修回日期: 2013-01-30
接受日期: 2013-02-21
在线出版日期: 2013-03-08
溃疡性结肠炎(ulcerative colitis, UC)是一种主要局限于大肠黏膜和黏膜下层的慢性非特异性炎症性疾病, 呈反复发作, 临床表现主要为腹痛、腹泻、黏液脓血便. 有资料统计, 该病发病率和患病率在我国有明显增加趋势. 但其确切病因和发病机制至今仍未阐明, 治疗上也缺乏特异有效的药物. 建立理想的, 模拟人类溃疡性结肠炎的动物模型是非常重要的, 因其对于UC病因、发病机制和新的治疗药物探讨有着重要意义. 本文主要对近年来溃疡性结肠炎的几种动物模型进行述评.
引文著录: 罗凤燕, 白爱平. 溃疡性结肠炎动物模型的研究进展. 世界华人消化杂志 2013; 21(7): 607-613
Revised: January 30, 2013
Accepted: February 21, 2013
Published online: March 8, 2013
Ulcerative colitis (UC) is a chronic, recurrent inflammatory disease of the colon, characterized clinically by bloody diarrhea and abdominal pain. UC has been a clinical challenge due to its increasing incidence and prevalence, unknown etiology and pathogenesis, and the lack of effective treatment. Animal models have been widely used to investigate the pathogenesis of various diseases. So far, many animal models of UC have been developed, which play a crucial role in studying the pathogenesis of UC and finding new potential treatments. This article reviews the recent progress in the development of animal models of UC.
- Citation: Luo FY, Bai AP. Animal models of ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2013; 21(7): 607-613
- URL: https://www.wjgnet.com/1009-3079/full/v21/i7/607.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i7.607
溃疡性结肠炎(ulcerative colitis, UC)是一种病因未明的直肠和结肠炎症, 呈反复发作, 主要局限于大肠黏膜和黏膜下层, 属于炎症性肠病(inflammatory bowel disease, IBD)一种. 有报告指出该病发病率和患病率在我国呈逐年上升趋势[1]. 目前认为UC可能机制是在肠腔内抗原诱导下遗传易感患者免疫反应过度激活引起的[2]. UC患者肠道菌群失调, 肠腔内致病菌和条件致病菌增多, 且肠黏膜通透性增加, 导致肠腔内细菌及/或细菌产物向黏膜固有层移位, 引起免疫细胞的激活及炎症反应[3]. UC临床表现主要为腹痛、腹泻、黏液脓血便等, 内镜下结肠呈糜烂、溃疡等弥漫性炎症, 组织病理学表现为黏膜或黏膜下弥漫性炎症反应、杯状细胞减少、隐窝结构破坏[4,5]. 目前认为UC为复合性Th细胞反应, 以Th2为主[6]. 迄今UC确切病因及发病机制仍未明了. 由于UC人体研究的局限, 因此建立理想动物模型对于该病病因、发病机制及新的治疗方案的研究是非常重要的. 本文对化学诱导、基因敲除、转基因和自发性溃疡性结肠炎几种动物模型进行综述.
化学法诱导的UC因其制作简单、重复性好、费用较少, 在实际研究应用较为广泛. 其最大不足就是病变主要为急性炎症性反应, 一般不具有UC慢性反复发作特点. 主要应用于溃疡性结肠炎新药的研发, 也可应用于UC发病机制研究.
目前主要的大鼠乙酸模型方法如下[7]: 乙醚麻醉Wistar大鼠, 将聚乙烯导管从肛门插入结肠8 cm处, 缓慢注入3%乙酸2 mL, 并保持仰卧头下脚上的位置30 s, 以防止结肠内液体流出. 小鼠模型如下[8]: 昆明种小鼠禁食12 h后, 5%乙酸0.2 mL经直径1 mm灌肠器注入距肛门约3.5 cm近端结肠处, 20 s后, 注入生理盐水1 mL冲洗管腔. 造模后出现腹泻、血便, 第3天病变达高峰期, 病变以远端结肠为主. 组织病理学表现也类似于人类UC, 主要表现为上皮细胞坏死, 黏膜下水肿, 出血及中性粒细胞浸润.
