口服食物抗原诱导的类风湿性关节炎动物模型的建立及评价
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摘要
类风湿关节炎(rheumatoid arthritis, RA)是一种以慢性、进行性、侵袭性关节炎为主要表现的全身性自身免疫疾病。如果不经过正规治疗,患者病情会逐渐发展,最终导致关节畸形、功能丧失。RA具有很高的致残率,严重影响患者的健康和生活质量,同时也给患者家庭和社会造成巨大的经济负担。
众多研究已表明食物与RA的发生密切相关。目前通过皮下注射Ⅱ型胶原蛋白诱导的RA模型是最佳的RA实验动物模型。尽管通过注射的方式能成功有效地诱导大鼠产生类风湿关节炎,但皮下注射的诱导方式并不符合人体摄食模式,其忽略了胃肠道在RA发病中的重要性,使RA发病机制的研究出现了一个极为重要的空白点：即食物抗原在人体摄食过程中如何通过肠上皮粘膜屏障进入肠道粘膜固有层,引起肠道相关免疫组织细胞的一系列免疫应答,扰乱肠粘膜免疫组织的固有与适应性免疫反应,并通过分子拟态和旁观者效应打破免疫耐受,进而导致RA发生的机理。为了深入RA发病机制的研究,建立一种与人RA发病机制及病理相同或相似的动物模型(口服食物抗原诱导的RA动物模型)在RA研究中的作用也就显得尤为重要。
目的：
建立口服牛Ⅱ型胶原蛋白诱导的RA大鼠模型；确定口服食物抗原与RA的相关性；并在动物模型的基础上,对肠道通透性在食物抗原诱导的RA发病机理中的作用进行初步探索,为临床RA的预防和治疗提供理论依据。
方法：
本研究选择Wistar大鼠作为实验动物。从牛软骨中提取牛Ⅱ型胶原蛋白,先用阿司匹林破坏大鼠的肠道粘膜屏障功能,然后灌胃给予大鼠较大剂量的牛Ⅱ型胶原蛋白,诱导大鼠类风湿关节炎的发生。将4-5周龄雌性Wistar大鼠随机分成四组：对照组(生理盐水；生理盐水)、M1组(生理盐水；生理盐水+CC14+LPS)、M2组(5mg/kg阿司匹林；牛Ⅱ型胶原蛋白+CC14+LPS)、M3组(10mg/kg阿司匹林；牛Ⅱ型胶原蛋白+CC14+LPS)。在阿司匹林灌胃期间,每七天灌胃给予大鼠一定量的乳果糖和甘露醇,用代谢笼收集大鼠24h尿,高效液相色谱仪(HPLC)检测并计算乳果糖、甘露醇比值(L/M),并将M2组、M3组与对照组相比,间接评价大鼠肠道通透性的变化情况。建模过程中,用游标卡尺测量并记录大鼠右后腿踝关节的直径,两周一次,一共5次,并进行关节指数(AI)评定。建模结束后,取大鼠血清、空肠组织和踝关节组织。采用双抗体夹心ELISA法测定各组大鼠血清中牛Ⅱ型胶原蛋白特异性抗体水平、细胞因子TNF-a、IFN-r和IL-4水平；将所取实验动物的空肠和踝关节组织用固定液固定后,石蜡包埋切片,苏木素-伊红(HE)染色,光学显微镜下观察其病理形态结构的变化以及淋巴细胞浸润渗透的情况；用荧光免疫组织化学的方法,以小鼠来源的牛Ⅱ型胶原蛋白单克隆抗体作为一抗,以FITC标记的山羊抗小鼠的IgG作为二抗,定位空肠中的牛Ⅱ型胶原蛋白,观察其是否能够通过肠粘膜的屏障从而进入肠道粘膜固有层；用荧光免疫组织化学的方法,以小鼠来源的牛Ⅱ型胶原蛋白单克隆抗体作为一抗,以FITC标记的山羊抗小鼠的IgG作为二抗,定位关节滑膜上的牛Ⅱ型胶原蛋白,观察其在关节滑膜上的沉积情况。通过以上指标对所建立的类风湿关节炎大鼠模型进行综合评价。
结果：
在建模结束后,M2组、M3组大鼠踝关节呈现不同程度的肿胀；M2组、M3组大鼠血清中抗牛Ⅱ型胶原蛋白特异性抗体显著升高(P<0.05),血清中TNF-a和IFN-r水平明显升高(P<0.05),并且IL-4水平明显降低(P<0.05)；M2组、M3组大鼠空肠病理学改变明显：肠粘膜损伤严重,粘膜下层中性粒细胞浸润明显,肠绒毛水肿肥大,肠粘膜上皮细胞广泛脱落等；荧光免疫组化显示未经消化的大分子牛Ⅱ型胶原蛋白透过损伤的肠上皮粘膜屏障进入肠道粘膜固有层；在M2组、M3组大鼠踝关节标本组织学中观察到滑膜组织增生,其局部骨吸收破坏明显,软骨表层胶原纤维松解断裂、软骨细胞变性坏死,软骨表面凸凹不平等；并通过荧光免疫组化的方法观察到M2组、M3组大鼠关节滑膜上牛Ⅱ型胶原蛋白的沉积。双糖实验,M2组、M3组大鼠尿中的甘露醇浓度降低(P<0.05),乳果糖浓度升高(P<0.01),L/M升高(P<0.05),说明M2组、M3组大鼠的肠道通透性增加。
结论：
在肠黏膜损伤的条件下,口服牛Ⅱ型胶原蛋白可成功诱导大鼠产生类风湿关节炎。
Rheumatoid arthritis (RA) is a kind of systemic autoimmune disease with chronic, progressive, and invasive arthritis as its main manifestation. The patients' condition will deteriorate, leading to joint deformity and losing function eventually if they are not be treated regularly. Owing to the high rate of mutilation, RA seriously affects the health and the quality of life of the patients, and causes huge economic burden to patients'families and society.
Many studies have shown that food is closely related to the incidence of RA. Now the RA animal model induced by subcutaneous injection of type II collagen is the best animal model of RA. The subcutaneous injection of type II collagen to rat can successfully induce the occurence of RA, but the induction of subcutaneous injection is incompatible with the pattern of human feeding, because it ignored the importance of gastrointestinal tract in the incident of RA, so a very importan gap appears in the research of pathogenesis of RA:the mechanism how the food antigen pass intestinal epithelium mucous membrane barrier into lamina propria of intestinal mucosa in the process of human feeding, and cause a series of immune responses of gut associated immune cells, and desrupt the inherent and adaptive immune responses of the intestinal mucosal immune tissues, and break immune tolerance by molecular mimicry and bystander effect, leading to the occurence of RA ultimately are remain unclear.
