感染后肠易激综合征小鼠肠道免疫的研究
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摘要
第一部分感染后肠易激综合征小鼠模型的建立
目的观察旋毛虫肠道急性感染后不同造模时间点小鼠内脏敏感性和结肠肌条收缩的变化,以建立模拟人感染后肠易激综合征内脏高敏感的动物模型。方法旋毛虫幼虫囊胞(350～400条)感染成年NIH小鼠,分别于感染后2、4、8、12周后称量小鼠体重的变化,通过腹壁回撤反应(AWR)评分评估感染前后不同造模点小鼠对结直肠扩张(CRD)的内脏敏感性,处死小鼠取空肠、末端回肠、近端结肠和远端结肠行HE染色观察肠道病理并对炎症情况进行评分,观察结肠肌条收缩变化。结果2周、4周组体重增长率低于正常组(P<0.05),8、12周组体重增长率与正常对照组无差异(P>0.05)。2周、4周组肠道各部位炎症评分高于正常组(Bonferroni校正P<0.05/10)；8、12周组与正常组相比均无差异(Bonferroni校正P>0.05/10)。在扩张压力为30、45、60 mm Hg时,各模型组AWR评分均高于正常组(P<0.05)；所有模型组疼痛阈值、容量阈值均低于同时间点正常对照组(P<0.05),以2周组变化最为明显；感染后小鼠结肠肌条收缩均增高,以2周时增加最为明显(P<0.05)。结论小鼠旋毛虫急性感染后8周肠道炎症消退,但内脏敏感性和结肠肌条高收缩性维持增高,因此适合作为感染后肠易激综合征内脏高敏感动物模型。
第二部分感染后肠易激综合征小鼠肠道Thl1/Th2的漂移
目的观察感染后肠易激综合征模型小鼠肠道组织中Th1类细胞因子IL-12和Th2类细胞因子IL-4表达的变化方法旋毛虫幼虫囊胞(350-400条)感染成年NIH小鼠,感染后每周测量小鼠体重,于感染后8周通过腹壁回撤反应(AWR)评分评估造模前后小鼠对结直肠扩张(CRD)的内脏敏感性,处死小鼠取空肠、末端回肠、近端结肠、远端结肠行病理切片HE染色观察肠道炎症情况。应用RT-PCR和Western-blot检测肠道各部位组织中IL-12、IL-4的mRNA和蛋白的表达量结果感染后2周小鼠体重明显下降(P<0.05),感染后8周体重变化与正常对照组无差异(P>0.05)。感染后2周急性感染期肠道炎症明显,感染后8周肠道无明显炎症表现。在结直肠扩张压力为30、45、60 mm Hg时,模型组AWR评分均高于正常组(P<0.05)；模型组疼痛阈值、容量阈值均低于正常对照组(P<0.05)。PI-IBS小鼠末端回肠和近端结肠组织中IL-12 mRNA及蛋白表达量均高于正常对照组(P<0.05),IL-4 mRNA及蛋白在各肠段中的表达均低于正常对照组(P<0.05)。结论PI-IBS小鼠肠道组织中Th1类细胞因子表达增高,Th2类细胞因子表达降低,存在Th1/Th2平衡的漂移。
第三部分感染后肠易激综合征小鼠肠道固有层树突状细胞表型和功能的改变
目的树突状细胞(Dendritic cell, DC)作为肠道固有层一种重要的抗原提呈细胞,可能与肠道粘膜免疫激活有关从而导致感染后肠易激综合征(Postinfectious irritable bowel syndrome, PI-IBS)的发生。本试验即研究肠道固有层DCs (Lamina propria DCs, LPDCs)在PI-IBS小鼠模型发生发展过程中表型和功能的改变。方法旋毛虫感染NIH小鼠,通过记录结直肠扩张下的腹壁回撤反射(Abdominal withdrawal reflex, AWR)评价其内脏敏感性。酶消化法结合磁珠分选技术分离肠道固有层的DCs。流式细胞术检测LPDCs表面膜分子标志。研究LPDCs的内吞活性、混合淋巴细胞刺激反应(mixed lymphocyte reaction, MLR)以及趋化能力。ELISA检测LPDCs分泌的细胞因子。结果急性感染期肠道炎症明显,感染后8周肠道炎症基本消退而内脏高敏感存留。急性期LPDCs表面膜分子CD86和MHCII低表达,而在慢性期表达增加。在急性感染期LPDCs内吞活性增加,但是刺激和趋化CD4+T淋巴细胞的能力减弱。然而,在慢性感染PI-IBS期,LPDCs内吞活性降低但趋化和刺激CD4+T淋巴细胞增殖的能力增强。LPDCs在急性期分泌细胞因子以IL-4为主,而在PI-IBS期以INF-γ和IL-23为主。结论在PI-IBS的发生发展过程中,肠道固有层树突状细胞表型和功能发生了改变,使肠道粘膜免疫激活长期存在,诱导内脏高敏感,为感染后肠易激综合征的治疗提供新的方向。
PartⅠEstablishment of a mouse model of postinfectious irritable bowel syndrome
Objective To observe the changes of visceral sensitivity and colonic muscle strip contractions at different time points after acute Trichinella infectious mice, and to establish a visceral hyperalgesia model imitating patients with post-infectious irritable bowel syndrome (PI-IBS). Methods Mice were infected by Trichinella spiralis (350-400 Trichinella). The weight of the mice at 2,4,8 and 12 weeks was measured. Visceral sensitivity of colorectal distention in mice was accessed by abdominal withdrawal reflex (AWR) at different time points before and after infection. Tissues of jejunum, terminal ileum, proximal colon and distal colon were collected after mice were dead. Histological pathology and inflammation were accessed with HE staining. Contractions of the colonic longitudinal muscle strip were recorded. Results The weight growth rates