Hp相关性胃炎脾胃湿热证病机转化规律及其代谢组学研究

发布时间：2018-04-09 12:01

本文选题：脾胃湿热　切入点：病机转化　出处：《湖北中医药大学》2017年博士论文

【摘要】：目的Hp相关性胃炎的发展存在这样一种病理演进路径:慢性非萎缩性胃炎一慢性萎缩性胃炎一肠上皮化生一不典型增生一癌变。当前大部分中医学者认为Hp与脾胃湿热关系密切,从中医的病因理论看,Hp应当是一种湿热病邪,Hp相关性胃炎与湿热温病关系紧密。叶天士在《临证指南医案》中提出“初病湿热在经,久则瘀热入络”,尤在泾在《金匮要略心典》中也有:“无邪不有毒,热从毒化,变从毒起,瘀从毒结也”的观点。湿热致病病程绵长,逐渐生变。湿热之邪侵犯人体,其初起病情较为轻浅,但湿热胶结、蕴蒸日久则化瘀化毒、瘀毒互结,入里入络,致使疾病日趋严重。湿热化毒瘀似乎和Hp相关性胃炎的病理演变有某种暗合。中医推崇上工治未病,如何从中医温病理论中发掘Hp相关性胃炎的发病规律?Hp相关性胃炎向胃癌发展过程中是否伴随有湿热化毒瘀的过程?这种转化存在客观物质基础吗?本课题围绕这些核心问题展开,在分析传统中医经典理论和现代中医学者研究的基础上,从中发掘Hp相关性胃炎脾胃湿热证病机转化的规律,同时采用代谢组学研究的方法,寻找脾胃湿热及湿热转化的相关物质基础。方法1.理论研究:在梳理了中医湿热病的发展与源流后,我们集中整理了明清温病学家所阐发的相关理论,并对现代中医学者有关Hp相关性胃炎的相关研究进行分类总结。2.代谢组学研究:采集2015年1月至2016年1月在武汉地区5家医院确诊的慢性胃炎、胃癌患者各100例,进行14C尿素呼气试验检测Hp、胃镜检查等,并进行中医辨证分型。入选实验对象为符合纳入标准的脾胃湿热型慢性胃炎患者20例,脾胃湿热型胃癌患者20例,另选取在武汉市中医医院保健科体检的健康人群20例设为健康对照组。EP管收集符合纳入标准的患者及健康志愿者的中段晨尿10ml,采集尿液的核磁谱图,对得到的相关数据采用pca和pls-da进行分析并验证。结果1.理论研究结果1.1脾胃湿热病机的主要转化方式尽管新感温病和伏气温病在发病上有所不同,但在湿热病机的传变方面并没有太大差异。从卫气营血辨证来看,脾胃湿热证会向营血分发展,也可能因治疗得当,在气分而愈。从三焦辨证看,脾胃湿热证发生在中焦脾胃,可以蕴蒸其中“在一经不移”,也可以向下传及下焦之脏肝肾或下焦之腑大肠、小肠、膀胱;还可以向上传及肺、心包、脑。从经络来看,脾胃湿热证拖延日久,会出现久病入络,合并血瘀证。“实则阳明,虚则太阴”,脾胃阳气的强盛与否影响着脾胃湿热证的转化方向。再者,体质类型影响着脾胃湿热证的转归结局,阴虚之人出现脾胃湿热容易阴液更亏,最终出现阴虚风动证,阳虚之人的脾胃湿热证最终出现肾阳虚。体质条件对脾胃湿热证的发生、转化和结局有至关重要的影响。1.2hp相关性胃炎至胃癌的中医病机转化研究hp感染通过不同的作用机制导致慢性胃炎,在疾病的后果及严重程度上除了细菌因素起重要作用外,宿主的免疫反应也是hp相关性疾病发生,特别是胃癌发生的重要决定因素。hp在胃黏膜定植后,在其繁殖、孳生、蔓延的过程中分泌毒素,暗耗人体阴阳气血,破坏人体平衡。hp所致胃病的发病特点符合温病中伏气温病的特点,发病过程中隐现湿热化毒瘀的病机转化规律。2.代谢组学研究结果2.1一般情况在进行证候判别、病理分级确诊病例并筛选后,入选实验对象60例,分为a、c、d三个组,每组20例。a组为脾胃湿热型慢性胃炎组,c组为脾胃湿热型胃癌组,d组为健康对照组。三组人员在性别、年龄、体重指数上的差异无统计学意义。2.2代谢组学分析结果本实验通过对样本的1h-nmr谱图进行分析,并对其种类进行归类后,找到可以定性定量的代谢物共59种:Ⅰ.氨基酸及其衍生物(20种);Ⅱ.氨基化合物与混合胺(9种);Ⅲ.糖类(5种);Ⅳ.有机酸类(15种);Ⅴ.其他类(10种)。通过对三组人员进行尿液代谢组学检测分析发现:在pca图中可以看到健康对照组与胃炎组,健康对照组与胃癌组有分开趋势,但胃炎组与胃癌组两组样本无法分离,进一步通过pls-da分析方法发现胃炎组与胃癌组样本有分开趋势,胃癌组与健康对照组样本有分开趋势,胃炎组与健康对照组样本分离。并通过vip图等找到三组尿液中差异代谢物11种,最后筛选出8种代谢物的差异具有显著性意义,分别是:岩藻糖、磷酸肌酸、马尿酸、甘油、葫芦巴碱、牛磺酸、氧化三甲胺、n-苯乙酰甘氨酸。通过对脾胃湿热证组(a+c组)和健康对照组(d组)进行尿液代谢组学检测分析,在pca得分图中可以看出脾胃湿热证组与健康对照组样本有分开趋势。进一步在pls-da得分图中可以看出,脾胃湿热证组样本和健康对照组样本明显分离,说明其代谢轮廓相异。并通过vip图等找到两组尿液中差异代谢物12种,最后筛选出8种代谢物为脾胃湿热证的潜在生物标志物:马尿酸、牛磺酸、岩藻糖、甘油、葫芦巴碱、氧化三甲胺、磷酸肌酸、葡萄糖。相对于健康对照组而言,脾胃湿热证组中上调的差异代谢物为:牛磺酸、岩藻糖、甘油、氧化三甲胺、葡萄糖。下调的差异代谢物为:马尿酸、葫芦巴碱、磷酸肌酸。结论1、从温病的经典著作和现代中医学者的研究总结来看,hp相关性胃炎湿热病机传变在总体上呈现这一趋势:湿热久蕴,正气日损,瘀毒渐生。2、hp作为致病因素可以归属于湿热伏气,hp相关性胃炎更容易形成脾胃湿热证,hp的发作与它的毒素基因类型有关,也与宿主的体质紧密相关,阳虚质、气虚质、痰湿质、湿热质患者更易罹患本病,hp相关性胃病发展与湿热化毒瘀,正气耗损有关。3、脾胃湿热证组与健康对照组的代谢组学差异提示脾胃湿热证存在客观物质基础。慢性胃炎脾胃湿热证与胃癌脾胃湿热证的代谢组学差异表明二者病机不尽相同,也说明病机有病的特殊性。病机的转化往往早于证的表现。4、中医的优势在于对于疾病发生发展整体性、恒动性的认知和针对病患个体进行差异性的施治。揭示疾病的中医病机,尤其是疾病转化规律,从而寻找到关键的治疗节点具有重要的临床价值。
[Abstract]:Development of Hp associated gastritis there is a pathological evolution path: chronic non atrophic gastritis of chronic atrophic gastritis with intestinal metaplasia is a typical hyperplasia of cancer. Most Chinese scholars believe that Hp and spleen is closely related to the etiology of Chinese medicine theory, Hp should be a damp heat pathogen. Hp associated gastritis and damp febrile disease closely. Ye Tianshi in "a guide to clinical practice" proposed "disease