Objectives
The objectives of this study are to establish rat model of RA induced by oralling bovine type II collagen and make sure the relevance of oralling food antigen between RA; On the basis of the animal model, we will preliminarily explore the role of intestinal permeability in the pathogenesis of RA induced by food antigen and provide theoretical basis for clinical prevention and treatment of RA.
Methods
The Wistar rats were selected as experimental animals in this study. The bovine typeⅡcollagen was extract from bovine cartilage. The function of rats'intestinal mucosal barrier was damaged with aspirin first in the experiment, then the rats were fed with larger doses of bovine typeⅡcollagen to induce the occurrence of rheumatoid arthritis. The 4-5 week-old's male Wistar rats were allocated into four groups randomly: control group(physiological saline; physiological saline), group M1 (physiological saline; physiological saline+CCl4+LPS), group M2 (5mg/kg aspirin; bovine type II collagen+CCl4+LPS), and group M3 (10mg/kg aspirin; bovine type II collagen+CCl4+LPS). During the period of aspirin feeding, the rats fed with a certain amount of lactulose and mannitol every seven days, then the rats'24h urinary were collected with metabolic cage, and lactulose and mannitol ratio(L/M) were detected and calculated by high performance liquid chromatography (HPLC), finally the comparisions were done between group M2、group M3 and control groups for evaluating the changes of intestinal permeability indirectly. After modeling, the serum, jejunum tissue and ankle joint tissue were obtained from rats. During the modeling, the diameter of the right hind ankle was measured and recorded with vernier caliper once two weeks, for a total of five times, and the articular index (AI) was assessed; Double antibody ELISA method was used to detected the level of special anti-bovine-type-II-collagen antibody, and the level of TNF-a, IFN-r and IL-4; The the jejunum tissues and the ankle joint tissues were put into fixative, made into paraffin sections, and HE stained; The pathological changes of the structure and the infiltration situation of lymphocytic were observed under light microscope; The method of immunohistochemistry was used to locate the bovine type II collagen in jejunum, in order to observe whether it can pass intestinal epithelium mucous membrane barrier into lamina propria of intestinal mucosa; The method of immunohistochemistry was used to locate the bovine type II collagen on the joint synovial, in order to observe its deposition on joint synovial. The reliability of model-establishing method in this experiment was comprehensively evaluated through the above indicators.
