Guan G W, Gao L, Wang J W, Wen X J, Mao T H, Peng S W, Zhang T, Chen X M, Lu F M
Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Hepatology Institute, Peking University People's Hospital, Beijing 100044, China.
Zhonghua Gan Zang Bing Za Zhi. 2020 Feb 20;28(2):100-106. doi: 10.3760/cma.j.issn.1007-3418.2020.02.002.
To explore and analyze the possible mechanism of liver injury in patients with coronavirus disease 2019 (novel coronavirus pneumonia, NCP). The correlation between ALT, AST and other liver enzyme changes condition and NCP patients' disease status reported in the literature was comprehensively analyzed. ACE2 expression in liver tissue for novel coronavirus was analyzed based on single cell sequencing (GSE115469) data. RNA-Seq method was used to analyze Ace2 expression and transcription factors related to its expression in liver tissues at various time-points after hepatectomy in mouse model of acute liver injury with partial hepatectomy. -test or Spearman rank correlation analysis was used for statistical analysis. ALT and AST were abnormally elevated in some patients with novel coronavirus infection, and the rate and extent of ALT and AST elevation in severe NCP patients were higher than those in non-severe patients. Liver tissue results of single cell sequencing and immunohistochemistry showed that ACE2 was only expressed in bile duct epithelial cells of normal liver tissues, and very low in hepatocytes. In a mouse model of acute liver injury with partial hepatectomy, Ace2 expression was down-regulated on the first day, but it was elevated up to twice of the normal level on the third day, and returned to normal level on seventh day when the liver recovered and hepatocyte proliferation stopped. Whether this phenomenon suggests that the bile duct epithelial cells with positive expression of Ace2 participate in the process of liver regeneration after partial hepatectomy deserves further study. In RNA-Seq data, 77 transcription factors were positively correlated with the expression of Ace2 ( > 0.2, FDR < 0.05), which were mainly enriched in the development, differentiation, morphogenesis and cell proliferation of glandular epithelial cells. We assumed that in addition to the over activated inflammatory response in patients with NCP, the up-regulation of ACE2 expression in liver tissue caused by compensatory proliferation of hepatocytes derived from bile duct epithelial cells may also be the possible mechanism of liver tissue injury caused by 2019 novel coronavirus infection.
探索并分析2019冠状病毒病(新型冠状病毒肺炎,NCP)患者肝损伤的可能机制。综合分析文献报道的谷丙转氨酶(ALT)、谷草转氨酶(AST)等肝酶变化情况与NCP患者病情状态之间的相关性。基于单细胞测序(GSE115469)数据,分析新型冠状病毒在肝组织中的血管紧张素转换酶2(ACE2)表达情况。采用RNA测序方法分析部分肝切除急性肝损伤小鼠模型肝组织在肝切除术后不同时间点Ace2的表达及其相关转录因子。采用t检验或Spearman秩相关分析进行统计学分析。部分新型冠状病毒感染患者ALT和AST异常升高,重症NCP患者ALT和AST升高的发生率及幅度高于非重症患者。单细胞测序和免疫组化的肝组织结果显示,ACE2仅在正常肝组织的胆管上皮细胞中表达,在肝细胞中表达极低。在部分肝切除急性肝损伤小鼠模型中,Ace2表达在第一天下调,但在第三天升高至正常水平的两倍,在第七天肝脏恢复且肝细胞增殖停止时恢复至正常水平。这种现象是否提示Ace2阳性表达的胆管上皮细胞参与了部分肝切除术后的肝再生过程值得进一步研究。在RNA测序数据中,77个转录因子与Ace2的表达呈正相关(r>0.2,FDR<0.05),主要富集于腺上皮细胞的发育、分化、形态发生和细胞增殖。我们推测,除了NCP患者过度激活的炎症反应外,胆管上皮细胞来源的肝细胞代偿性增殖导致肝组织中ACE2表达上调也可能是2019新型冠状病毒感染引起肝组织损伤的可能机制。