PDF(1805 KB)
SARS-CoV-2感染的年龄分布与肺部ACE2表达的关系——源自小鼠不同发育阶段RAS通路表达情况的思考
娄丽丽, 谢亮, 胡煜, 陈莉娜, 梁萍, 石芳, 刘才俊, 刘瀚旻
中国当代儿科杂志 ›› 2020, Vol. 22 ›› Issue (10) : 1119-1124.
PDF(1805 KB)
PDF(1805 KB)
SARS-CoV-2感染的年龄分布与肺部ACE2表达的关系——源自小鼠不同发育阶段RAS通路表达情况的思考
Association of age distribution with the expression of angiotensin-converting enzyme 2 in lung tissues in severe acute respiratory syndrome coronavirus 2 infection: reflections from the study of RAS pathway expression in mice
目的 探讨正常小鼠在发育不同时期血管紧张素转换酶2（ACE2）及RAS通路其他关键分子的表达情况，为儿童2019冠状病毒病（COVID-19）的感染机制及诊治提供思路。方法 将不同发育阶段的小鼠按日龄分为胎鼠（孕14.5 d、孕18.5 d）、新生鼠（生后第0、3、7、14、21天）、幼鼠（生后第28、42天）、成年鼠（生后第84天）10个组，胎鼠组每个时间点取4只孕鼠的所有胎鼠肺组织，其余时间点每组取4只小鼠，采用全转录组测序法检测小鼠肺组织中AGT、ACE、ACE2、Renin、Agtr1a、Agtr1b、Agtr2、Mas1基因的表达情况。结果 ACE2在小鼠胚胎期到成年期肺部表达有一定变化趋势，于生后逐渐上升并在第3天达峰，随后下降（P < 0.05），第14天到达表达低点后又上升；AGT表达水平在小鼠生后第0天及生后第7天呈双峰表达，于出生后第21天降至低值（P < 0.05）；ACE表达量在小鼠生后迅速升高，至生后第21天达峰（P < 0.05）；Agtr1a表达量于小鼠生后第21天达峰（P < 0.05）；Agtr2在小鼠出生后逐渐下降呈低水平表达；Renin、Agtr1b、Mas1在不同时期小鼠肺组织中均呈低水平表达。结论 在小鼠不同发育阶段，ACE2存在动态表达变化，其在早期新生鼠及成年鼠肺部表达量较高，同时RAS通路中其他关键分子也各有其表达趋势。提示COVID-19儿童患者临床特点不同于成人患者这一现象与不同时期ACE2表达水平可能存在一定的相关性，具体作用机制需进一步研究。
Objective To study the expression of angiotensin-converting enzyme 2 (ACE2) and other key molecules of the RAS pathway in normal mice at different developmental stages, and to provide ideas for understanding the infection mechanism of coronavirus disease 2019 (COVID-19) as well as the diagnosis and treatment of children with COVID-19. Methods The mice at different developmental stages were enrolled, including fetal mice (embryonic days 14.5 and 18.5), neonatal mice (0, 3, 7, 14, and 21 days old), young mice (28 and 42 days old), and adult mice (84 days old). The lung tissues of all fetal mice from 4 pregnant mice were collected at each time point in the fetal group. Four mice were sampled in other age groups at each time point. Whole transcriptome resequencing was used to measure the mRNA expression of AGT, ACE, ACE2, Renin, Agtr1a, Agtr1b, Agtr2, and Mas1 in mouse lung tissue. Results The expression of ACE2 in the lungs showed changes from embryonic stage to adult stage. It increased gradually after birth, reached a peak on day 3 after birth, and reached a nadir on day 14 after birth (P < 0.05). The expression of AGT reached a peak on days 0 and 7 after birth and reached a nadir on day 21 after birth (P < 0.05). The expression of ACE increased rapidly after birth and reached a peak on day 21 after birth (P < 0.05). Agtr1a expression reached a peak on day 21 after birth (P < 0.05). Agtr2 expression gradually decreased to a low level after birth. Renin, Agtr1b, and Mas1 showed low expression in lung tissues at all developmental stages. Conclusions At different developmental stages of mice, ACE2 has dynamic expression changes, with high expression in early neonatal and adult mice. The other key molecules of the RAS pathway have their own expression patterns. These suggest that the difference in clinical features between children and adults with COVID-19 might be associated with the different expression levels of ACE2 in the different stages, and further studies are needed for the mechanism.