Results
After the modeling, varying degrees of ankle swelling were observed in rats of group M2 and group M3; The level of blood serum anti-CII antibody of group M2 and group M3 had a significant rise compared with cotrol group (P＜0.05), the level of blood serum TNF-a and IFN-r of group M2 and group M3 had a significant rise compared with cotrol group (P<0.05), and the level of blood serum IL-4 of group M2 and group M3 had a significant decline compared with cotrol group (P＜0.05); Pathological changes in jejunum of group M2 and group M3 rats were significant. The changes included that the intestinal mucosa was damaged severely, submucosal neutrophils infiltrated obviously, intestinal villi were dropsical, and intestinal epithelial cells losed widespreadly. It showed that undigested or incompletely digested macromolecules bovine type II collagen can pass intestinal epithelium mucous membrane barrier into lamina propria of intestinal mucosa with immunofluorescence. Synovial hyperplasia of histological specimens of the ankle joint in group M2 and group M3 was observed, the destruction of local bone resorption was obvious, surface collagen fiber of cartilage was released and broken, cartilage cells were degenerated and necrosed, and the surface of cartilage was regged. The study found that bovine type II collagen was deposited on the joints synovial of experimental group rats with immunofluorescence. The study also found that the concentration of mannitol in urine of group M2 and group M3 rats was declined significantly(P<0.05), the concentration of lactulose increased(P<0.05), L/M also increased(P<0.05) with double-sugar tests, which indicated that intestinal permeability of rats in group M2 and group M3 was increased.
Conclusions
The occurence of rheumatoid arthritis in rats can be induced successfully by oralling bovine type II collagen, under the condition of intestinal mucous membrane damaged.
众多研究已表明食物与RA的发生密切相关。目前通过皮下注射Ⅱ型胶原蛋白诱导的RA模型是最佳的RA实验动物模型。尽管通过注射的方式能成功有效地诱导大鼠产生类风湿关节炎,但皮下注射的诱导方式并不符合人体摄食模式,其忽略了胃肠道在RA发病中的重要性,使RA发病机制的研究出现了一个极为重要的空白点：即食物抗原在人体摄食过程中如何通过肠上皮粘膜屏障进入肠道粘膜固有层,引起肠道相关免疫组织细胞的一系列免疫应答,扰乱肠粘膜免疫组织的固有与适应性免疫反应,并通过分子拟态和旁观者效应打破免疫耐受,进而导致RA发生的机理。为了深入RA发病机制的研究,建立一种与人RA发病机制及病理相同或相似的动物模型(口服食物抗原诱导的RA动物模型)在RA研究中的作用也就显得尤为重要。
目的：
建立口服牛Ⅱ型胶原蛋白诱导的RA大鼠模型；确定口服食物抗原与RA的相关性；并在动物模型的基础上,对肠道通透性在食物抗原诱导的RA发病机理中的作用进行初步探索,为临床RA的预防和治疗提供理论依据。
方法：
