温肾健脾法对腹泻型肠易激综合征大鼠疗效及其作用机制初探
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摘要
肠易激综合征(irritable bowel syndrome, IBS)是以腹痛或腹部不适,伴有大便性状及排便习惯改变为特征的慢性或反复发作胃肠道功能紊乱性肠病。IBS的发病机制及病因目前尚不甚明确,现普遍认为IBS是多种发病机制共同作用的结果,包括胃肠动力异常、内脏感觉敏感性增高、肠道炎症和免疫功能改变以及心理社会因素等,且上述各种发病机制之间相互关联。IBS的病理生理学基础主要是胃肠动力和内脏感知异常,造成这些变化的机制尚未完全阐明,而神经、内分泌和免疫之间的关系是近年来关注的热点。祖国医学并没有IBS这一病名,根据其临床表现,归属于“腹痛”、“泄泻”、“郁证”等范畴,其发病与感受外邪、饮食不节、情志失调及脏腑虚弱等有关。现代医学对IBS的治疗主要包括对患者的安慰、饮食、对症等治疗,但有效安全的药物治疗证据不多。古代医家和现代中医学者辨证论治IBS临床报道及Meta分析显示出中医药治疗本病的特色和优势,显示了中医药在治疗IBS领域中的巨大潜力。因此,探寻IBS的病因病机和有效治疗方法,是当前临床应用中的关键科学问题,具有重要社会意义和临床价值。
本论文研究分为文献综述和实验研究两部分。文献综述主要从IBS动物模型研究进展和神经、内分泌、免疫与IBS的关系研究进展两方面进行了简单归纳和总结。实验研究着重从IBS-D大鼠模型的建立及温肾健脾法干预IBS-D的疗效评估和温肾健脾法干预IBS-D大鼠疗效机理初探两个方面探索温肾健脾法对IBS-D的疗效作用机制,为中医药治疗IBS-D贡献力量。
第一部分文献综述
综述一主要从IBS研究对象的选择、IBS模型复制方法、IBS证候模型研究及存在的不足与展望等方面介绍了IBS动物模型研究进展情况。
综述二主要从神经调节与IBS、内分泌调节与IBS、免疫调控与IBS等方面简单介绍了神经-内分泌-免疫网络与IBS的关系研究进展情况。
第二部分实验研究
第一节IBS-D大鼠模型的建立及温肾健脾法干预IBS-D大鼠的疗效评估
目的：建立实验性IBS-D大鼠模型,从大鼠一般情况、大便性状、AWR评分及组织病理学观察等方面对温肾健脾法干预IBS-D的疗效进行评估。
方法：参照AL-Chaer造模方法复制IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,并以四神丸方免煎剂为对照,观察用药前后大鼠一般情况、大便性状、AWR评分及组织病理学改变情况。
结果：(1)除大鼠体重相对增长率无差异(p>0.05)外,与正常组比较,治疗前各组大鼠在排便粒数、粪便Bristol分级、平均稀便级、粪便干湿比重方面比较均有差异性,表现为造模结束后大鼠排便粒数增多(p<0.05)、粪便Bristol分级高于正常组(p<0.05)、平均稀便级高于正常组(p<0.05)、大鼠粪便干湿比重高于正常组(p<0.05)、在容量为1.5ml时,大鼠AWR评分高于正常组(p<0.05)。(2)治疗后各组大鼠一般情况均有不同程度的好转,其中温肾健脾方高、中剂量组大鼠一般情况改善情况疗效最佳；治疗前后各组大鼠体重均匀增加,体重相对增长率无差异性(p>0.05)；治疗后中药高、中剂量组及对照组排便粒数、Bristol分级评分、平均稀便级、粪便干湿比重及AWR评分均有不同程度的减少和降低,且温肾健脾方高、中剂量组普遍优于对照组和／或中药低剂量组(p<0.05)；各组大鼠组织标本大体观与病理学观察均未见器质性改变。
结论：(1)此批模型大鼠进行内脏高敏感性IBS-D研究可靠；(2)温肾健脾法能减少IBS-D大鼠排便粒数、降低Bristol分级评分、平均稀便级和粪便干湿比重,在一定程度能降低大鼠内脏高敏感性。
第二节温肾健脾法干预IBS-D大鼠疗效机理初探
实验一温肾健脾法对IBS-D大鼠结肠黏膜、回盲部MC及T细胞亚群的影响
目的：通过观察温肾健脾法对IBS-D大鼠MC、T细胞亚群的影响,尝试从免疫学角度验证温肾健脾法治疗IBS-D的作用机制。
方法：参照AL-Chaer造模方法建立IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,并以四神丸方免煎剂为对照,检测用药后各组大鼠结肠黏膜、回盲部MC及治疗后血清T细胞亚群的变化。
结果：(1)治疗后温肾健脾方高、中、低剂量组及对照组大鼠结肠黏膜、回盲部MC数目减少,MC平均光密度降低,且中药高、中剂量组优于对照组及中药低剂量组(p<0.05)；(2)结肠黏膜与回盲部MC数目比较：回盲部MC数目略高于结肠黏膜,但MC平均光密度则无差异(p>0.05)。(3)治疗后温肾健脾方高、中、低剂量组及对照组大鼠血清中CD4+/CD8+比值升高,且中药高、中剂量组疗效优于对照组及中药低剂量组(p<0.05)。
结论：(1)温肾健脾法通过降低IBS-D大鼠结肠黏膜及回盲部MC数目及MC平均光密度,抑制MC的表型活化及脱颗粒功能而发挥一定免疫应答作用；(2)通过提高大鼠血清中CD4+/CD8+比值升高,进而发挥调控T细胞亚群的免疫调节作用。
实验二温肾健脾法对IBS-D大鼠结肠黏膜、回盲部CCK、MOT的影响
目的：通过观察温肾健脾法对IBS-D大鼠结肠黏膜、回盲部CCK、MOT的影响,尝试从胃肠激素角度验证温肾健脾法治疗IBS-D的作用机制。
方法：参照AL-Chaer造模方法建立IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,并以四神丸方免煎剂为对照组,分别利用免疫组化法和Western-blot法检测用药后各组大鼠结肠黏膜、回盲部CCK、MOT的变化。
结果：治疗后温肾健脾方高、中、低剂量组及对照组大鼠结肠黏膜、回盲部CCK、 MOT含量表达均呈现不同程度的降低(p<0.05),且中药高、中剂量组疗效普遍优于对照组及中药低剂量组(p<0.05)。
结论：温肾健脾法通过降低IBS-D大鼠结肠黏膜及回盲部释放CCK、MOT的敏感性,从而降低肠道敏感性,减少CCK、MOT的释放量,以及加快已存在的CCK、MOT的的降解从而缓解IBS-D的临床症状。
实验三温肾健脾法对IBS-D大鼠结肠黏膜、回盲部VIP及腰膨大P物质的影响
目的：通过观察温肾健脾法对IBS-D大鼠结肠黏膜、回盲部VIP及腰膨大P物质的影响,尝试从神经内分泌角度验证温肾健脾法治疗IBS-D的作用机制。
方法：参照AL-Chaer造模方法建立IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,以四神丸方免煎剂为对照组,利用免疫组化法和Western-blot法检测用药后各组大鼠结肠黏膜、回盲部VIP及腰膨大P物质的变化。