乙酸结肠炎模型是常用的UC模型之一, 机制可能与利用乙酸的化学刺激造成结肠上皮细胞凋亡、黏膜屏障结构破坏, 使肠黏膜通透性增加, 诱导炎症细胞浸润、炎症介质的表达[肿瘤坏死因子(tumor necrosis factor, TNF)、白介素-6(interleukin-6, IL-6)等][7]. 该法简单易行、成本低、稳定可靠、周期短、成功率高、重复性好, 适合用于新药的开发和疗效评估. 但该模型的不足之处在于乙酸直接刺激造成结肠灼伤, 不能反映人UC的免疫和遗传机制, 且病变进展和愈合迅速. 不适于观察时间较长的药物疗效.
DSS结肠炎模型分为急性和慢性模型. 急性DSS模型的常见诱导方法[9]为自由饮用含3%-5%DSS蒸馏水5-7 d, 小鼠即出现体质量下降和便血等表现, 体质量下降在给予DSS后第4天开始明显下降, 在第7天和第8天达到最低. 急性期模型结肠炎病变以直肠、乙状结肠最为明显, 光镜下病理表现为隐窝破坏, 上皮细胞损伤, 黏膜及黏膜下主要以中性粒细胞浸润为主, 溃疡形成. 慢性DSS模型的常见诱导方法[10]是给予动物自由饮含3%-5%DSS蒸馏水, 连续5 d后改为饮用正常水10 d, 此为一个循环, 3个循环后即可转变为溃疡性结肠炎慢性期. 慢性期病理表现为灶性小溃疡, 分化隐窝减少, 广泛隐窝脓肿形成, 以淋巴细胞、单核细胞为主的慢性炎症细胞浸润, 上皮呈过度增生. DSS结肠炎模型的机制可能与DSS破坏肠黏膜屏障, 导致肠道菌群向黏膜固有层移位, 诱导巨噬细胞过度激活[11], 并导致Th1/Th2/Th17细胞功能失调[10].
DSS急性结肠炎模型也是常用的结肠炎模型之一, 因其制备简单、成功率高, 且与人类UC病变相似, 是研究UC发病机制和评估药物疗效较为理想的模型. 但不足之处在于其黏膜病变为急性化学损伤所诱导, 而并非自发的慢性炎症, 且动物饮水量不能精确控制, 可能导致小鼠间病变差异较大. 慢性DSS模型可用于UC相关结肠癌的研究[12], 是UC相关结肠癌较为理想的模型.
大鼠TNBS模型的制备方法为[13,14], 异戊巴比妥麻醉Wistar大鼠后, 将钝头导管从肛门插至距肛门8 cm处, 按80 mg/kg TNBS(20 mg TNBS溶解于50%乙醇1 mL, 4 mL/kg大鼠体质量)缓慢灌肠, 诱导急性结肠炎. 15 d后再次给予30 mg/kg TNBS溶液(20 mg TNBS溶解于500 mL/L乙醇1 mL, 1.5 mL/kg)灌肠, 造成复发性结肠炎. 第一次TNBS诱导时大鼠快速发展成严重结肠炎, 其典型症状包括腹泻、血便、体质量明显下降、活动减少. 第2周大鼠腹泻改善, 饮食增加. 第2次TNBS灌肠后, 上述症状再次出现. 急性小鼠TNBS模型的诱导方法[15]为, 小鼠麻醉后, 将2.5 mg TNBS溶解于500 mL/L乙醇缓慢灌肠, 每只小鼠量为0.1 mL. 复发性小鼠TNBS模型常见诱导方法[15]是将0.50、0.75、1.00、1.25、1.50 mg TNBS溶于500 mL/L乙醇中, 然后分别在第1、8、15、22、29天给予每只小鼠0.1 mL. 上述TNBS结肠炎模型的病理学改变为结肠炎黏膜灶性溃疡形成, 杯状细胞及隐窝细胞减少, 炎性细胞浸润.