本研究选择Wistar大鼠作为实验动物。从牛软骨中提取牛Ⅱ型胶原蛋白,先用阿司匹林破坏大鼠的肠道粘膜屏障功能,然后灌胃给予大鼠较大剂量的牛Ⅱ型胶原蛋白,诱导大鼠类风湿关节炎的发生。将4-5周龄雌性Wistar大鼠随机分成四组：对照组(生理盐水；生理盐水)、M1组(生理盐水；生理盐水+CC14+LPS)、M2组(5mg/kg阿司匹林；牛Ⅱ型胶原蛋白+CC14+LPS)、M3组(10mg/kg阿司匹林；牛Ⅱ型胶原蛋白+CC14+LPS)。在阿司匹林灌胃期间,每七天灌胃给予大鼠一定量的乳果糖和甘露醇,用代谢笼收集大鼠24h尿,高效液相色谱仪(HPLC)检测并计算乳果糖、甘露醇比值(L/M),并将M2组、M3组与对照组相比,间接评价大鼠肠道通透性的变化情况。建模过程中,用游标卡尺测量并记录大鼠右后腿踝关节的直径,两周一次,一共5次,并进行关节指数(AI)评定。建模结束后,取大鼠血清、空肠组织和踝关节组织。采用双抗体夹心ELISA法测定各组大鼠血清中牛Ⅱ型胶原蛋白特异性抗体水平、细胞因子TNF-a、IFN-r和IL-4水平；将所取实验动物的空肠和踝关节组织用固定液固定后,石蜡包埋切片,苏木素-伊红(HE)染色,光学显微镜下观察其病理形态结构的变化以及淋巴细胞浸润渗透的情况；用荧光免疫组织化学的方法,以小鼠来源的牛Ⅱ型胶原蛋白单克隆抗体作为一抗,以FITC标记的山羊抗小鼠的IgG作为二抗,定位空肠中的牛Ⅱ型胶原蛋白,观察其是否能够通过肠粘膜的屏障从而进入肠道粘膜固有层；用荧光免疫组织化学的方法,以小鼠来源的牛Ⅱ型胶原蛋白单克隆抗体作为一抗,以FITC标记的山羊抗小鼠的IgG作为二抗,定位关节滑膜上的牛Ⅱ型胶原蛋白,观察其在关节滑膜上的沉积情况。通过以上指标对所建立的类风湿关节炎大鼠模型进行综合评价。
结果：
在建模结束后,M2组、M3组大鼠踝关节呈现不同程度的肿胀；M2组、M3组大鼠血清中抗牛Ⅱ型胶原蛋白特异性抗体显著升高(P<0.05),血清中TNF-a和IFN-r水平明显升高(P<0.05),并且IL-4水平明显降低(P<0.05)；M2组、M3组大鼠空肠病理学改变明显：肠粘膜损伤严重,粘膜下层中性粒细胞浸润明显,肠绒毛水肿肥大,肠粘膜上皮细胞广泛脱落等；荧光免疫组化显示未经消化的大分子牛Ⅱ型胶原蛋白透过损伤的肠上皮粘膜屏障进入肠道粘膜固有层；在M2组、M3组大鼠踝关节标本组织学中观察到滑膜组织增生,其局部骨吸收破坏明显,软骨表层胶原纤维松解断裂、软骨细胞变性坏死,软骨表面凸凹不平等；并通过荧光免疫组化的方法观察到M2组、M3组大鼠关节滑膜上牛Ⅱ型胶原蛋白的沉积。双糖实验,M2组、M3组大鼠尿中的甘露醇浓度降低(P<0.05),乳果糖浓度升高(P<0.01),L/M升高(P<0.05),说明M2组、M3组大鼠的肠道通透性增加。
结论：
在肠黏膜损伤的条件下,口服牛Ⅱ型胶原蛋白可成功诱导大鼠产生类风湿关节炎。
Rheumatoid arthritis (RA) is a kind of systemic autoimmune disease with chronic, progressive, and invasive arthritis as its main manifestation. The patients' condition will deteriorate, leading to joint deformity and losing function eventually if they are not be treated regularly. Owing to the high rate of mutilation, RA seriously affects the health and the quality of life of the patients, and causes huge economic burden to patients'families and society.
Many studies have shown that food is closely related to the incidence of RA. Now the RA animal model induced by subcutaneous injection of type II collagen is the best animal model of RA. The subcutaneous injection of type II collagen to rat can successfully induce the occurence of RA, but the induction of subcutaneous injection is incompatible with the pattern of human feeding, because it ignored the importance of gastrointestinal tract in the incident of RA, so a very importan gap appears in the research of pathogenesis of RA:the mechanism how the food antigen pass intestinal epithelium mucous membrane barrier into lamina propria of intestinal mucosa in the process of human feeding, and cause a series of immune responses of gut associated immune cells, and desrupt the inherent and adaptive immune responses of the intestinal mucosal immune tissues, and break immune tolerance by molecular mimicry and bystander effect, leading to the occurence of RA ultimately are remain unclear.