结果：(1)治疗后温肾健脾方高、中、低剂量组及对照组大鼠结肠黏膜、回盲部VIP含量表达均降低,且中药高、中剂量组疗效优于对照组(p<0.05)；(2)治疗后温肾健脾方高、中剂量组及对照组大鼠腰膨大SP蛋白表达降低,且中药高、中剂量组疗效优于对照组疗(p<0.05)。
结论：温肾健脾法通过降低IBS-D大鼠结肠黏膜及回盲部释放VIP,干扰了胃肠道动力与分泌吸收功能；通过降低SP抑制小肠和结肠粘膜分泌水和电解质,在一定程度上能够调节VIP、SP分泌异常或使肠道对VIP、SP的敏感性增强可能是其治疗IBS-D的作用机制之一。
实验四温肾健脾法对IBS-D大鼠细胞因子的影响
目的：通过观察温肾健脾法对IBS-D大鼠Th1和Th2细胞因子的影响,尝试从肠道低度炎症角度验证温肾健脾法治疗IBS-D的作用机制。
方法：参照AL-Chaer造模方法建立IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,以四神丸方免煎剂为对照组,利用Elisa法和免疫组化法检测用药后各组大鼠血清和组织中Th1和Th2细胞因子的变化。
结果：(1)治疗后温肾健脾方高、中、低剂量组及对照组均能不同程度的降低IBS-D大鼠血清和组织中Th1细胞因子含量,提高Th2细胞因子含量,且中药高、中剂量组疗效普遍优于对照组和／或中药低剂量组(p<0.05)；(2)大鼠回盲部Th1和Th2细胞因子的含量普遍高于结肠黏膜中的含量(p<0.05)。
结论：温肾健脾法通过降低IBS-D大鼠降低活化的免疫细胞数目,减少促炎性细胞因子Th1的表达,上调抗炎性细胞因子Th2的表达,增强其抗炎活性,从而调控Th1/Th2起到抗炎和调节免疫作用。
Irritable bowel syndrome (IBS), as a functional bowel disorder, is a symptom-based diagnosis characterized by chronic or repetitive abdominal pain and discomfort, alteration of stool consistency and a change of bowel habits. To date, its organic cause and pathogenesis is yet unknown. It is widely believed that IBS is caused by joint efforts of various interrelated factors, including gastrointestinal hypomotility, increased sensitivity of visceral organs, intestinal inflammation, the immune system's malfunction, and psychosocial factors. IBS's pathophysiological basis mainly lies in gastrointestinal hypomotility and abnormal sensitivity of visceral organs, the cause of which is not yet elaborated. In recent years, more focus has been on studying the interrelation between the nervous system, endocrine system and immune system to probe into the cause of IBS. IBS is not included in the name of diseases defined in the field of traditional Chinese medicine. Based on its clinical phenomena, IBS shall fall into the category of abdominal pain, loose bowels and melancholia, mainly caused by exogenous pathogenic factors, improper diet, emotional disorder and frail visceral organs etc. Basically, in modern medicine, treatments like dietary adjustments, medication and psychological interventions are often used to help relieve some symptoms of IBS. Yet there is a lack of drug therapy that proves to be safe and effective. Meta analysis of reports on IBS clinical treatment based on syndrome differentiation widely used by traditional Chinese medical workers in ancient times and nowadays highlights the strengths of traditional Chinese medicines in the management of IBS and its huge potential for a cure for IBS. In the light of this, the key is to probe into the pathogeny and mechanism of IBS and then to derive an effective treatment for better clinical results, with added clinical value and positive social outcomes.