TNBS结肠炎模型机制为, TNBS作为半抗原, 与肠组织蛋白结合形成完全抗原, 导致肠黏膜免疫反应的发生, 造成肠黏膜的损伤. TNBS诱导的结肠炎其免疫反应以Th1/Th17反应为主[16], 有报道[17]整合素a1缺陷小鼠TNBS模型的病情较野生小鼠轻, 说明整合素α1β1介导了TNBS模型固有免疫反应的建立. TNBS模型症状和组织学改变与人类UC类似, 可模拟了UC慢性复发性过程, 可用来评估新的治疗方法对人类UC的治疗作用. 然而, 目前普遍认为TNBS模型的Th免疫反应与克罗恩病更加类似, 故多用于克罗恩病的研究.
恶唑酮模型的方法为[18,19], 腹部皮肤剃毛(2 cm×2 cm), 皮肤涂抹200 μL 3%恶唑酮(溶解于无水乙醇中)2 d, 以预先致敏小鼠. 第8天异乙醚麻醉小鼠, 将直径2 mm的硅胶管从肛门插入小鼠肠道约4 cm, 将溶解于50%乙醇的1%恶唑酮150 μL缓慢注入, 完成后倒提鼠尾约30-60 s, 使溶液完全流入肠道充分吸收. 小鼠灌肠后24 h即出现体质量逐渐下降. 镜下表现为上皮细胞缺失、糜烂和浅溃疡形成, 杯状细胞减少, 腺体密度减低. 炎症局限于黏膜和黏膜下层, 黏膜固有层可见多种炎症细胞浸润. 其机制可能是以Th2反应为主, 是由分泌IL-13的NKT细胞所介导的[18]. 恶唑酮诱导的结肠炎较好地复制了人类UC组织病理学表现, 制模简单, 重复性好, 可作为研究UC发病机制和药物疗效的评估, 但因其维持时间短, 自愈性强, 不适合模拟慢性复发性UC的研究.
针对特定基因的缺失或过度表达的基因修饰小鼠是现代医学研究的重要工具. 这些小鼠的表型不仅很好地描述了单个基因在疾病的病理生理中的作用, 也为进一步深入了解特定基因在机体内的功能研究提供了很好的研究方法和模型, 如类风湿性关节炎[20]、阿茨海默症[21]、IBD[22]等. 用基因修饰小鼠所诱导的IBD模型, 是近年来IBD研究的方法学热点, 对于IBD的免疫机制、药物治疗等研究提供了极大的便利, 但其缺点为动物价格昂贵, 基因修饰的技术要求高, 喂养及繁殖条件严格, 目前国内应用相对较少. 下面介绍几种基因修饰模型.
TCR是介导T细胞免疫反应的重要受体, 参与了抗原的识别和递呈[23]. TCR基因缺陷小鼠被广泛用于研究T细胞和肠道细菌抗原在IBD发病中作用的研究[24]. 基因敲除的TCR-α-/-小鼠, 在无致病菌的环境下可自发产生慢性结肠炎, 组织病理学和免疫学特征均与UC类似. 该模型主要是由分泌IL-4的Th2细胞介导的, 对肠道抗原(包括正常细菌和食物)产生免疫反应, 诱导类似UC的病理组织学变化[25,26]. 有文献报道IL-4抗体可抑制TCR-α-/-小鼠结肠炎病情[22]. 另外, 该模型小鼠可暴露于一氧化碳(CO, 香烟的主要成分), 以模拟吸烟等环境因素对人类UC的影响[25]. 该模型为自发性病理机制, 对UC免疫机制的研究提供一定的帮助, 且可模拟环境因素对于人类UC影响.
