幼鼠肠易激综合征模型建立及其发病机制的实验研究
发布时间：2018-08-28 14:59
【摘要】： 第一部分苏州市儿童肠易激综合征(IBS)的流行病学危险因素研究 目的探讨苏州市区小学生肠易激综合征(IBS)的患病率及危险因素。方法采用流行病学横断面研究方法对苏州市沧浪、平江及金阊辖区内公办小学1～6年级小学生进行问卷调查。采用多阶段、随机整群抽样的方法获取调查样本。在调查对象中,按罗马Ⅱ诊断标准,排除其他器质性疾病后确诊IBS病例,其他非IBS病例为对照。拟合非条件logistic多元回归模型,分析影响IBS发病可能的危险因素,为儿童IBS的预防提供科学的依据。结果共发放问卷8000份,回收有效问卷7472份,回收率93.4%;苏州市区1～6年级小学生有症状符合罗马Ⅱ诊断标准的IBS患病率为10.81%。男、女IBS患病率差异无统计学意义(10.3%vs11.3%)。多因素logistic回归模型分析提示:有食物过敏史(OR=1.53,95%CI:1.13～2.07)、儿童期有肠炎史(OR=1.29,95%CI:1.00～1.63)、喜食油炸食物(OR=1.62,95%CI:1.34～1.96)、心情焦虑(OR=1.49,95%CI:1.16～1.93)、儿童幼年时有意外打击史(OR=1.47,95%CI:1.02～2.20)及父母有便秘史(OR=1.81,95%CI:1.46～2.24)为男女儿童IBS发病最可能的危险因素。儿童年龄越大,IBS发病危险有逐渐下降的趋势(OR=0.94,95%CI:0.89～0.99)结论IBS是苏州市区小学生的常见病。影响苏州市区小学生IBS可能的危险因素是:年龄小、有食物过敏史、儿童期有肠炎史、喜食油炸食物、心情焦虑、儿童幼年时有意外打击史及父母有便秘史。因此,提示临床医师应重视此病,积极防治肠炎,调整儿童饮食,避免多食油炸食品及过敏的食物,以更好地防治本病。 第二部分幼鼠肠易激综合征模型的建立及鉴定 目的建立适合儿童肠易激综合征(IBS)研究的幼鼠IBS动物模型并鉴定。方法应用20只SD新生大鼠,随机分为IBS模型组和正常对照组,IBS模型组进行母子分离、改良机械束缚、结肠芥子油刺激等综合因素干预幼鼠建立IBS的动物模型;正常组不作干预。用自制的扩张器对幼鼠进行直肠扩张,评估不同压力下腹部收缩反射(AWR)阈值,测定幼鼠腹壁肌电活动;利用血管球囊扩张导管以5ml、10ml分别扩张IBS模型组、对照组幼鼠直肠,分别采集两组鼠脑部的fMRI数据,采用脑功能成像分析软件进行数据处理,应用血氧水平依赖性功能性MRI(BOLD-fMRI)技术,研究直肠球囊扩张刺激下肠易激综合征模型幼鼠脑内脏痛觉中枢兴奋情况及其兴奋区分布情况;取乙状结肠降段结肠用分层刮片技术刮取由外向内取1-4层细胞,丫啶橙荧光染色观察幼老细胞的比值并对肠粘膜上皮细胞进行美兰还原反应时间测定;并行结肠组织病理检测;干预后称两组幼鼠体重,观察粪便性状,查粪常规,并收集粪便称湿重和干重,应用Bristol分型观察各组粪便性状进行评分。结果直肠扩张时,在不同压力下模型组腹壁收缩反射(AWR)评分较对照组阈值显著降低(P值均0.01);不同扩张压力下,腹壁肌电活动随压力增加明显增加(P0.01);直肠球囊刺激后可引起IBS模型组幼鼠脑内与内脏相关的脑区(脑岛皮质、额前皮质、丘脑及扣带前皮质)神经元活动增强,表现为高兴奋区,而对照组幼鼠无相应兴奋区表现;结肠黏膜分层刮片后丫啶橙染色见IBS模型组粘膜上皮最外层细胞幼老细胞比值较正常对照组明显减少,美蓝还原时间延长(P0.05);结肠病理检查两组均未见明显异常;IBS模型组腹泻症状明显较正常对照组增加(P0.05),模型组粪便多为软的团块或泥浆样,而对照组为柔软的香肠状或团块状,两组粪便湿重存在显著差异(P0.05),而体重、粪便常规检查两组间无明显差异。两组Bristol分型评分比较有显著性差异(P0.05)。