in 2 and 4-week groups were lower than that in the control group (P<0.05). The rates of 8,12-week groups had no statistical differences with the control groups. In all the groups the intestinal pathologic scores of the 2 weeks group was the highest, the 8,12 weeks groups recovered from the intestinal inflammation, and had no statistical differences with the control groups. At 30,45,60 mmHg, the AWR scores of all the infectious groups were higher than that in the control groups, The perceptual thresholds of all the infectious groups were lower than that in the control groups. Colonic muscle hypercontractility emerged after infection, and was distinguished in the acute infection group. Conclusion The intestinal inflammation in mice dissipated 8 weeks after Trichinella spiralis infection. However, visceral hypersensitivity and colonic muscle hypercontractility remained. Therefore, those mice were suitable for models of visceral hypersensitivity imitating patients with post-infectious irritable bowel syndrome.
PartⅡTh1/Th2 shift in the intestine of postinfectious irritable bowel syndrome mouse
Objective To observe the expression of Thl type cytokine IL-12 and Th2 type cytokine IL-4 in the intestine of the mouse model of post-infectious irritable bowel syndrome (PI-IBS). Methods Mice were infected by Trichinella spiralis (350-400 Trichinella). The weight of the mice was measured every week after infection. Visceral sensitivity of colorectal distention in mice was accessed by abdominal withdrawal reflex (AWR) at 0 and 8 weeks after infection. Tissues of jejunum, terminal ileum, proximal colon and distal colon were collected after mice were dead. Histological pathology and inflammation were accessed with HE staining. The mRNA and protein expressions of IL-12 and IL-4 were examined by RT-PCR and Western blotting, respectively. Results The weight growth rates decreased in 2 weeks acute infectious period (P<0.05). The rates of 8 weeks PI-IBS group had no statistical differences with the control group (P>0.05). Severe inflammation was observed in the intestine of 2 weeks acute infectious period, but after 8 weeks of infection it recovered from the intestinal inflammation, and had no differences with the control group. At 30,45,60 mmHg, the AWR scores of the infectious group was higher than that in the control group, The perceptual thresholds of the infectious group were lower than that in the control group(P<0.05). Increased expression of IL-12 mRNA and protein was observed in the ileocecum and proximal colon of PI-IBS mouse, and decreased expression of IL-4 mRNA and protein was observed in all the parts of intestine of PI-IBS mouse (P<0.05). Conclusion Th1 type cytokine increased but Th2 type cytokine decreased in PI-IBS mouse implied that Th1/Th2 shift may exist in the intestine of post infectious irritable bowel syndrome.