early in the long, damp heat, blood stasis and heat in collaterals", but also in the < you Zaijing jinkuiyaolue > heart Code: "innocent not poisonous, heat from the poison from poison, poison from blood stasis is the" point of view. Damp heat pathogenic lingering course and gradually changed. Damp heat invading the body, its initial condition is more shallow, but in the course of time the steam heat cements, removing blood stasis toxin, and blood stasis, enters into the network, resulting in the disease has become increasingly serious. Heat of the poison and blood stasis appears to Hp Pathological gastritis evolution has some coincidence. Respected Chinese work zhiweibing, how to explore the pathogenesis of Hp related gastritis from epidemic febrile disease of TCM theory? Hp gastritis to gastric cancer development process is accompanied by the process of heat toxin and blood stasis? This existed in the transformation of the objective material basis? This paper focuses on these core issues based on the analysis, the classical theory of traditional Chinese medicine and modern Chinese scholars, from which to explore the correlation between Hp of spleen stomach damp heat syndrome pathogenesis transformation rules, at the same time by using the method of Metabonomics Study for hot and damp heat, spleen stomach damp transformation related material basis. Methods: 1. theoretical research in combing the origin and development of traditional Chinese medicine damp heat disease, we focus on studying the theories on Febrile Diseases by the elucidation of the Ming and Qing Dynasties, and summarize the related research about the classification of.2. Hp associated gastritis of modern Chinese scholars Metabonomic study: from January 2015 to January 2016 in 5 hospitals in Wuhan were diagnosed as chronic gastritis, gastric cancer in 100 cases, 14C urea breath test Hp, gastroscopy, and TCM syndrome type. The subjects were selected in accordance with the inclusion of 20 patients with spleen stomach damp heat syndrome of chronic gastritis and 20 cases of the standard. Patients with spleen stomach damp heat syndrome of gastric cancer, and other selected in the healthy population of Wuhan City Health Department of Chinese medicine hospital physical examination of 20 cases of healthy controls were collected.EP tube met the inclusion criteria of patients and healthy volunteers midpiece urine 10ml, urine collection of NMR spectra, the data obtained by PCA and PLS-DA to analyze and verify the main way of transformation. Results of the 1. theoretical research results 1.1 pathogenesis of spleen stomach damp heat despite the new sense of febrile disease and epidemic febrile diseases in the pathogenesis of different, but in the pathogenesis of damp heat transfer and there is no big difference Different from weiqiyingxue syndrome, spleen stomach damp heat syndrome to camp blood development, may also be due to proper treatment in gas and more. From Sanjiao