This dissertation is comprised of two main parts:literature review and laboratory test. To facilitate the study, IBS-D rat group modeling is established and Warming Kidney and Tonifying Spleen interventions are introduced to probe into its curative effects on IBS-D and to see how it functions, with the aim to explore a probable treatment of diarrhea-predominant irritable bowel syndrome with the use of traditional Chinese medicine.
Part Ⅰ Literature Review
1) The state of art of IBS animal model research is presented in aspects of IBS target group selection, IBS model duplicate, IBS syndrome model research shortcomings and prospects.
2) The state of art of the study on the positive effects of proper modulation of nervous-endocrine-immune system on the management of IBS.
Part Ⅱ Laboratory Test
Section I:IBS-D Rat Group Modeling and Assessment on the Effects of Warming Kidney and Tonifying Spleen Interventions on IBS-D
Objective:IBS-D rat group modeling is established to assess the effects of Wanning Kidney and Tonifying Spleen Interventions on IBS-D through observing the rats'general status, stool properties, AWR ranking and histopathological changes.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat group. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, their general status, stool properties, AWR ranking and histopathological changes are observed.
Findings:1) Compared with the normal group, zero variance is observed in terms of their relative growth rate (p>0.05) but there are prominent changes in their stool properties characterized by increased quantity of stool grains (p<0.05), higher Bristol ranking (p <0.05), higher average ranking of loose stool (p<0.05), higher dry and wet ratio (p<0.05). Their AWR ranking is p<0.05(on the basis of1.5ml), also higher than the normal group.2) After receiving treatment, the general status of all the groups gets better. Among them, those treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions have the best curative effects. During the process, all the rats get some weight in a normal manner, with zero variance in their relative growth rate (p>0.05). After the treatment, the rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions and the control group both recover to different degrees, yet with the former better than the latter and the LDG group in aspects of the quantity of stool grains, Bristol ranking, average ranking of loose stool, dry and wet ratio as well as the AWR ranking. A general view of tissue specimen and pathological observation of all the groups highlight no pathological changes in visceral organs.
Conclusion:1) Study on this batch of model rats proves that high sensitivity of visceral organs is an appropriate point of intervention to probe into IBS-D.2) Wanning Kidney and Tonifying Spleen interventions prove to be effective to reduce the quantity of stool grains, lower the Bristol ranking, the average ranking of loose stool as well as the dry and wet ratio, contributing to the reduction of sensitivity of the rats'visceral organs to some extent.