PartⅢCharacteristics of intestinal lamina propria dendritic cells in a mouse model of postinfectious irritable bowel syndrome
Background & Aims Dendritic cell (DC), as an important antigen presenting cell in the intestinal lamina propria, may contribute to intestinal mucosal immune activation in the pathogenesis of postinfectious irritable bowel syndrome (PI-IBS). The aim of this research was to study the phenotypic and functional changes of intestinal lamina propria DCs (LPDCs) in the development of PI-IBS mouse model. Methods Mice infected with T. spiralis underwent abdominal withdrawal reflex (AWR) to evaluate visceral sensitivity. LPDCs were isolated and purified by intestine digestion and magnetic label-based technique. The surface markers of LPDCs were analyzed by flow cytometry. Endocytic activity, mixed lymphocyte reaction (MLR) and chemotaxis were studied. Cytokine production of the LPDCs was determined. Results Intestinal inflammation was serious in acute infection mice, but resolved after 8 weeks infection with sustained visceral hyperalgesia. The surface markers CD86 and MHCII were lower in the acute infection group, but increased in the PI-IBS stage. Enhanced ability of endocytic activity and decreased abilities to attract and stimulate CD4+ T cell proliferation were observed in acute infection group. However, LPDCs in PI-IBS stage showed weakened endocytic ability with enhanced abilities to attract and stimulate CD4+ T cell proliferation. LPDCs secreted more cytokine of IL-4 in acute infection group, while they secreted more cytokines of INF-y and IL-23 in PI-IBS stage. Conclusions The phenotype and function of LPDCs changed in the development of PI-IBS, which induced the maintenance of intestinal mucosal immune activation and might provide a clue for the treatment of the disease.
目的观察旋毛虫肠道急性感染后不同造模时间点小鼠内脏敏感性和结肠肌条收缩的变化,以建立模拟人感染后肠易激综合征内脏高敏感的动物模型。方法旋毛虫幼虫囊胞(350～400条)感染成年NIH小鼠,分别于感染后2、4、8、12周后称量小鼠体重的变化,通过腹壁回撤反应(AWR)评分评估感染前后不同造模点小鼠对结直肠扩张(CRD)的内脏敏感性,处死小鼠取空肠、末端回肠、近端结肠和远端结肠行HE染色观察肠道病理并对炎症情况进行评分,观察结肠肌条收缩变化。结果2周、4周组体重增长率低于正常组(P<0.05),8、12周组体重增长率与正常对照组无差异(P>0.05)。2周、4周组肠道各部位炎症评分高于正常组(Bonferroni校正P<0.05/10)；8、12周组与正常组相比均无差异(Bonferroni校正P>0.05/10)。在扩张压力为30、45、60 mm Hg时,各模型组AWR评分均高于正常组(P<0.05)；所有模型组疼痛阈值、容量阈值均低于同时间点正常对照组(P<0.05),以2周组变化最为明显；感染后小鼠结肠肌条收缩均增高,以2周时增加最为明显(P<0.05)。结论小鼠旋毛虫急性感染后8周肠道炎症消退,但内脏敏感性和结肠肌条高收缩性维持增高,因此适合作为感染后肠易激综合征内脏高敏感动物模型。
第二部分感染后肠易激综合征小鼠肠道Thl1/Th2的漂移
目的观察感染后肠易激综合征模型小鼠肠道组织中Th1类细胞因子IL-12和Th2类细胞因子IL-4表达的变化方法旋毛虫幼虫囊胞(350-400条)感染成年NIH小鼠,感染后每周测量小鼠体重,于感染后8周通过腹壁回撤反应(AWR)评分评估造模前后小鼠对结直肠扩张(CRD)的内脏敏感性,处死小鼠取空肠、末端回肠、近端结肠、远端结肠行病理切片HE染色观察肠道炎症情况。应用RT-PCR和Western-blot检测肠道各部位组织中IL-12、IL-4的mRNA和蛋白的表达量结果感染后2周小鼠体重明显下降(P<0.05),感染后8周体重变化与正常对照组无差异(P>0.05)。感染后2周急性感染期肠道炎症明显,感染后8周肠道无明显炎症表现。在结直肠扩张压力为30、45、60 mm Hg时,模型组AWR评分均高于正常组(P<0.05)；模型组疼痛阈值、容量阈值均低于正常对照组(P<0.05)。PI-IBS小鼠末端回肠和近端结肠组织中IL-12 mRNA及蛋白表达量均高于正常对照组(P<0.05),IL-4 mRNA及蛋白在各肠段中的表达均低于正常对照组(P<0.05)。结论PI-IBS小鼠肠道组织中Th1类细胞因子表达增高,Th2类细胞因子表达降低,存在Th1/Th2平衡的漂移。
