黄穗平诊治胃痛（FD）特点及四君子汤治疗脾虚型FD机制
发布时间：2018-09-05 08:21
【摘要】：目的:功能性消化不良(Funtional dyspepsia,FD)是十分普遍的消化系统疾病。依据中医学理论,功能性消化不良餐后不适综合征属于"痞满"范畴,上腹痛综合征则属于"胃痛"的范畴。为从整体上把握对胃痛的认识,了解数据挖掘技术及其在中医药研究的运用,本研究对胃痛病因病机、辨证论治的相关文献进行了整理;并对数据挖掘概念和其在中医药领域运用现状的文献进行了分析。为系统了解国内外功能性消化不良机制以及其中的内脏高敏感性机制研究现状,我们对相关文献进行了整理和综述。为展现胃痛(FD)的证型特征,对胃痛(FD)的病案资料进行了证型数理统计;为指导临床胃痛(FD)的治疗提供客观依据,利于学术经验传承,对黄穗平教授治疗胃痛(FD)的用药特点进行了数据挖掘。为了探究脾虚证功能性消化不良内脏高敏感性的机制以及健脾药物的治疗机制,在蛋白表达水平和基因转录水平为中药治疗作用提供客观和定量的指标,建立了脾虚证功能性消化不良的内脏高敏感性模型;在我们既往研究的基础上,结合病案研究结果,选择健脾方四君子汤进行干预。方法:临床研究以2015年6月-2016年6月于广东省中医院黄穗平教授处治疗胃痛的门诊病例为信息来源,筛选出胃痛(FD)病历,对原始资料进行数据整理,建立了规范化的Excel胃痛证治数据库。以此为基础,采用SPSS19.0和Clementine12.0软件,运用频数分析、关联规则和因子分析分析胃痛(FD)证治数据。根据统计结果,进行胃痛(FD)基线特征、证型分布、常用药物、常用药物配伍和药证关系的分析,总结治疗特点。实验研究以SD雄性大鼠为研究对象,共36只,随机分为空白组、模型组、四君子汤组、莫沙必利组,每组各9只。空白组不予造模,其余三组采用碘乙酰胺+站小平台法+隔日禁食,建立脾虚证FD内脏高敏感性大鼠模型。空白组和模型组给予生理盐水灌胃,中药组给予四君子汤灌胃,西药组给予莫沙必利灌胃,共用药14天。观测各组大鼠症状、体重;记录反应胃感觉运动的肌电图;运用免疫组化技术、荧光定量聚合酶链式反应(Real-time PCR)技术测量胃窦组织神经生长因子(NGF)、磷酯酶Cγ(PLC Y)和瞬时受体电位辣椒素亚型1(TRPV1)通道的表达。结果:临床研究门诊胃痛(FD)患者中,中青年人占89.65%;女性占73.16%。病因以饮食因素最多;共出现12个胃痛(FD)证型,最多的证型是脾虚气滞。黄穗平教授辨治胃痛(FD)最常用的10味药物是党参、木香、法半夏、延胡索、炙甘草、陈皮、白术、砂仁、茯苓、厚朴;本研究挖掘出黄教授的19个常用药对,6个常用五味药物组合,3个证型与药物的相关组合。因子分析共显示7个公因子,其中有意义的公因子是4个,分别是在白术、山药、炒白术、白扁豆具有较大的载荷的第二个公因子;在茯苓、茯神、合欢皮具有较大的载荷的第三个公因子;在厚朴、海螵蛸、枳实具有较大的载荷的第六个公因子;在桔梗具有较大的载荷的第七个公因子。实验研究脾气虚型造模后,大鼠蜷缩,懒动,反应较迟钝,毛发枯槁,大便欠成形,体重明显减轻,符合中医脾虚证的表现。治疗后,中西药组大鼠活动较活跃,反应迟钝改善,毛发色泽变亮,大便成形,脾虚症状得到改善。造模后脾虚证FD内脏高敏感模型大鼠体重明显低于正常组大鼠,差异有统计学意义(P0.05),模型各组大鼠体重无显著差异。药物干预后,四君子汤组大鼠平均体重较模型组升高,但差异无统计学意义(P0.05);莫沙必利组大鼠体重与模型组差异无统计学意义(P0.05)。记录反应胃感觉运动的肌电图显示,相比空白组,模型组大鼠肌电图波幅出现相对较大的增加,符合FD内脏高敏感性肌电图变化。治疗后,相比模型组,治疗组的肌电图波幅增加变小,中药组的波幅变化与正常组相近,从趋势上显示四君子汤降低了内脏高敏感性。免疫组化结果显示NGF、PLCγ、TRPV1在细胞质表达。在蛋白表达水平,与空白组对照,模型组NGF出现阳性表达增加,两者的差异具有统计学意义(P0.05);药物治疗后,NGF出现阳性表达减少,但是不存在统计学差异(P0.05);西药组与中药组的表达差异不存在统计学意义(P0.05)。在蛋白表达水平,与空白组对照,模型组PLCγ出现阳性表达增加,具有统计学差异(P0.05);药物治疗后,PLCγ出现阳性表达减少,其中中药组与模型组的差异具有统计学意义(P0.05);中药组和西药组差异无统计学意义(P0.05)。在蛋白表达水平,与空白组对照,模型组TRPV1出现阳性表达增加,具有统计学差异(P0.05);药物治疗后,TRPV1出现阳性表达减少,中药组与模型组的差异具有统计学意义(P0.05);中药组和西药组差异无统计学意义(P0.05)。在mRNA转录水平,相比空白组,模型组的PLCγ、TRPV1 mRNA表达水平显著上调,具有统计学差异(P0.05);在药物治疗后,西药组和中药组出现PLCγ、TRPV1 mRNA表达水平下调,与模型组对照,西药组表达水平下调无统计学差异(P0.05),中药组表达水平下调则存在显著统计学差异(P0.05);中药组和西药组差异无统计学意义(P0.05)。结论:临床研究门诊胃痛(FD)患者以中青年人和女性居多;饮食因素是重要的病因;胃痛(FD)证型以脾虚气滞证最多。黄穗平教授治疗胃痛(FD)最常用健脾药、理气药、活血止痛药、祛湿药;其常用药对既有独特的药物组合,又有四君子汤、六君子汤、异功散、香砂六君子汤方剂的药物组合运用;其治疗胃痛(FD)代表方剂为六君子汤或香砂六君子或两者分别合延胡索加减;其治疗胃痛(FD)的脾虚气滞证以香砂六君子汤为底方,肝郁脾虚证以逍遥散为底方,脾胃虚寒证以理中汤合四君子汤为底方。因子分析分别展现黄教授在治疗脾虚湿盛、失眠、胃胀满、反酸和咽病方面独特用药规律。黄穗平教授治疗胃痛(FD)的主要特点可概括为探求病因、补益脾胃、理气止痛、祛湿清热。实验研究NGF-PLC γ-TRPV1信号通路可能参与了脾虚型FD的内脏高敏感发生。四君子汤可能通过PLC-TRPV1信号通路降低脾虚型FD内脏高敏感性,从而起治疗作用。
[Abstract]:Objective: Functional dyspepsia (FD) is a very common digestive system disease. According to the theory of traditional Chinese medicine, functional dyspepsia postprandial discomfort syndrome belongs to the category of "fullness" and epigastralgia syndrome belongs to the category of "stomachache". In order to systematically understand the mechanism of functional dyspepsia and the visceral hypersensitivity mechanism, we summarized the related literatures on the etiology, pathogenesis, syndrome differentiation and treatment of gastralgia. In order to show the characteristics of syndromes of gastralgia (FD), the data of syndromes of gastralgia (FD) were analyzed by mathematical statistics, and to provide objective basis for guiding the treatment of clinical gastralgia (FD) and facilitate the transmission of academic experience, the medication characteristics of Professor Huang