Section II Study on the Mechanism of Warming Kidney and Tonifying Spleen Interventions'Effects on IBS-D
Test I Warming Kidney and Tonifying Spleen interventions'effects on IBS-D rats' colonic mucosa, ileocecal MC and T cell subsets
Objective:Observe the effects of Warming Kidney and Tonifying Spleen interventions on IBS-D rats'colonic mucosa, ileocecal MC and T cell subsets to probe into the underlying mechanism from the immunological perspective.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat model. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, observe the changes in their colonic mucosa, ileocecal MC and serum T cell subsets.
Findings:1) After the treatment, both the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group have decreased quantity of colonic mucosa and ileocecal MC as well as lowered mean optical density. Rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to recover much better than those treated with LDG Warming Kidney and Tonifying Spleen interventions and the control group (p<0.05).2) Comparative analysis of the quantity of colonic mucosa and ileocecal MC:quantity of ileocecal MC is a little bit higher than that of ileocecal mucosa, while the mean optical density has zero variance (p>0.05).3) After the treatment, the ratio of CD4+/CD8+in the serum of the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group becomes higher. Rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to have better results than those treated with LDG Warming Kidney and Tonifying Spleen interventions and the control group (p<0.05).
Conclusion:Warming Kidney and Tonifying Spleen interventions prove to be effective to reduce the quantity of colonic mucosa and ileocecal MC as well as the mean optical density of MC, which in turn stimulates some immune response to restrain MC phenotype activation and degranulation. Moreover, through the interventions, the ratio of CD4+/CD8+in the serum of the rats becomes higher, which further contributes to the modulation of T cell subsets for improved immunity.
Test Ⅱ Warming Kidney and Tonifying Spleen Interventions'Effects on the colonic mucosa and ileocecal CCK and MOT of IBS-D Rats
Objective:Observe the effects of Warming Kidney and Tonifying Spleen interventions on IBS-D rats'colonic mucosa, ileocecal CCK and MOT to probe into the underlying mechanism from the gastrointestinal hormone perspective.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat model. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, immunohistochemistry and Western-blot analysis is employed to observe the changes in their colonic mucosa, ileocecal CCK and MOT.
Findings:After the treatment, the quantity of colonic mucosa, ileocecal CCK and MOT in the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group is reduced to varying degrees (p<0.05). Basically, rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to have better results than those treated with LDG Warming Kidney and Tonifying Spleen interventions and the control group (p<0.05)
Conclusion:Warming Kidney and Tonifying Spleen interventions prove to be effective to reduce the quantity of colonic mucosa and the amount of released ileocecal CCK and MOT, which in turn reduces the intestinal sensitivity and also accelerate the degradation of CCK and MOT present in their body. This helps relieve some symptoms of IBS-D.
Test Ⅲ Warming Kidney and Tonifying Spleen interventions'effects on IBS-D rats' colonic mucosa, ileocecal VIP and lumbar intumescence Substance P
Objective:Observe the effects of Warming Kidney and Tonifying Spleen interventions on IBS-D rats'colonic mucosa, ileocecal VIP and lumbar intumescence Substance P subsets to probe into the underlying mechanism from the neuroendocrine perspective.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat model. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, observe the changes in their colonic mucosa, ileocecal VIP and lumbar intumescence Substance P subsets via immunohistochemical and Western-blot.
Findings:1) After the treatment, both the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group have decreased quantity of colonic mucosa and ileocecal VIP as well as lowered mean optical density. Rats treated with HDG and MDG Wanning Kidney and Tonifying Spleen interventions prove to recover much better than CG (p<0.05).2) After the treatment, both the rats treated with HDG, MDG and the control group have decreased the protein expression of lumbar intumescence Substance P as well as lowered mean optical density. Rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to recover much better than the control group (p<0.05).
Conclusion:Warming Kidney and Tonifying Spleen interventions prove to be effective to reduce the quantity of colonic mucosa and ileocecal VIP via interferring with the function of gastrointestinal dynamic absorption and secretion;inhibiting the small intestine and colon mucosa secretion of water and electrolytes by reducing SP, which can adjust the VIP, SP secretion or make the intestinal sensitivity of VIP, SP to a certain extent.
Test Ⅳ Warming Kidney and Tonifying Spleen interventions' effects on IBS-D rats'cytokines
Objective:Observe the effects of Warming Kidney and Tonifying Spleen interventions on IBS-D rats'Th1and Th2cytokines subsets to probe into the underlying mechanism from the neuroendocrine perspective.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat model. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, observe the changes in their serum,colonic mucosa,ileocecal Th1and Th2cytokines subsets via Elisa and Western-blot.