第三部分感染后肠易激综合征小鼠肠道固有层树突状细胞表型和功能的改变
目的树突状细胞(Dendritic cell, DC)作为肠道固有层一种重要的抗原提呈细胞,可能与肠道粘膜免疫激活有关从而导致感染后肠易激综合征(Postinfectious irritable bowel syndrome, PI-IBS)的发生。本试验即研究肠道固有层DCs (Lamina propria DCs, LPDCs)在PI-IBS小鼠模型发生发展过程中表型和功能的改变。方法旋毛虫感染NIH小鼠,通过记录结直肠扩张下的腹壁回撤反射(Abdominal withdrawal reflex, AWR)评价其内脏敏感性。酶消化法结合磁珠分选技术分离肠道固有层的DCs。流式细胞术检测LPDCs表面膜分子标志。研究LPDCs的内吞活性、混合淋巴细胞刺激反应(mixed lymphocyte reaction, MLR)以及趋化能力。ELISA检测LPDCs分泌的细胞因子。结果急性感染期肠道炎症明显,感染后8周肠道炎症基本消退而内脏高敏感存留。急性期LPDCs表面膜分子CD86和MHCII低表达,而在慢性期表达增加。在急性感染期LPDCs内吞活性增加,但是刺激和趋化CD4+T淋巴细胞的能力减弱。然而,在慢性感染PI-IBS期,LPDCs内吞活性降低但趋化和刺激CD4+T淋巴细胞增殖的能力增强。LPDCs在急性期分泌细胞因子以IL-4为主,而在PI-IBS期以INF-γ和IL-23为主。结论在PI-IBS的发生发展过程中,肠道固有层树突状细胞表型和功能发生了改变,使肠道粘膜免疫激活长期存在,诱导内脏高敏感,为感染后肠易激综合征的治疗提供新的方向。
PartⅠEstablishment of a mouse model of postinfectious irritable bowel syndrome
Objective To observe the changes of visceral sensitivity and colonic muscle strip contractions at different time points after acute Trichinella infectious mice, and to establish a visceral hyperalgesia model imitating patients with post-infectious irritable bowel syndrome (PI-IBS). Methods Mice were infected by Trichinella spiralis (350-400 Trichinella). The weight of the mice at 2,4,8 and 12 weeks was measured. Visceral sensitivity of colorectal distention in mice was accessed by abdominal withdrawal reflex (AWR) at different time points before and after infection. Tissues of jejunum, terminal ileum, proximal colon and distal colon were collected after mice were dead. Histological pathology and inflammation were accessed with HE staining. Contractions of the colonic longitudinal muscle strip were recorded. Results The weight growth rates in 2 and 4-week groups were lower than that in the control group (P<0.05). The rates of 8,12-week groups had no statistical differences with the control groups. In all the groups the intestinal pathologic scores of the 2 weeks group was the highest, the 8,12 weeks groups recovered from the intestinal inflammation, and had no statistical differences with the control groups. At 30,45,60 mmHg, the AWR scores of all the infectious groups were higher than that in the control groups, The perceptual thresholds of all the infectious groups were lower than that in the control groups. Colonic muscle hypercontractility emerged after infection, and was distinguished in the acute infection group. Conclusion The intestinal inflammation in mice dissipated 8 weeks after Trichinella spiralis infection. However, visceral hypersensitivity and colonic muscle hypercontractility remained. Therefore, those mice were suitable for models of visceral hypersensitivity imitating patients with post-infectious irritable bowel syndrome.