Objectives
The objectives of this study are to establish rat model of RA induced by oralling bovine type II collagen and make sure the relevance of oralling food antigen between RA; On the basis of the animal model, we will preliminarily explore the role of intestinal permeability in the pathogenesis of RA induced by food antigen and provide theoretical basis for clinical prevention and treatment of RA.
Methods
The Wistar rats were selected as experimental animals in this study. The bovine typeⅡcollagen was extract from bovine cartilage. The function of rats'intestinal mucosal barrier was damaged with aspirin first in the experiment, then the rats were fed with larger doses of bovine typeⅡcollagen to induce the occurrence of rheumatoid arthritis. The 4-5 week-old's male Wistar rats were allocated into four groups randomly: control group(physiological saline; physiological saline), group M1 (physiological saline; physiological saline+CCl4+LPS), group M2 (5mg/kg aspirin; bovine type II collagen+CCl4+LPS), and group M3 (10mg/kg aspirin; bovine type II collagen+CCl4+LPS). During the period of aspirin feeding, the rats fed with a certain amount of lactulose and mannitol every seven days, then the rats'24h urinary were collected with metabolic cage, and lactulose and mannitol ratio(L/M) were detected and calculated by high performance liquid chromatography (HPLC), finally the comparisions were done between group M2、group M3 and control groups for evaluating the changes of intestinal permeability indirectly. After modeling, the serum, jejunum tissue and ankle joint tissue were obtained from rats. During the modeling, the diameter of the right hind ankle was measured and recorded with vernier caliper once two weeks, for a total of five times, and the articular index (AI) was assessed; Double antibody ELISA method was used to detected the level of special anti-bovine-type-II-collagen antibody, and the level of TNF-a, IFN-r and IL-4; The the jejunum tissues and the ankle joint tissues were put into fixative, made into paraffin sections, and HE stained; The pathological changes of the structure and the infiltration situation of lymphocytic were observed under light microscope; The method of immunohistochemistry was used to locate the bovine type II collagen in jejunum, in order to observe whether it can pass intestinal epithelium mucous membrane barrier into lamina propria of intestinal mucosa; The method of immunohistochemistry was used to locate the bovine type II collagen on the joint synovial, in order to observe its deposition on joint synovial. The reliability of model-establishing method in this experiment was comprehensively evaluated through the above indicators.
Results
After the modeling, varying degrees of ankle swelling were observed in rats of group M2 and group M3; The level of blood serum anti-CII antibody of group M2 and group M3 had a significant rise compared with cotrol group (P＜0.05), the level of blood serum TNF-a and IFN-r of group M2 and group M3 had a significant rise compared with cotrol group (P<0.05), and the level of blood serum IL-4 of group M2 and group M3 had a significant decline compared with cotrol group (P＜0.05); Pathological changes in jejunum of group M2 and group M3 rats were significant. The changes included that the intestinal mucosa was damaged severely, submucosal neutrophils infiltrated obviously, intestinal villi were dropsical, and intestinal epithelial cells losed widespreadly. It showed that undigested or incompletely digested macromolecules bovine type II collagen can pass intestinal epithelium mucous membrane barrier into lamina propria of intestinal mucosa with immunofluorescence. Synovial hyperplasia of histological specimens of the ankle joint in group M2 and group M3 was observed, the destruction of local bone resorption was obvious, surface collagen fiber of cartilage was released and broken, cartilage cells were degenerated and necrosed, and the surface of cartilage was regged. The study found that bovine type II collagen was deposited on the joints synovial of experimental group rats with immunofluorescence. The study also found that the concentration of mannitol in urine of group M2 and group M3 rats was declined significantly(P<0.05), the concentration of lactulose increased(P<0.05), L/M also increased(P<0.05) with double-sugar tests, which indicated that intestinal permeability of rats in group M2 and group M3 was increased.
Conclusions
The occurence of rheumatoid arthritis in rats can be induced successfully by oralling bovine type II collagen, under the condition of intestinal mucous membrane damaged.
引文
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