2019冠状病毒病 / 严重急性呼吸综合征冠状病毒2 / 血管紧张素转换酶2 / 小鼠
Coronavirus disease 2019 / Severe acute respiratory syndrome coronavirus 2 / Angiotensin-converting enzyme 2 / Mice
[1] COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU)[EB/OL].[2020-09-15]. https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6.
[2] 中华人民共和国国家卫生健康委员会疾病预防控制局. 《中国-世界卫生组织新型冠状病毒肺炎(COVID-19)联合考察报告》发布[EB/OL]. (2020-02-29)[2020-03-05]. http://www.nhc.gov.cn/jkj/s3578/202002/87fd92510d094e4b9bad597608f5cc2c.shtml.
[3] 杨斌斌, 朱月玲. 儿童与成人新型冠状病毒肺炎的流行病学与治疗现状分析[J]. 西安交通大学学报(医学版), 2020, 41(4):483-487.
[4] 中华人民共和国国家卫生健康委员会医政医管局. 关于印发新型冠状病毒肺炎诊疗方案(试行第七版)的通知[EB/OL]. (2020-03-04)[2020-03-05]. http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml.
[5] Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China[J]. Pediatrics, 2020, 145(6):e20200702.
[6] She J, Liu L, Liu W. COVID-19 epidemic:disease characteris-tics in children[J]. J Med Virol, 2020, 92(7):747-754.
[7] Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa[J]. Int J Oral Sci, 2020, 12(1):8.
[8] Baig AM, Khaleeq A, Ali U, et al. Evidence of the COVID-19 virus targeting the CNS:tissue distribution, host-virus interaction, and proposed neurotropic mechanisms[J]. ACS Chem Neurosci, 2020, 11(7):995-998.
[9] Kruse RL. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China[J]. F1000Res, 2020, 9:72.
[10] 刘茜, 王荣帅, 屈国强, 等.新型冠状病毒肺炎死亡尸体系统解剖大体观察报告[J]. 法医学杂志, 2020, 36(1):21-23.
[11] Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome[J]. Lancet Respir Med, 2020, 8(4):420-422.
[12] 王一平, 程在玉. 人与小鼠染色体的同源性及遗传病动物模型[J]. 国外医学(遗传学分册), 1988(2):72-75.
[13] Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019[J]. N Engl J Med, 2020, 382(8):727-733.
[14] Wan Y, Shang J, Graham R, et al. Receptor recognition by the novel coronavirus from Wuhan:an analysis based on decade-long structural studies of SARS coronavirus[J]. J Virol, 2020, 94(7):e00127-20.
[15] Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019(COVID-19) outbreak-an update on the status[J]. Mil Med Res, 2020, 7(1):11.
[16] 彭文艺, 甘雪晴, 谭艳, 等. 新型冠状病毒感染性疾病心血管系统损害机制与治疗进展[J]. 中华医院感染学杂志, 2020, 30(8):1177-1182.
[17] Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9[J]. Circ Res, 2000, 87(5):E1-E9.
[18] Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase[J]. J Biol Chem, 2000, 275(43):33238-33243.
[19] Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure[J]. Nature, 2005, 436(7047):112-116.
[20] Boskabadi J, Askari VR, Hosseini M, et al. Immunomodulatory properties of captopril, an ACE inhibitor, on LPS-induced lung inflammation and fibrosis as well as oxidative stress[J]. Inflammopharmacology, 2019, 27(3):639-647.
[21] Yang P, Gu H, Zhao Z, et al. Angiotensin-converting enzyme 2(ACE2) mediates influenza H7N9 virus-induced acute lung injury[J]. Sci Rep, 2014, 4:7027.
[22] Zhang L, Liu Y. Potential interventions for novel coronavirus in China:a systematic review[J]. J Med Virol, 2020, 92(5):479-490.
[23] 孙美丽,杨建民,孙玉萍, 等. RAS抑制剂是治疗新型冠状病毒肺炎的可能选择之一[J]. 中华结核和呼吸杂志, 2020, 43(3):219-222.
[24] Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor[J]. Cell, 2020, 181(2):271-280.e8.
[25] Zhang H, Kang ZJ, Gong HY, et al. Digestive system is a potential route of COVID-19:an analysis of single-cell coexpression pattern of key proteins in viral entry process[J]. Gut, 2020, 69(6):1010-1018.
[26] Chen W, Lan Y, Yuan X, et al. Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity[J]. Emerg Microbes Infect, 2020, 9(1):469-473.
国家重点研发计划（2017YFC0211705）。