IL-2主要是由T淋巴细胞产生的, 参与细胞树突状细胞成熟、传统T细胞分化增殖[27]、促进激活B淋巴细胞分化[28], 及诱导调节性T细胞(Treg)的功能[29]. IL-2基因缺陷小鼠可以自发出现类似人类UC的肠道病理变化, 50%IL-2基因缺陷小鼠在4-9周龄时死亡, 剩余的动物则于6-15周龄时发生肠道炎症病变, 症状和组织病理表现与人类UC类似[30]. 给予IL-2则能缓解该模型的病情, 说明IL-2所调节的Treg功能缺陷在该模型结肠炎发病中起重要作用[29,31], 故该模型常被用于Treg诱导及功能的研究.
IL-7表达于T淋巴细胞、骨髓基质细胞和肠道杯状细胞[32]. Watanabe等[33]发现IL-7转基因小鼠过度表达IL-7, 可自发出现急、慢性结肠炎的表现, 切组织病理学改变类似人类UC. 新近学者发现, IL-7及其受体IL-7Ra对于慢性结肠炎的维持起重要作用[34,35], 机制为IL-7通过多种途径促进CD4+效应和记忆T细胞存活, 进而诱发IBD, 如上调Bcl-2和激活JAK/STAT信号通路[36]. 该模型常被用于研究慢性UC的发病机制和药物治疗作用.
T-bet是Th1特异性的转录因子, 调节TH1细胞干扰素-γ(interferon-γ, IFN-γ)的表达[37]及TH2转录因子GATA3的表达[38]. 有学者发现[39], T-bet-/- RAG2-/-缺陷小鼠出现自发性UC表现, 其机制可能为T-bet缺陷的树突状细胞过度产生TNF, 诱导上皮细胞死亡,导致上皮细胞屏障功能受损. 给予TNF中和抗体能阻止上皮细胞的凋亡及该模型炎症反应的发生. 故该模型常被用于研究UC的固有和适应性免疫免疫机制及药物治疗效果.
MDR基因在人类中表现为2种形式: MDR1, MDR2, 而在啮齿动物类动物中已经发现3种MDR基因: MDR1a、MDR1b、MDR2[40]. 人类MDR基因位于第7号染色体(7q21.1)上, 是IBD易感基因位点, 他能够产生P-糖蛋白(P-gp)[41]. Panwala等[42]发现MDR1a缺陷小鼠在无特定病原菌条件下可以出现自发性结肠炎, 20%-25%MDR1a敲除小鼠1周龄时出现稀便、腹泻等表现, 组织病理学改变类似于UC, 表现为上皮细胞增生, 隐窝脓肿、溃疡形成及炎症细胞浸润. 其机制可能与MDR1a基因缺陷使得P-gp产生减少, 导致肠黏膜屏障受损, 渗透性增加,肠道固有层中Foxp3+Treg细胞数减少[43-46]. 该模型常用于UC早期炎症反应机制的研究.
IL-10表达于多种细胞中, 如T细胞, 单核细胞/巨噬细胞, 树突状细胞[47]. IL-10可调节多种免疫细胞的功能, 如T细胞、B细胞、自然杀伤细胞、肥大细胞的分化和增殖[48]. Kühn等[49]发现在清洁环境下饲养, IL-10基因敲除小鼠在7至11周龄时可发生结肠炎, 组织病理学表现为结肠黏膜溃疡、炎症细胞浸润, 肉芽肿形成等; 而在无病原菌的环境中, 这些小鼠的结肠炎发生率较低. 该模型的机制为肠道病菌诱导肠黏膜免疫细胞产生IL-12, 诱导TH1/TH17免疫反应[50], 而Treg的功能受抑制[51]. 给予抗IL-12抗体、抗生素、IL-10等可以预防IL-10基因敲除小鼠结肠炎的发生[52]. 该模型多被用于探讨肠道细菌在IBD发病中的作用, 及肠道免疫细胞的功能研究.
Toll样受体(Toll-like receptors, TLRs)在先天免疫和适应性免疫反应中发挥重要作用, 参与调节细胞增殖、凋亡, 血管生成的过程中的外源性和内源性配体的受体家族, 组织重塑和修复[53]. 有文献报道[53], TLR基因缺陷小鼠35%-40%可自发性发展为结肠炎, 以直肠脱垂、体质量下降、便血为特点, 组织病理上主要表现为炎症细胞浸润, 隐窝上皮破坏, 水肿, 上皮细胞增生等, 其机制可能与对于肠道寄生菌防御减弱, 且促炎因子IL-1β、TNF-α、Th1细胞因子(IFN-γ和IL-12p70)、Th17细胞因子(IL-17和IL-23)表达增多有关.
