHI C, SCHEIM DE, BANCOD A, et al.SARS-CoV-2 spike protein induces hemagglutination: implications for COVID-19 morbidities and therapeutics and for vaccine adverse effects[J]. Int J Mol Sci, 2022, 23(24): 15480.
[15] HAO W, MA B, LI Z, et al.Binding of the SARS-CoV-2 spike protein to glycans[J]. Sci Bull (Beijing), 2021, 66(12): 1205-1214.
[16] REZAIE AR.Protease-activated receptor signalling by coagulation proteases in endothelial cells[J]. Thromb Haemost, 2014, 112(5): 876-882.
[17] VERAS FP, PONTELLI MC, SILVA CM, et al.SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology[J]. J Exp Med, 2020, 217(12): e20201129.
[18] FUCHS TA, BRILL A, DUERSCHMIED D, et al.Extracellular DNA traps promote thrombosis[J]. Proc Natl Acad Sci USA, 2010, 107(36): 15880-15885.
[19] LO MW, KEMPER C, WOODRUFF TM.COVID-19: complement, coagulation, and collateral Damage[J]. J Immunol, 2020, 205(6): 1488-1495.
[20] SUBRAMANIAM S, JURK K, HOBOHM L, et al.Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development[J]. Blood, 2017, 129(16): 2291-2302.
[21] WOJTA J, HUBER K, VALENT P.New aspects in thrombotic research: complement induced switch in mast cells from a profibrinolytic to a prothrombotic phenotype[J]. Pathophysiol Haemost Thromb, 2003, 33(5-6): 438-441.
[22] HAMMING I, TIMENS W, BULTHUIS ML, et al.Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis[J]. J Pathol, 2004, 203(2): 631-637.
[23] JARAJAPU YPR.Targeting angiotensin-converting enzyme-2/angiotensin-(1-7)/mas receptor axis in the vascular progenitor cells for cardiovascular diseases[J]. Mol Pharmacol, 2021, 99(1): 29-38.
[24] CUI S, CHEN S, LI X, et al.Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia[J]. J Thromb Haemost, 2020, 18(6): 1421-1424.
[25] VARGA Z, FLAMMER AJ, STEIGER P, et al.Endothelial cell infection and endotheliitis in COVID-19[J]. Lancet, 2020, 395(10234): 1417-1418.
[26] ACKERMANN M, VERLEDEN SE, KUEHNEL M, et al.Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19[J]. N Engl J Med, 2020, 383(2): 120-128.
[27] MILLER SE.Visualization of SARS-CoV-2 in the Lung[J]. N Engl J Med , 2020, 383(27):2689.
[28] PATEL BV, ARACHCHILLAGE DJ, RIDGE CA, et al.Pulmonary angiopathy in severe COVID-19: physiologic, imaging, and hematologic observations[J]. Am J Respir Crit Care Med, 2020, 202(5): 690-699.
[29] PERICO L, MORIGI M, GALBUSERA M, et al.SARS-CoV-2 spike protein 1 activates microvascular endothelial cells and complement system leading to platelet aggregation[J]. Front Immunol, 2022, 13: 827146.
[30] ZUCHI C, TRITTO I, CARLUCCIO E, et al.Role of endothelial dysfunction in heart failure[J]. Heart Fail Rev, 2020, 25(1): 21-30.
[31] ZHOU Z, CONNELL MC, MACEWAN DJ.TNFR1-induced NF-kappaB, but not ERK, p38 MAPK or JNK activation, mediates TNF-induced ICAM-1 and VCAM-1 expression on endothelial cells[J]. Cell Signal, 2007, 19(6): 1238-1248.
[32] ZHANG G, QIN Q, ZHANG C, et al.NDRG1 signaling is essential for endothelial inflammation and vascular remodeling[J]. Circ Res, 2023, 132(3): 306-319.
[33] BECKMAN JD, DASILVA A, ARONOVICH E, et al.JAK-STAT inhibition reduces endothelial prothrombotic activation and leukocyte-endothelial proadhesive interactions[J]. J Thromb Haemost, 2023, 21(5): 1366-1380.
[34] DING HM, LI YJ, HUA XQ, et al.Research progress on the mechanism of ischemic stroke caused by SARS-CoV-2[J]. Chinese Journal of Virology(病毒学报), 2023, 39(1): 231-237.
[35] JIN Q, SU H, YANG R, et al.C1q/TNF-related protein-9 ameliorates hypoxia-induced pulmonary hypertension by regulating secretion of endothelin-1 and nitric oxide mediated by AMPK in rats[J]. Sci Rep, 2021, 11(1): 11372.
[36] PATTERSON EK, CEPINSKAS G, FRASER DD.Endothelial glycocalyx degradation in critical illness and injury[J]. Front Med (Lausanne), 2022, 9: 898592.
[37] MYLVAGANAM S, PLUMB J, YUSUF B, et al.The spectrin cytoskeleton integrates endothelial mechanoresponses[J]. Nat Cell Biol, 2022, 24(8): 1226-1238.
[38] YAMAOKA-TOJO M.Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19[J]. Biomed J, 2020, 43(5): 399-413.
[39] KOUPENOVA M, CORKREY HA, VITSEVA O, et al.The role of platelets in mediating a response to human influenza infection[J]. Nat Commun, 2019, 10(1): 1780.
[40] COLLING ME, TOURDOT BE, KANTHI Y.Inflammation, infection and venous thromboembolism[J]. Circ Res, 2021, 128(12): 2017-2036.
[41] MANNE BK, DENORME F, MIDDLETON EA, et al.Platelet gene expression and function in patients with COVID-19[J]. Blood, 2020, 136(11): 1317-1329.
[42] ZOU Z, YANG Y, CHEN J, et al.Prognostic factors for severe acute respiratory syndrome: a clinical analysis of 165 cases[J]. Clin Infect Dis, 2004, 38(4): 483-489.
[43] KOUPENOVA M, CORKREY HA, VITSEVA O, et al.The role of platelets in mediating a response to human influenza infection[J]. Nat Commun, 2019, 10(1): 1780.
[44] SKENDROS P, MITSIOS A,CHRYSANTHOPOULOU A, et al.Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis[J]. J Clin Invest, 2020, 130(11): 6151-6157.
[45] RUAN CC, GE Q, LI Y, et al.Complement-mediated macrophage polarization in perivascular adipose tissue contributes to vascular injury in deoxycorticosterone acetate-salt mice[J]. Arterioscler Thromb Vasc Biol, 2015, 35(3): 598-606.
[46] ISRAELOW B, SONG E, MAO T, et al.Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling[J]. JExp Med, 2020,125(12): 20201241.
[47] BRUMBACK BD, DMYTRENKO O, ROBINSON AN, et al.Human cardiac pericytes are susceptible to SARS-CoV-2 infection[J]. JACC Basic Transl Sci, 2023, 8(2): 109-120.
[48] ZHANG L, LI YH, KIBLER K, et al.Viral anti-inflammatory serpin reduces immuno-coagulopathic pathology in SARS-CoV-2 mouse models of infection[J]. EMBO Mol Med, 2023, 15(9): e17376.
[49] SEFIK E, ISRAELOW B, MIRZA H, et al.A humanized mouse model of chronic COVID-19[J]. Nat Biotechnol, 2022, 40(6): 906-920.