Findings:1) After the treatment, both the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group have decreased quantity of serum, colonic mucosa and ileocecal Th1cytokines and enhance Th2cytokines From different levels as well as lowered mean optical density. Rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to recover much better than CG and/or LDG (p<0.05).2) Both quantity of Th1cytokines and Th2cytokines in rats ileocecal are higher than colonic mucosa(p<0.05).
Conclusion:Warming Kidney and Tonifying Spleen interventions prove to be effective to reduce the number of activation immune cells, reduce the expression of Th1cytokines, increase the expression of Th2cytokines, thereby regulating Th1/Th2anti-inflammatory and immune regulation.
本论文研究分为文献综述和实验研究两部分。文献综述主要从IBS动物模型研究进展和神经、内分泌、免疫与IBS的关系研究进展两方面进行了简单归纳和总结。实验研究着重从IBS-D大鼠模型的建立及温肾健脾法干预IBS-D的疗效评估和温肾健脾法干预IBS-D大鼠疗效机理初探两个方面探索温肾健脾法对IBS-D的疗效作用机制,为中医药治疗IBS-D贡献力量。
第一部分文献综述
综述一主要从IBS研究对象的选择、IBS模型复制方法、IBS证候模型研究及存在的不足与展望等方面介绍了IBS动物模型研究进展情况。
综述二主要从神经调节与IBS、内分泌调节与IBS、免疫调控与IBS等方面简单介绍了神经-内分泌-免疫网络与IBS的关系研究进展情况。
第二部分实验研究
第一节IBS-D大鼠模型的建立及温肾健脾法干预IBS-D大鼠的疗效评估
目的：建立实验性IBS-D大鼠模型,从大鼠一般情况、大便性状、AWR评分及组织病理学观察等方面对温肾健脾法干预IBS-D的疗效进行评估。
方法：参照AL-Chaer造模方法复制IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,并以四神丸方免煎剂为对照,观察用药前后大鼠一般情况、大便性状、AWR评分及组织病理学改变情况。
结果：(1)除大鼠体重相对增长率无差异(p>0.05)外,与正常组比较,治疗前各组大鼠在排便粒数、粪便Bristol分级、平均稀便级、粪便干湿比重方面比较均有差异性,表现为造模结束后大鼠排便粒数增多(p<0.05)、粪便Bristol分级高于正常组(p<0.05)、平均稀便级高于正常组(p<0.05)、大鼠粪便干湿比重高于正常组(p<0.05)、在容量为1.5ml时,大鼠AWR评分高于正常组(p<0.05)。(2)治疗后各组大鼠一般情况均有不同程度的好转,其中温肾健脾方高、中剂量组大鼠一般情况改善情况疗效最佳；治疗前后各组大鼠体重均匀增加,体重相对增长率无差异性(p>0.05)；治疗后中药高、中剂量组及对照组排便粒数、Bristol分级评分、平均稀便级、粪便干湿比重及AWR评分均有不同程度的减少和降低,且温肾健脾方高、中剂量组普遍优于对照组和／或中药低剂量组(p<0.05)；各组大鼠组织标本大体观与病理学观察均未见器质性改变。
结论：(1)此批模型大鼠进行内脏高敏感性IBS-D研究可靠；(2)温肾健脾法能减少IBS-D大鼠排便粒数、降低Bristol分级评分、平均稀便级和粪便干湿比重,在一定程度能降低大鼠内脏高敏感性。
第二节温肾健脾法干预IBS-D大鼠疗效机理初探
实验一温肾健脾法对IBS-D大鼠结肠黏膜、回盲部MC及T细胞亚群的影响
目的：通过观察温肾健脾法对IBS-D大鼠MC、T细胞亚群的影响,尝试从免疫学角度验证温肾健脾法治疗IBS-D的作用机制。
方法：参照AL-Chaer造模方法建立IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,并以四神丸方免煎剂为对照,检测用药后各组大鼠结肠黏膜、回盲部MC及治疗后血清T细胞亚群的变化。
结果：(1)治疗后温肾健脾方高、中、低剂量组及对照组大鼠结肠黏膜、回盲部MC数目减少,MC平均光密度降低,且中药高、中剂量组优于对照组及中药低剂量组(p<0.05)；(2)结肠黏膜与回盲部MC数目比较：回盲部MC数目略高于结肠黏膜,但MC平均光密度则无差异(p>0.05)。(3)治疗后温肾健脾方高、中、低剂量组及对照组大鼠血清中CD4+/CD8+比值升高,且中药高、中剂量组疗效优于对照组及中药低剂量组(p<0.05)。
结论：(1)温肾健脾法通过降低IBS-D大鼠结肠黏膜及回盲部MC数目及MC平均光密度,抑制MC的表型活化及脱颗粒功能而发挥一定免疫应答作用；(2)通过提高大鼠血清中CD4+/CD8+比值升高,进而发挥调控T细胞亚群的免疫调节作用。
实验二温肾健脾法对IBS-D大鼠结肠黏膜、回盲部CCK、MOT的影响
目的：通过观察温肾健脾法对IBS-D大鼠结肠黏膜、回盲部CCK、MOT的影响,尝试从胃肠激素角度验证温肾健脾法治疗IBS-D的作用机制。
方法：参照AL-Chaer造模方法建立IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,并以四神丸方免煎剂为对照组,分别利用免疫组化法和Western-blot法检测用药后各组大鼠结肠黏膜、回盲部CCK、MOT的变化。
结果：治疗后温肾健脾方高、中、低剂量组及对照组大鼠结肠黏膜、回盲部CCK、 MOT含量表达均呈现不同程度的降低(p<0.05),且中药高、中剂量组疗效普遍优于对照组及中药低剂量组(p<0.05)。
结论：温肾健脾法通过降低IBS-D大鼠结肠黏膜及回盲部释放CCK、MOT的敏感性,从而降低肠道敏感性,减少CCK、MOT的释放量,以及加快已存在的CCK、MOT的的降解从而缓解IBS-D的临床症状。
实验三温肾健脾法对IBS-D大鼠结肠黏膜、回盲部VIP及腰膨大P物质的影响