Suiping in treating gastralgia (FD) were analyzed by data mining. The mechanism of visceral hypersensitivity in dyspepsia and the therapeutic mechanism of invigorating spleen drugs provide objective and quantitative indexes for the therapeutic effect of traditional Chinese medicine at protein expression level and gene transcription level. Methods: From June 2015 to June 2016, the outpatient cases of stomachache treated by Professor Huang Suiping of Guangdong Hospital of Traditional Chinese Medicine were selected as the information source. The original data were sorted out and a standardized Excel database of stomachache syndrome and treatment was established. Based on the statistical results, the baseline characteristics of gastralgia (FD), the distribution of syndromes, the relationship between common medicines, compatibility of common medicines and syndromes were analyzed, and the therapeutic characteristics were summarized. There were 9 rats in each group: blank group, model group, Sijunzi Decoction group and Mosapride group. No model was made in blank group, and the other three groups were given iodoacetamide + small platform + fasting every other day to establish visceral hypersensitivity model of FD with spleen deficiency syndrome. Sapride was administered intragastrically for 14 days. Symptoms, body weight, electromyogram (EMG) reflecting gastric sensory movement, and the expression of nerve growth factor (NGF), phospholipase C gamma (PLC Y) and transient receptor potential capsaicin subtype 1 (TRPV1) channels in antral tissues were measured by immunohistochemistry and Real-time PCR. Results: Among the patients with stomachache (FD), 89.65% were young and middle-aged, 73.16% were females. In this study, 19 common drug pairs, 6 common five-flavor drug combinations, and 3 syndromes and drug combinations were excavated. Shen, Albizzia julibrissin bark has the third common factor of greater load; in Magnolia officinalis, Octopus, Fructus Aurantii has the sixth common factor of greater load; in Platycodon grandiflorum has the seventh common factor of greater load. After the experimental study of the model of spleen-qi deficiency, the rats curled up, lazy, slow reaction, hairy and hairy, feces underformed, weight significantly reduced, accord with. After treatment, the rats in the traditional Chinese and Western medicine group were more active, their reactions were improved, their hair color became brighter, stool formed, and spleen deficiency symptoms were improved. After drug intervention, the average weight of rats in Sijunzi Decoction group was higher than that in model group, but the difference was not statistically significant (P 0.05). There was no significant difference in body weight between Mosapride group and model group (P 0.05). After treatment, compared with the model group, the EMG amplitude of the treatment group increased and decreased, and the amplitude of the traditional Chinese medicine group was similar to that of the normal group. The trend showed that Sijunzi Decoction decreased the visceral hypersensitivity. Compared with the control group, the positive expression of NGF increased in the model group, and the difference was statistically significant (P 0.05); After drug treatment, the positive expression of NGF decreased, but there was no statistical difference (P 0.05); There was no statistical significance between the Western medicine group and the Chinese medicine group (P 0.05). The positive