PartⅡTh1/Th2 shift in the intestine of postinfectious irritable bowel syndrome mouse
Objective To observe the expression of Thl type cytokine IL-12 and Th2 type cytokine IL-4 in the intestine of the mouse model of post-infectious irritable bowel syndrome (PI-IBS). Methods Mice were infected by Trichinella spiralis (350-400 Trichinella). The weight of the mice was measured every week after infection. Visceral sensitivity of colorectal distention in mice was accessed by abdominal withdrawal reflex (AWR) at 0 and 8 weeks after infection. Tissues of jejunum, terminal ileum, proximal colon and distal colon were collected after mice were dead. Histological pathology and inflammation were accessed with HE staining. The mRNA and protein expressions of IL-12 and IL-4 were examined by RT-PCR and Western blotting, respectively. Results The weight growth rates decreased in 2 weeks acute infectious period (P<0.05). The rates of 8 weeks PI-IBS group had no statistical differences with the control group (P>0.05). Severe inflammation was observed in the intestine of 2 weeks acute infectious period, but after 8 weeks of infection it recovered from the intestinal inflammation, and had no differences with the control group. At 30,45,60 mmHg, the AWR scores of the infectious group was higher than that in the control group, The perceptual thresholds of the infectious group were lower than that in the control group(P<0.05). Increased expression of IL-12 mRNA and protein was observed in the ileocecum and proximal colon of PI-IBS mouse, and decreased expression of IL-4 mRNA and protein was observed in all the parts of intestine of PI-IBS mouse (P<0.05). Conclusion Th1 type cytokine increased but Th2 type cytokine decreased in PI-IBS mouse implied that Th1/Th2 shift may exist in the intestine of post infectious irritable bowel syndrome.
PartⅢCharacteristics of intestinal lamina propria dendritic cells in a mouse model of postinfectious irritable bowel syndrome
Background & Aims Dendritic cell (DC), as an important antigen presenting cell in the intestinal lamina propria, may contribute to intestinal mucosal immune activation in the pathogenesis of postinfectious irritable bowel syndrome (PI-IBS). The aim of this research was to study the phenotypic and functional changes of intestinal lamina propria DCs (LPDCs) in the development of PI-IBS mouse model. Methods Mice infected with T. spiralis underwent abdominal withdrawal reflex (AWR) to evaluate visceral sensitivity. LPDCs were isolated and purified by intestine digestion and magnetic label-based technique. The surface markers of LPDCs were analyzed by flow cytometry. Endocytic activity, mixed lymphocyte reaction (MLR) and chemotaxis were studied. Cytokine production of the LPDCs was determined. Results Intestinal inflammation was serious in acute infection mice, but resolved after 8 weeks infection with sustained visceral hyperalgesia. The surface markers CD86 and MHCII were lower in the acute infection group, but increased in the PI-IBS stage. Enhanced ability of endocytic activity and decreased abilities to attract and stimulate CD4+ T cell proliferation were observed in acute infection group. However, LPDCs in PI-IBS stage showed weakened endocytic ability with enhanced abilities to attract and stimulate CD4+ T cell proliferation. LPDCs secreted more cytokine of IL-4 in acute infection group, while they secreted more cytokines of INF-y and IL-23 in PI-IBS stage. Conclusions The phenotype and function of LPDCs changed in the development of PI-IBS, which induced the maintenance of intestinal mucosal immune activation and might provide a clue for the treatment of the disease.
引文
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