目的：通过观察温肾健脾法对IBS-D大鼠结肠黏膜、回盲部VIP及腰膨大P物质的影响,尝试从神经内分泌角度验证温肾健脾法治疗IBS-D的作用机制。
方法：参照AL-Chaer造模方法建立IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,以四神丸方免煎剂为对照组,利用免疫组化法和Western-blot法检测用药后各组大鼠结肠黏膜、回盲部VIP及腰膨大P物质的变化。
结果：(1)治疗后温肾健脾方高、中、低剂量组及对照组大鼠结肠黏膜、回盲部VIP含量表达均降低,且中药高、中剂量组疗效优于对照组(p<0.05)；(2)治疗后温肾健脾方高、中剂量组及对照组大鼠腰膨大SP蛋白表达降低,且中药高、中剂量组疗效优于对照组疗(p<0.05)。
结论：温肾健脾法通过降低IBS-D大鼠结肠黏膜及回盲部释放VIP,干扰了胃肠道动力与分泌吸收功能；通过降低SP抑制小肠和结肠粘膜分泌水和电解质,在一定程度上能够调节VIP、SP分泌异常或使肠道对VIP、SP的敏感性增强可能是其治疗IBS-D的作用机制之一。
实验四温肾健脾法对IBS-D大鼠细胞因子的影响
目的：通过观察温肾健脾法对IBS-D大鼠Th1和Th2细胞因子的影响,尝试从肠道低度炎症角度验证温肾健脾法治疗IBS-D的作用机制。
方法：参照AL-Chaer造模方法建立IBS-D大鼠模型,分别予温肾健脾方免煎剂高、中、低剂量灌胃治疗,以四神丸方免煎剂为对照组,利用Elisa法和免疫组化法检测用药后各组大鼠血清和组织中Th1和Th2细胞因子的变化。
结果：(1)治疗后温肾健脾方高、中、低剂量组及对照组均能不同程度的降低IBS-D大鼠血清和组织中Th1细胞因子含量,提高Th2细胞因子含量,且中药高、中剂量组疗效普遍优于对照组和／或中药低剂量组(p<0.05)；(2)大鼠回盲部Th1和Th2细胞因子的含量普遍高于结肠黏膜中的含量(p<0.05)。
结论：温肾健脾法通过降低IBS-D大鼠降低活化的免疫细胞数目,减少促炎性细胞因子Th1的表达,上调抗炎性细胞因子Th2的表达,增强其抗炎活性,从而调控Th1/Th2起到抗炎和调节免疫作用。
Irritable bowel syndrome (IBS), as a functional bowel disorder, is a symptom-based diagnosis characterized by chronic or repetitive abdominal pain and discomfort, alteration of stool consistency and a change of bowel habits. To date, its organic cause and pathogenesis is yet unknown. It is widely believed that IBS is caused by joint efforts of various interrelated factors, including gastrointestinal hypomotility, increased sensitivity of visceral organs, intestinal inflammation, the immune system's malfunction, and psychosocial factors. IBS's pathophysiological basis mainly lies in gastrointestinal hypomotility and abnormal sensitivity of visceral organs, the cause of which is not yet elaborated. In recent years, more focus has been on studying the interrelation between the nervous system, endocrine system and immune system to probe into the cause of IBS. IBS is not included in the name of diseases defined in the field of traditional Chinese medicine. Based on its clinical phenomena, IBS shall fall into the category of abdominal pain, loose bowels and melancholia, mainly caused by exogenous pathogenic factors, improper diet, emotional disorder and frail visceral organs etc. Basically, in modern medicine, treatments like dietary adjustments, medication and psychological interventions are often used to help relieve some symptoms of IBS. Yet there is a lack of drug therapy that proves to be safe and effective. Meta analysis of reports on IBS clinical treatment based on syndrome differentiation widely used by traditional Chinese medical workers in ancient times and nowadays highlights the strengths of traditional Chinese medicines in the management of IBS and its huge potential for a cure for IBS. In the light of this, the key is to probe into the pathogeny and mechanism of IBS and then to derive an effective treatment for better clinical results, with added clinical value and positive social outcomes.