结论用母子分离、改良机械束缚、结肠芥子油刺激等综合因素干预幼鼠可成功建立适合儿童的幼鼠IBS动物模型,其机制可能为内脏敏感性增高。功能MRI是一种较为直观且准确的观察脑功能活动的脑显像技术,本研究显示IBS幼鼠中枢内脑岛皮质、额前皮质及丘脑可能是参与内脏感觉的主要部位。幼鼠IBS模型结肠粘膜上皮细胞功能处于抑制状态。 第三部分ICC细胞和脑肠肽在幼鼠IBS模型中作用机制的实验研究 目的旨在通过检测幼鼠结肠、脊髓和丘脑组织中脑肠肽NPY和cGRP的mRNA表达和结肠ICC细胞c-kit阳性细胞的表达,探讨脑肠肽、脑肠轴及ICC细胞在幼鼠IBS模型发病机制中的作用。方法根据简单数字法随机将乳鼠分成IBS模型组和正常对照组二组,各10只。IBS模型组用母子分离、改良机械束缚、结肠芥子油刺激等综合因素干预的方法造模,对照组则不做任何干预。采用半定量逆转录多聚酶链式反应法检测二组幼鼠结肠、脊髓、丘脑组织中NPY和cGRP mRNA的表达。另取结肠组织通过免疫组化检测肌间ICC细胞c-kit阳性表达细胞数。结果IBS模型组中NPY在结肠、脊髓、丘脑组织中mRNA表达明显较正常对照组降低,t值分别为9.66,8.55,12.65,(均P0.01);而cGRP则在脑肠轴各个层面(结肠、脊髓、丘脑)的表达中,IBS组明显较正常对照组增加,t值分别为14.41,12.85,12.41,(均P0.01)。二组幼鼠结肠ICC细胞c-kit阳性表达细胞数有差异(t=5.294,P0.01)。结论ICC细胞、脑肠肽可能在幼鼠IBS模型的发生、发展中起重要作用,本研究为深入研究儿童IBS发病机制提供了实验依据。 第四部分马来酸曲美布汀干预幼鼠IBS模型的疗效观察 目的探讨马来酸曲美布汀干预幼鼠肠易激综合征(IBS)模型后的治疗疗效。方法用母子分离、改良机械束缚、结肠芥子油刺激等综合的方法建立幼鼠IBS模型共20只,随机选10只在干预同时用马来酸曲美布汀3mg/kg.d灌服治疗为治疗组,另10只为模型组,取同期正常生长幼鼠10只为正常对照组。分别对三组幼鼠行肛门直肠球囊扩张刺激下测腹壁肌电活动,AWR评分;处死后取结肠对其肠粘膜上皮细胞进行分层刮片、荧光染色和还原能力测定,RT-PCR检测结肠、脊髓、丘脑中NPY和cGRP的mRNA表达。结果IBS模型组和正常对照组间不同压力下AWR评分均有显著性差异(P0.05),而治疗组和正常对照组间差异无显著性(P0.05);在8mmHg压力时,IBS模型组腹壁收缩次数增加达(6.65±1.04)次/3 min ,肌电图振幅增高,与另二组比较有显著性(P0.01),而治疗组、正常对照组间腹壁收缩活动和肌电图振幅差异无显著性(p0.05);在12mmHg、15mmHg扩张压力下,IBS模型组腹壁收缩活动增加,肌电图振幅增高(P0.05),但正常对照组与治疗组间无显著差异(p0.05);在28mmHg压力扩张下,三组幼鼠腹壁收缩次数及肌电图振幅增高差异均无显著性(P0.05);三组结肠粘膜由外向内1-4层取材标本中,IBS模型组的肠粘膜上皮细胞美蓝还原反应时间最长(11.8±1.45)min ;NPY在IBS模型组结肠、脊髓、丘脑三个部位的表达均较另二组低,F值分别为11.29,34.15,27.13(均P0.05),而治疗组和对照组间差异无显著性;cGRP在模型组三个部位的表达均较正常对照组和治疗组增强,F值分别为98.58,39.12,82.67(均P0.01),而治疗组和对照组间表达无显著性差异(P0.05)。结论马来酸曲美布汀治疗幼鼠IBS模型有效,可改善其肠道运动功能及内脏高敏感性。
[Abstract]:Part one: epidemiological risk factors for irritable bowel syndrome (IBS) in children in Suzhou.