expression of PLC-gamma was increased, with a statistical difference (P 0.05); after drug treatment, the positive expression of PLC-gamma decreased, and the difference between the traditional Chinese medicine group and the model group was statistically significant (P 0.05); there was no significant difference between the traditional Chinese medicine group and the western medicine group (P 0.05). There was statistical difference (P 0.05); TRPV1 positive expression decreased after drug treatment, the difference between the Chinese medicine group and the model group was statistically significant (P 0.05); There was no significant difference between the Chinese medicine group and the western medicine group (P 0.05). In the mRNA transcription level, compared with the blank group, the expression level of PLC gamma and TRPV1 mRNA in the model group was significantly up-regulated, with statistical difference (P 0.0). 5) After drug treatment, the expression levels of PLC-gamma and TRPV1 mRNA were down-regulated in the western medicine group and the Chinese medicine group. Compared with the model group, there was no significant difference (P 0.05) in the western medicine group, but there was significant difference (P 0.05) in the Chinese medicine group. Conclusion: There was no significant difference between the Chinese medicine group and the western medicine group (P 0.05). Most of the patients with gastralgia (FD) are young and middle-aged women; dietary factors are important causes; the most common types of gastralgia (FD) are spleen-deficiency and Qi-stagnation syndrome. Professor Huang Suiping is the most commonly used Spleen-strengthening drug, Qi-Regulating drug, blood-activating analgesic drug, and Dampness-eliminating drug in the treatment of gastralgia (FD); his common medicines include not only a unique combination of drugs, but also Sijunzi decoction, Liujunzi decoction, Yigong powder, Xiangsha Liu The representative prescription of treating stomachache (FD) is Liujunzi Decoction or Xiangsha Liujunzi Decoction or both of them are added and subtracted by Yanhusuo respectively; the basic prescription of treating stomachache (FD) is Xiangsha Liujunzi Decoction for spleen deficiency and Qi stagnation, Xiaoyao powder for liver depression and spleen deficiency, Lizhong Decoction for spleen-stomach deficiency and cold, and Sijunzi Decoction for factor. The main characteristics of Professor Huang Suiping's treatment of gastralgia (FD) can be summarized as exploring the etiology, tonifying the spleen and stomach, regulating qi and relieving pain, dispelling dampness and clearing heat. Experimental study on NGF-PLC gamma-TRPV1 signaling pathway may be involved in the visceral hypersensitivity of FD of spleen deficiency type. Sijunzi Decoction may reduce the visceral hypersensitivity of FD of spleen deficiency type through PLC-TRPV1 signaling pathway, thus playing a therapeutic role.
【学位授予单位】：广州中医药大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R259
