張 倩,劉江寧,秦 川
(北京協(xié)和醫(yī)學院比較醫(yī)學中心 中國醫(yī)學科學院醫(yī)學實驗動物研究所,衛(wèi)生部人類疾病比較醫(yī)學重點實驗室,北京 100021)
乙型病毒性肝炎動物模型的比較分析
張 倩,劉江寧,秦 川
(北京協(xié)和醫(yī)學院比較醫(yī)學中心 中國醫(yī)學科學院醫(yī)學實驗動物研究所,衛(wèi)生部人類疾病比較醫(yī)學重點實驗室,北京 100021)
全世界有近2.4億慢性乙型病毒性肝炎(HBV)患者,盡管已有HBV疫苗和抗病毒治療藥物的產(chǎn)生,但乙肝仍是嚴重威脅人類健康的傳染病。由于缺乏理想的動物模型,使得對于乙型病毒性肝炎的研究受到局限。本綜述按照現(xiàn)有HBV動物模型進行對比分析,探討各種模型病原學和病理與病理生理學應(yīng)用的區(qū)別,以期為科研人員在今后的HBV研究中更好的利用相關(guān)資源,提供參考。
乙型病毒性肝炎;動物模型;病原學;病理與病理生理學
全世界約有2.4億慢性乙型病毒性肝炎患者,其中15%~40%很有可能發(fā)展成嚴重的肝臟疾病,如肝硬化、肝細胞肝癌。每年有超過78萬人因此失去生命。盡管已有HBV疫苗和抗病毒治療藥物的產(chǎn)生,但乙肝仍是嚴重威脅人類健康的傳染病。HBV感染和復(fù)制并不能直接損傷肝臟細胞,臨床癥狀由宿主免疫反應(yīng)和病毒復(fù)雜的相互作用起引起[1-3],從而導致肝硬化和肝癌的發(fā)生[4]。由于HBV宿主的局限性,目前仍沒有理想的HBV動物模型用于研究HBV與宿主之間如何相互作用從而導致慢性感染[5]。同時關(guān)于慢性感染如何導致肝臟損傷,肝硬化和肝細胞肝癌的機制,目前并不十分清楚。本綜述對現(xiàn)有的HBV動物模型,根據(jù)其感染的病原種類,導致的病生理變化,發(fā)展成為肝癌的情況分別進行介紹,探討各種模型的應(yīng)用比較,以使科研人員在今后的HBV研究中更好的利用相關(guān)資源,提供參考。
我們把現(xiàn)有的HBV動物模型分為3類,(1) 直接感染HBV動物模型,如:黑猩猩、樹鼩,同時對小鼠進行了改造,把人的肝細胞移植到小鼠肝臟上,使得可以直接感染HBV的人源化肝臟嵌合體小鼠模型等;(2) HBV類似病毒的動物模型,如:土撥鼠肝炎病毒模型、鴨肝炎病毒模型等;(3) HBV DNA轉(zhuǎn)染小鼠模型,如:水流動力學轉(zhuǎn)染HBV基因組小鼠模型等(表1)。
HBV的感染和復(fù)制并不能直接造成肝臟細胞的損傷,肝臟病變是由于病毒與機體的免疫相互作用導致。對表現(xiàn)出急、慢性肝炎的一些病理與病理生理上變化的HBV動物模型進行歸類比較(表2)。
根據(jù)動物模型的應(yīng)用范圍,比較其優(yōu)缺點,對各種模型的應(yīng)用進行分析討論,從而為科學研究提供一定的參考(表3)。
表1 病原學特征比較
表2 病理與病理生理學特征比較
表3 各類模型的應(yīng)用比較
在疾病的研究中,理想的HBV感染動物模型,至少應(yīng)具備兩個基本條件:(1)HBV在肝臟細胞內(nèi)保持高水平的復(fù)制;(2)能模擬HBV感染人的病理過程,也就是伴有持續(xù)性HBV感染及相應(yīng)的病理變化特征[26]。由于HBV嚴格種屬特異性的特點,導致一直缺乏合適的HBV體內(nèi)感染的實驗?zāi)P?,使得HBV的相關(guān)基礎(chǔ)和臨床研究不能得到很好發(fā)展。雖然小鼠不是HBV天然宿主,但經(jīng)改造,可達到讓小鼠感染HBV的目的。此綜述從3個不同角度對HBV感染模型進行比較闡述,在模型的使用中既要考慮到適用性,也要考慮到課題組的實用性。我國是乙肝大國,對于建立HBV更理想的動物模型一直在不懈的研究和探索,NTCP受體的發(fā)現(xiàn),給轉(zhuǎn)基因小鼠打開了另一扇窗,在不久的將來,一定會出現(xiàn)合適的模型,讓我們?nèi)スタ薍BV。
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Comparative analysis of animal models of hepatitis B viral hepatitis
ZHANG Qian,LIU Jiang-ning,QIN Chuan
(Comparative Medicine Center, Peking Union Medical College (PUMC); Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS); Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing 100021, China)
There are approximately 240 million patients with chronic hepatitis B virus (HBV) in the world. Despite the production of HBV vaccines and antiviral drugs, HBV still remains a serious threat as an infectious disease to human health. Due to the lack of an ideal animal model, the study of HBV is limited. This review was to analyze in accordance with existing HBV animal model, to explore the differences in applications of various models regarding their etiology, pathology and pathophysiology. thus, to provide a reference for researchers in future HBV research to better use the resources.
Hepatitis B virus; Animal model; Etiology; Pathology; Pathophysiology
艾滋病、病毒性肝炎、結(jié)核病及其他新發(fā)突發(fā)傳染病實驗動物的研究專項,編號:(2012ZX10004501)。
張倩,女,博士研究生,研究方向:病理學與病理生理學,傳染性疾病與動物模型的研究。E-mail: zhangqianbisheng@163.com。
秦川,女,研究院,教授,博士生導師,研究方向:病理學與病理生理學。Email: qinchuan@pumc.edu.cn。
綜述與專論
R-33
A
1671-7856(2017) 06-0072-05
10.3969.j.issn.1671-7856. 2017.06.015
2016-09-30