Objective To investigate the prevalence and risk factors of irritable bowel syndrome (IBS) among pupils in Suzhou. Methods A cross-sectional epidemiological study was conducted among the pupils of grade 1 to 6 in Canglang, Pingjiang and Jinlong primary schools. According to Rome II diagnostic criteria, IBS cases were diagnosed after excluding other organic diseases, and other non-IBS cases were compared. Unconditional logistic multiple regression model was fitted to analyze the possible risk factors affecting the incidence of IBS and provide scientific basis for the prevention of IBS in children. There was no significant difference in the prevalence of IBS between males and females (10.3% vs 11.3%). Multivariate logistic regression analysis showed that there was a history of food allergy (OR = 1.53, 95% CI: 1.13-2.07), a history of enteritis in childhood (OR = 1.29, 95% CI: 1.00-1.63), and a preference for food. Fried food (OR = 1.62,95% CI: 1.34-1.96), mood anxiety (OR = 1.49,95% CI: 1.16-1.93), history of unintentional attack in childhood (OR = 1.47,95% CI: 1.02-2.20) and history of constipation in parents (OR = 1.81,95% CI: 1.46-2.24) were the most likely risk factors for IBS in boys and girls. Conclusion IBS is a common disease among pupils in Suzhou. The possible risk factors affecting IBS among pupils in Suzhou are: younger age, history of food allergy, history of enteritis in childhood, preference for fried food, anxiety, history of accidental attack in childhood and history of constipation in parents. We should actively prevent and treat enteritis, adjust children's diet, avoid eating more fried food and allergic food, so as to prevent and cure the disease better.
The second part is the establishment and identification of irritable bowel syndrome model in young rats.