[Abstract]:Objective: Functional dyspepsia (FD) is a very common digestive system disease. According to the theory of traditional Chinese medicine, functional dyspepsia postprandial discomfort syndrome belongs to the category of "fullness" and epigastralgia syndrome belongs to the category of "stomachache". In order to systematically understand the mechanism of functional dyspepsia and the visceral hypersensitivity mechanism, we summarized the related literatures on the etiology, pathogenesis, syndrome differentiation and treatment of gastralgia. In order to show the characteristics of syndromes of gastralgia (FD), the data of syndromes of gastralgia (FD) were analyzed by mathematical statistics, and to provide objective basis for guiding the treatment of clinical gastralgia (FD) and facilitate the transmission of academic experience, the medication characteristics of Professor Huang Suiping in treating gastralgia (FD) were analyzed by data mining. The mechanism of visceral hypersensitivity in dyspepsia and the therapeutic mechanism of invigorating spleen drugs provide objective and quantitative indexes for the therapeutic effect of traditional Chinese medicine at protein expression level and gene transcription level. Methods: From June 2015 to June 2016, the outpatient cases of stomachache treated by Professor Huang Suiping of Guangdong Hospital of Traditional Chinese Medicine were selected as the information source. The original data were sorted out and a standardized Excel database of stomachache syndrome and treatment was established. Based on the statistical results, the baseline characteristics of gastralgia (FD), the distribution of syndromes, the relationship between common medicines, compatibility of common medicines and syndromes were analyzed, and the therapeutic characteristics were summarized. There were 9 rats in each group: blank group, model group, Sijunzi Decoction group and Mosapride group. No model was made in blank group, and the other three groups were given iodoacetamide + small platform + fasting every other day to establish visceral hypersensitivity model of FD with spleen deficiency syndrome. Sapride was administered intragastrically for 14 days. Symptoms, body weight, electromyogram (EMG) reflecting gastric sensory movement, and the expression of nerve growth factor (NGF), phospholipase C gamma (PLC Y) and transient receptor potential capsaicin subtype 1 (TRPV1) channels in antral tissues were measured by immunohistochemistry and Real-time PCR. Results: Among the patients with stomachache (FD), 89.65% were young and middle-aged, 73.16% were females. In this study, 19 common drug pairs, 6 common five-flavor drug combinations, and 3 syndromes and drug combinations were excavated. Shen, Albizzia julibrissin bark has the third common factor of greater load; in Magnolia officinalis, Octopus, Fructus Aurantii has the sixth common factor of greater load; in Platycodon grandiflorum has the seventh common factor of greater load. After the experimental study of the model of spleen-qi deficiency, the rats curled up, lazy, slow reaction, hairy and hairy, feces underformed, weight significantly reduced, accord with. After treatment, the rats in the traditional Chinese and Western medicine group were more active, their reactions were improved, their hair color became brighter, stool formed, and spleen deficiency symptoms were improved. After drug intervention, the average weight of rats in Sijunzi Decoction group was higher than that in model group, but the difference was not statistically significant (P 0.05). There was no significant difference in body weight between Mosapride group and model group (P 0.05). After treatment, compared with the model group, the EMG amplitude of the treatment group increased and decreased, and the amplitude of the traditional Chinese medicine group was similar to that of the normal group. The trend showed that Sijunzi Decoction decreased