This dissertation is comprised of two main parts:literature review and laboratory test. To facilitate the study, IBS-D rat group modeling is established and Warming Kidney and Tonifying Spleen interventions are introduced to probe into its curative effects on IBS-D and to see how it functions, with the aim to explore a probable treatment of diarrhea-predominant irritable bowel syndrome with the use of traditional Chinese medicine.
Part Ⅰ Literature Review
1) The state of art of IBS animal model research is presented in aspects of IBS target group selection, IBS model duplicate, IBS syndrome model research shortcomings and prospects.
2) The state of art of the study on the positive effects of proper modulation of nervous-endocrine-immune system on the management of IBS.
Part Ⅱ Laboratory Test
Section I:IBS-D Rat Group Modeling and Assessment on the Effects of Warming Kidney and Tonifying Spleen Interventions on IBS-D
Objective:IBS-D rat group modeling is established to assess the effects of Wanning Kidney and Tonifying Spleen Interventions on IBS-D through observing the rats'general status, stool properties, AWR ranking and histopathological changes.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat group. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, their general status, stool properties, AWR ranking and histopathological changes are observed.
Findings:1) Compared with the normal group, zero variance is observed in terms of their relative growth rate (p>0.05) but there are prominent changes in their stool properties characterized by increased quantity of stool grains (p<0.05), higher Bristol ranking (p <0.05), higher average ranking of loose stool (p<0.05), higher dry and wet ratio (p<0.05). Their AWR ranking is p<0.05(on the basis of1.5ml), also higher than the normal group.2) After receiving treatment, the general status of all the groups gets better. Among them, those treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions have the best curative effects. During the process, all the rats get some weight in a normal manner, with zero variance in their relative growth rate (p>0.05). After the treatment, the rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions and the control group both recover to different degrees, yet with the former better than the latter and the LDG group in aspects of the quantity of stool grains, Bristol ranking, average ranking of loose stool, dry and wet ratio as well as the AWR ranking. A general view of tissue specimen and pathological observation of all the groups highlight no pathological changes in visceral organs.
Conclusion:1) Study on this batch of model rats proves that high sensitivity of visceral organs is an appropriate point of intervention to probe into IBS-D.2) Wanning Kidney and Tonifying Spleen interventions prove to be effective to reduce the quantity of stool grains, lower the Bristol ranking, the average ranking of loose stool as well as the dry and wet ratio, contributing to the reduction of sensitivity of the rats'visceral organs to some extent.
Section II Study on the Mechanism of Warming Kidney and Tonifying Spleen Interventions'Effects on IBS-D
Test I Warming Kidney and Tonifying Spleen interventions'effects on IBS-D rats' colonic mucosa, ileocecal MC and T cell subsets
Objective:Observe the effects of Warming Kidney and Tonifying Spleen interventions on IBS-D rats'colonic mucosa, ileocecal MC and T cell subsets to probe into the underlying mechanism from the immunological perspective.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat model. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, observe the changes in their colonic mucosa, ileocecal MC and serum T cell subsets.
Findings:1) After the treatment, both the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group have decreased quantity of colonic mucosa and ileocecal MC as well as lowered mean optical density. Rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to recover much better than those treated with LDG Warming Kidney and Tonifying Spleen interventions and the control group (p<0.05).2) Comparative analysis of the quantity of colonic mucosa and ileocecal MC:quantity of ileocecal MC is a little bit higher than that of ileocecal mucosa, while the mean optical density has zero variance (p>0.05).3) After the treatment, the ratio of CD4+/CD8+in the serum of the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group becomes higher. Rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to have better results than those treated with LDG Warming Kidney and Tonifying Spleen interventions and the control group (p<0.05).