Methods Twenty SD neonatal rats were randomly divided into IBS model group and normal control group. The infant rats in IBS model group were intervened by maternal-fetal separation, improved mechanical restraint and colon mustard oil stimulation to establish an IBS animal model. Intervention: Rectal dilatation was performed with a self-made dilator to evaluate the abdominal contractile reflex (AWR) threshold under different pressures, and the abdominal wall electromyographic activity was measured. The IBS model group was dilated with a balloon dilator catheter of 5ml and 10ml respectively, and the control group was dilated with rectum. The fMRI data of the brains of the two groups were collected and analyzed by functional brain imaging. Data were processed by software and blood oxygen level-dependent functional MRI (BOLD-fMRI) technique was used to study the excitability of visceral pain center and the distribution of excitatory areas in the brains of irritable bowel syndrome (IBS) rats induced by rectal balloon dilatation. The ratio of young and old cells was observed by fluorescence staining and the methylene blue reduction reaction time of intestinal mucosal epithelial cells was determined. The colon histopathological examination was carried out. After intervention, the body weight of the two groups of young rats was weighed, the stool characteristics were observed, the stool routine was checked, and the wet and dry weights were collected. The stool characteristics of each group were scored by Bristol typing. The abdominal wall systolic reflex (AWR) score in the model group was significantly lower than that in the control group at different pressure (P 0.01); the abdominal wall electromyographic activity was significantly increased with the increase of pressure (P 0.01); rectal balloon stimulation could induce the viscera-related brain areas (insular cortex, prefrontal cortex, thalamus and anterior cortex) in the brain of the IBS model group. The activity of neurons in the anterior cingulate cortex was enhanced, showing the excitatory zone, but there was no corresponding excitatory zone in the control group. The symptoms of diarrhea in IBS model group were significantly higher than those in normal control group (P There was significant difference (P 0.05). Conclusion Infant mice with IBS can be successfully established by the intervention of maternal-fetal separation, modified mechanical restraint and colon mustard oil stimulation. The mechanism may be increased visceral sensitivity. Functional MRI is a more intuitive and accurate brain imaging technique for observing brain function. It is suggested that the insular cortex, prefrontal cortex and thalamus may be the main sites involved in visceral sensation in young rats with IBS.
The third part is the experimental study on the mechanism of ICC cell and brain gut peptide in the IBS model of young rats.
Objective To investigate the role of brain-gut peptide, brain-gut axis and ICC cells in the pathogenesis of infant rat IBS model by detecting the expression of brain-gut peptide NPY and cGRP mRNA in colon, spinal cord and thalamus and the expression of c-kit positive cells in colon ICC cells. Rats in the IBS model group were established by the method of maternal-fetal separation, modified mechanical restraint and colon mustard oil stimulation, while those in the control group were given no intervention. The expressions of NPY and cGRP mRNA in colon, spinal cord and thalamus were detected by Semi-quantitative reverse transcriptase polymerase chain reaction. Results The expression of NPY in colon, spinal cord and thalamus of IBS model group was significantly lower than that of normal control group, with T values of 9.66, 8.55 and 12.65 respectively (all P 0.01), while the expression of cGRP in all levels of brain-gut axis (colon, spinal cord, thalamus) was significantly higher in IBS model group than that of normal control group. There were significant differences in the number of c-kit positive cells between the two groups (t = 5.294, P 0.01). Conclusion ICC cells and brain-gut peptides may play an important role in the development of IBS model in young rats. This study provides experimental basis for further study of the pathogenesis of IBS in children.
The fourth part of trimebutine maleate intervened in the IBS model of young rats.
Objective To investigate the therapeutic effect of trimebutine maleate on irritable bowel syndrome (IBS) in young rats. Methods Twenty IBS models were established by maternal-fetal separation, modified mechanical restraint and colon mustard oil stimulation. Ten rats were randomly selected as the treatment group and 10 rats were treated with trimebutine maleate at the same time. The abdominal myoelectric activity and AWR score were measured under anorectal balloon dilatation stimulation, and the intestinal mucosal epithelial cells were scraped, stained and reduced by fluorescence. NPY and cGRP in colon, spinal cord, thalamus were detected by RT-PCR. Results There was significant difference in AWR score between IBS model group and normal control group (P 0.05), but there was no significant difference between treatment group and normal control group (P 0.05). At 8 mmHg pressure, the number of abdominal wall contractions in IBS model group increased by (6.65 (1.04) times/3 minutes, and the amplitude of electromyogram increased significantly (P 0.0). 1) There was no significant difference in abdominal wall contraction and EMG amplitude between the treatment group and the control group (p0.05); the abdominal wall contraction and EMG amplitude increased in the IBS model group under 12 mmHg and 15 mmHg dilatation pressure (P 0.05), but there was no significant difference between the normal control group and the treatment group (p 0.05); the abdominal wall contraction of the three groups of young rats under 28 mmHg dilatation pressure. There was no significant difference in frequency and amplitude of EMG (P 0.05). Among the three groups, methylene blue reduction reaction time of intestinal epithelial cells in IBS model group was the longest (11.8 The expression of cGRP in the three parts of the model group was higher than that of the normal control group and the treatment group, F values were 98.58, 39.12 and 82.67 respectively (all P 0.01), but there was no significant difference between the treatment group and the control group (P 0.05). Conclusion Trimebutine maleate is effective and can be modified in the treatment of IBS model in young rats. Good bowel movement function and visceral Gao Min sensibility.