the visceral hypersensitivity. Compared with the control group, the positive expression of NGF increased in the model group, and the difference was statistically significant (P 0.05); After drug treatment, the positive expression of NGF decreased, but there was no statistical difference (P 0.05); There was no statistical significance between the Western medicine group and the Chinese medicine group (P 0.05). The positive expression of PLC-gamma was increased, with a statistical difference (P 0.05); after drug treatment, the positive expression of PLC-gamma decreased, and the difference between the traditional Chinese medicine group and the model group was statistically significant (P 0.05); there was no significant difference between the traditional Chinese medicine group and the western medicine group (P 0.05). There was statistical difference (P 0.05); TRPV1 positive expression decreased after drug treatment, the difference between the Chinese medicine group and the model group was statistically significant (P 0.05); There was no significant difference between the Chinese medicine group and the western medicine group (P 0.05). In the mRNA transcription level, compared with the blank group, the expression level of PLC gamma and TRPV1 mRNA in the model group was significantly up-regulated, with statistical difference (P 0.0). 5) After drug treatment, the expression levels of PLC-gamma and TRPV1 mRNA were down-regulated in the western medicine group and the Chinese medicine group. Compared with the model group, there was no significant difference (P 0.05) in the western medicine group, but there was significant difference (P 0.05) in the Chinese medicine group. Conclusion: There was no significant difference between the Chinese medicine group and the western medicine group (P 0.05). Most of the patients with gastralgia (FD) are young and middle-aged women; dietary factors are important causes; the most common types of gastralgia (FD) are spleen-deficiency and Qi-stagnation syndrome. Professor Huang Suiping is the most commonly used Spleen-strengthening drug, Qi-Regulating drug, blood-activating analgesic drug, and Dampness-eliminating drug in the treatment of gastralgia (FD); his common medicines include not only a unique combination of drugs, but also Sijunzi decoction, Liujunzi decoction, Yigong powder, Xiangsha Liu The representative prescription of treating stomachache (FD) is Liujunzi Decoction or Xiangsha Liujunzi Decoction or both of them are added and subtracted by Yanhusuo respectively; the basic prescription of treating stomachache (FD) is Xiangsha Liujunzi Decoction for spleen deficiency and Qi stagnation, Xiaoyao powder for liver depression and spleen deficiency, Lizhong Decoction for spleen-stomach deficiency and cold, and Sijunzi Decoction for factor. The main characteristics of Professor Huang Suiping's treatment of gastralgia (FD) can be summarized as exploring the etiology, tonifying the spleen and stomach, regulating qi and relieving pain, dispelling dampness and clearing heat. Experimental study on NGF-PLC gamma-TRPV1 signaling pathway may be involved in the visceral hypersensitivity of FD of spleen deficiency type. Sijunzi Decoction may reduce the visceral hypersensitivity of FD of spleen deficiency type through PLC-TRPV1 signaling pathway, thus playing a therapeutic role.
【学位授予单位】：广州中医药大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R259
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