Conclusion:Warming Kidney and Tonifying Spleen interventions prove to be effective to reduce the quantity of colonic mucosa and ileocecal MC as well as the mean optical density of MC, which in turn stimulates some immune response to restrain MC phenotype activation and degranulation. Moreover, through the interventions, the ratio of CD4+/CD8+in the serum of the rats becomes higher, which further contributes to the modulation of T cell subsets for improved immunity.
Test Ⅱ Warming Kidney and Tonifying Spleen Interventions'Effects on the colonic mucosa and ileocecal CCK and MOT of IBS-D Rats
Objective:Observe the effects of Warming Kidney and Tonifying Spleen interventions on IBS-D rats'colonic mucosa, ileocecal CCK and MOT to probe into the underlying mechanism from the gastrointestinal hormone perspective.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat model. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, immunohistochemistry and Western-blot analysis is employed to observe the changes in their colonic mucosa, ileocecal CCK and MOT.
Findings:After the treatment, the quantity of colonic mucosa, ileocecal CCK and MOT in the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group is reduced to varying degrees (p<0.05). Basically, rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to have better results than those treated with LDG Warming Kidney and Tonifying Spleen interventions and the control group (p<0.05)
Conclusion:Warming Kidney and Tonifying Spleen interventions prove to be effective to reduce the quantity of colonic mucosa and the amount of released ileocecal CCK and MOT, which in turn reduces the intestinal sensitivity and also accelerate the degradation of CCK and MOT present in their body. This helps relieve some symptoms of IBS-D.
Test Ⅲ Warming Kidney and Tonifying Spleen interventions'effects on IBS-D rats' colonic mucosa, ileocecal VIP and lumbar intumescence Substance P
Objective:Observe the effects of Warming Kidney and Tonifying Spleen interventions on IBS-D rats'colonic mucosa, ileocecal VIP and lumbar intumescence Substance P subsets to probe into the underlying mechanism from the neuroendocrine perspective.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat model. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, observe the changes in their colonic mucosa, ileocecal VIP and lumbar intumescence Substance P subsets via immunohistochemical and Western-blot.
Findings:1) After the treatment, both the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group have decreased quantity of colonic mucosa and ileocecal VIP as well as lowered mean optical density. Rats treated with HDG and MDG Wanning Kidney and Tonifying Spleen interventions prove to recover much better than CG (p<0.05).2) After the treatment, both the rats treated with HDG, MDG and the control group have decreased the protein expression of lumbar intumescence Substance P as well as lowered mean optical density. Rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to recover much better than the control group (p<0.05).
Conclusion:Warming Kidney and Tonifying Spleen interventions prove to be effective to reduce the quantity of colonic mucosa and ileocecal VIP via interferring with the function of gastrointestinal dynamic absorption and secretion;inhibiting the small intestine and colon mucosa secretion of water and electrolytes by reducing SP, which can adjust the VIP, SP secretion or make the intestinal sensitivity of VIP, SP to a certain extent.
Test Ⅳ Warming Kidney and Tonifying Spleen interventions' effects on IBS-D rats'cytokines
Objective:Observe the effects of Warming Kidney and Tonifying Spleen interventions on IBS-D rats'Th1and Th2cytokines subsets to probe into the underlying mechanism from the neuroendocrine perspective.
Methodology:Referencing AL-Chaer modeling, make a duplicate IBS-D rat model. After that, HDG, MDG and LDG are used separately for target rat groups, while the control group is treated with Decocting-free Sishen pill. Then, observe the changes in their serum,colonic mucosa,ileocecal Th1and Th2cytokines subsets via Elisa and Western-blot.
Findings:1) After the treatment, both the rats treated with HDG, MDG and LDG Warming Kidney and Tonifying Spleen interventions and the control group have decreased quantity of serum, colonic mucosa and ileocecal Th1cytokines and enhance Th2cytokines From different levels as well as lowered mean optical density. Rats treated with HDG and MDG Warming Kidney and Tonifying Spleen interventions prove to recover much better than CG and/or LDG (p<0.05).2) Both quantity of Th1cytokines and Th2cytokines in rats ileocecal are higher than colonic mucosa(p<0.05).
Conclusion:Warming Kidney and Tonifying Spleen interventions prove to be effective to reduce the number of activation immune cells, reduce the expression of Th1cytokines, increase the expression of Th2cytokines, thereby regulating Th1/Th2anti-inflammatory and immune regulation.
引文
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