【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R725.7;R-332
[Abstract]:Part one: epidemiological risk factors for irritable bowel syndrome (IBS) in children in Suzhou.
Objective To investigate the prevalence and risk factors of irritable bowel syndrome (IBS) among pupils in Suzhou. Methods A cross-sectional epidemiological study was conducted among the pupils of grade 1 to 6 in Canglang, Pingjiang and Jinlong primary schools. According to Rome II diagnostic criteria, IBS cases were diagnosed after excluding other organic diseases, and other non-IBS cases were compared. Unconditional logistic multiple regression model was fitted to analyze the possible risk factors affecting the incidence of IBS and provide scientific basis for the prevention of IBS in children. There was no significant difference in the prevalence of IBS between males and females (10.3% vs 11.3%). Multivariate logistic regression analysis showed that there was a history of food allergy (OR = 1.53, 95% CI: 1.13-2.07), a history of enteritis in childhood (OR = 1.29, 95% CI: 1.00-1.63), and a preference for food. Fried food (OR = 1.62,95% CI: 1.34-1.96), mood anxiety (OR = 1.49,95% CI: 1.16-1.93), history of unintentional attack in childhood (OR = 1.47,95% CI: 1.02-2.20) and history of constipation in parents (OR = 1.81,95% CI: 1.46-2.24) were the most likely risk factors for IBS in boys and girls. Conclusion IBS is a common disease among pupils in Suzhou. The possible risk factors affecting IBS among pupils in Suzhou are: younger age, history of food allergy, history of enteritis in childhood, preference for fried food, anxiety, history of accidental attack in childhood and history of constipation in parents. We should actively prevent and treat enteritis, adjust children's diet, avoid eating more fried food and allergic food, so as to prevent and cure the disease better.
The second part is the establishment and identification of irritable bowel syndrome model in young rats.
Methods Twenty SD neonatal rats were randomly divided into IBS model group and normal control group. The infant rats in IBS model group were intervened by maternal-fetal separation, improved mechanical restraint and colon mustard oil stimulation to establish an IBS animal model. Intervention: Rectal dilatation was performed with a self-made dilator to evaluate the abdominal contractile reflex (AWR) threshold under different pressures, and the abdominal wall electromyographic activity was measured. The IBS model group was dilated with a balloon dilator catheter of 5ml and 10ml respectively, and the control group was dilated with rectum. The fMRI data of the brains of the two groups were collected and analyzed by functional brain imaging. Data were processed by software and blood oxygen level-dependent functional MRI (BOLD-fMRI) technique was used to study the excitability of visceral pain center and the distribution of excitatory areas in the brains of irritable bowel syndrome (IBS) rats induced by rectal balloon dilatation. The ratio of young and old cells was observed by fluorescence staining and the methylene blue reduction reaction time of intestinal mucosal epithelial cells was determined. The colon histopathological examination was carried out. After intervention, the body weight of the two groups of young rats was weighed, the stool characteristics were observed, the stool routine was checked, and the wet and dry weights were collected. The stool characteristics of each group were scored by Bristol typing. The abdominal wall systolic reflex (AWR) score in the model group was significantly lower than that in the control group at different pressure (P 0.01); the abdominal wall electromyographic activity was significantly increased with the increase of pressure (P 0.01); rectal balloon stimulation could induce the viscera-related brain areas (insular cortex, prefrontal cortex, thalamus and anterior cortex) in the brain of the IBS model group. The activity of neurons in the anterior cingulate cortex was enhanced, showing the excitatory zone, but there was no corresponding excitatory zone in the control group. The symptoms of diarrhea in IBS model group were significantly higher than those in normal control group (P There was significant difference (P 0.05). Conclusion Infant mice with IBS can be successfully established by the intervention of maternal-fetal separation, modified mechanical restraint and colon mustard oil stimulation. The mechanism may be increased visceral sensitivity. Functional MRI is a more intuitive and accurate brain imaging technique for observing brain function. It is suggested that the insular cortex, prefrontal cortex and thalamus may be the main sites involved in visceral sensation in young rats with IBS.