自然界中, 某些动物能在其生活过程中自发出现与人类UC相似的结肠炎, 这些模型症状和组织病理学表现类似于人类UC, 是研究人类UC较为理想的实验性模型. 但这些自发性动物模型由于这些动物稀少、昂贵且难以进行标准化控制, 目前尚难进行大规模实验及更深入研究.
棉顶绢毛猴是一种濒危灵长类动物, 1岁半至2岁时, 可自发出现类似于人类UC肠道炎症[56], 表现为黏液血便、体质量下降、腹泻等. 组织病理学表现为结肠上皮增生、杯状细胞减少、炎症细胞浸润、隐窝结构缺失等. 该动物结肠炎发病机制仍不清楚. Saunders等[57]认为其可能与尿激酶阴性的螺杆菌属细菌感染有关. 成年棉顶绢毛猴结肠炎呈反复发作, 且结肠炎相关腺癌发病率很高, 可作为结肠炎相关癌研究的理想模型.
C3H/He J小鼠一般在出生后2-4 wk出现黏液血便、体质量下降、腹泻等表现, 该模型特点为病变部位位于右半结肠的炎症, 呈自发性和慢性发作, 组织病理学表现与人类UC类似, 幽门螺杆菌感染可能与该模型结肠炎发病有一定相关性[58].
上述模型各有其优缺点, 但都只在某些病理学改变等方面与UC类似, 尚难成为研究UC的理想模型. UC病因及发病机制尤其免疫学机制非常复杂、病情迁延, 目前大多数认为人类UC免疫反应以Th2为主, 固有免疫、Th1、Th17等也参与的复合性免疫反应[6]. 目前所建立的动物模型较难反映人类UC的免疫学反应及机制. 目前普遍认为, 理想的IBD动物模型应具备以下特点[59]: (1)其肠道炎症进展、病理生理学改变与IBD类似; (2)实验动物须具备明确的遗传背景, 很好地反映出人与肠道菌群的互动; (3)特定抗原能诱导相应的肠道免疫反应, 具有很好的可重复性; (4)传统的IBD治疗方法对所诱导的模型有效; (5)肠道炎症应为自发性的, 而非经基因修饰或化学处理所引起. 很好的动物模型能为我们从不同角度探讨人类UC的病因、发病机制、及治疗药物的疗效探讨提供便利.
溃疡性结肠炎(UC)是遗传易感者在一定环境因素及肠腔内抗原诱导下所发生的慢性非特异性免疫反应. 今年来发病率逐渐升高, 已成为临床研究重点之一. 由于人体实验的限制, 建立理想的UC动物模型对于其病因、发病机制、诊断与治疗的研究具有重要意义.
陆伦根, 教授, 上海交通大学附属第一人民医院消化科
对于UC动物模型研究迄今已有一百余年, 但仍没有一种模型能够很好地模拟其发病机制, UC基因修饰模型仍需进一步研究.
本文概括了几种动物模型, 从不同角度阐述了UC发病机制、组织病理学特点.
基因工程实验动物的遗传背景定义清晰, 免疫特点突出, 便于制定确认造模成功或干预有效的标准.
溃疡性结肠炎: 也称非特异性溃疡性结肠炎, 发病原因尚不明确, 为一种自体免疫性疾病. 病灶局限于结肠黏膜及黏膜下层, 多位于乙状结肠和直肠, 也可延伸至降结肠, 甚至整个结肠. UC免疫反应以Th2为主, 固有免疫、Th1、Th17等也参与的复合性免疫反应.
本文所涉及的模型从不同角度模拟人类UC的发病机制或病理特征, 具有一定指导意义.
编辑: 田滢 电编: 鲁亚静
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