The third part is the experimental study on the mechanism of ICC cell and brain gut peptide in the IBS model of young rats.
Objective To investigate the role of brain-gut peptide, brain-gut axis and ICC cells in the pathogenesis of infant rat IBS model by detecting the expression of brain-gut peptide NPY and cGRP mRNA in colon, spinal cord and thalamus and the expression of c-kit positive cells in colon ICC cells. Rats in the IBS model group were established by the method of maternal-fetal separation, modified mechanical restraint and colon mustard oil stimulation, while those in the control group were given no intervention. The expressions of NPY and cGRP mRNA in colon, spinal cord and thalamus were detected by Semi-quantitative reverse transcriptase polymerase chain reaction. Results The expression of NPY in colon, spinal cord and thalamus of IBS model group was significantly lower than that of normal control group, with T values of 9.66, 8.55 and 12.65 respectively (all P 0.01), while the expression of cGRP in all levels of brain-gut axis (colon, spinal cord, thalamus) was significantly higher in IBS model group than that of normal control group. There were significant differences in the number of c-kit positive cells between the two groups (t = 5.294, P 0.01). Conclusion ICC cells and brain-gut peptides may play an important role in the development of IBS model in young rats. This study provides experimental basis for further study of the pathogenesis of IBS in children.
The fourth part of trimebutine maleate intervened in the IBS model of young rats.
Objective To investigate the therapeutic effect of trimebutine maleate on irritable bowel syndrome (IBS) in young rats. Methods Twenty IBS models were established by maternal-fetal separation, modified mechanical restraint and colon mustard oil stimulation. Ten rats were randomly selected as the treatment group and 10 rats were treated with trimebutine maleate at the same time. The abdominal myoelectric activity and AWR score were measured under anorectal balloon dilatation stimulation, and the intestinal mucosal epithelial cells were scraped, stained and reduced by fluorescence. NPY and cGRP in colon, spinal cord, thalamus were detected by RT-PCR. Results There was significant difference in AWR score between IBS model group and normal control group (P 0.05), but there was no significant difference between treatment group and normal control group (P 0.05). At 8 mmHg pressure, the number of abdominal wall contractions in IBS model group increased by (6.65 (1.04) times/3 minutes, and the amplitude of electromyogram increased significantly (P 0.0). 1) There was no significant difference in abdominal wall contraction and EMG amplitude between the treatment group and the control group (p0.05); the abdominal wall contraction and EMG amplitude increased in the IBS model group under 12 mmHg and 15 mmHg dilatation pressure (P 0.05), but there was no significant difference between the normal control group and the treatment group (p 0.05); the abdominal wall contraction of the three groups of young rats under 28 mmHg dilatation pressure. There was no significant difference in frequency and amplitude of EMG (P 0.05). Among the three groups, methylene blue reduction reaction time of intestinal epithelial cells in IBS model group was the longest (11.8 The expression of cGRP in the three parts of the model group was higher than that of the normal control group and the treatment group, F values were 98.58, 39.12 and 82.67 respectively (all P 0.01), but there was no significant difference between the treatment group and the control group (P 0.05). Conclusion Trimebutine maleate is effective and can be modified in the treatment of IBS model in young rats. Good bowel movement function and visceral Gao Min sensibility.
【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R725.7;R-332
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