differentiation of spleen stomach damp heat syndrome, occur in the spleen and stomach, which can accumulate in the steam does not move "once, can also pass and coke the liver kidney or lower Jiao Fu large intestine, small intestine, bladder and lung; also be able to upload, pericardium, brain. From the point of view of meridian, spleen and stomach damp heat syndrome delay time, there will be long into the network, combined with blood stasis syndrome." in Yangming, deficiency of Spleen Yang Taiyin, strong or not affects the transformation the direction of spleen stomach damp heat syndrome. Furthermore, physical type affects the outcome of spleen stomach damp heat syndrome, yin deficiency of Yin fluid more easily appear spleen deficient, eventually Yin pneumatic syndrome, Yang of spleen stomach damp heat syndrome of kidney yang deficiency constitution. Finally conditions on spleen stomach damp heat syndrome occurrence, transformation and ending to Influence of TCM pathogenesis of.1.2hp associated gastritis to gastric cancer transformation of HP infection through different mechanisms leading to chronic gastritis, in consequence of the disease and the severity in bacterial factors play an important role, the host immune response is associated with HP disease, especially the incidence of gastric cancer were important determinants of.Hp in the stomach in the mucosa after planting, breeding, breeding, the spread of toxin secretion in the process of human consumption of dark Yin and Yang Qi and blood, body balance caused by.Hp damage incidence characteristics of stomach in line with the characteristics of epidemic febrile disease of disease of the ambush gas, pathogenesis and transformation.2. metabolomics incidence in the process of looming heat of the poison stasis in the general case 2.1 the syndrome identification, pathology confirmed cases and screening, 60 cases of experimental subjects, divided into a, C, d three groups, 20 cases each group.A spleen stomach damp heat syndrome of chronic gastritis group, C group of spleen and stomach Damp heat type gastric cancer group, D group as the healthy control group. Three groups in gender, age, body mass index of the difference was not statistically significant.2.2 metabolomics analysis results of the experiment based on the sample were analyzed by 1H-NMR spectra, and the species were classified, can be found in qualitative and quantitative metabolite 59 of amino acid and its derivatives (20); II. Amino compounds with mixed amine (9); 3. Sugar (5); IV. Organic acids (15 kinds); v. Other classes (10). The three groups were urine metabolomics analysis found: in the the PCA map can be seen in the healthy control group and gastritis group, healthy control group and gastric cancer group have separate trend, but the gastritis group and gastric cancer group, two groups of samples can not be separated, further found that the gastritis group and gastric cancer group samples were separated by the method of PLS-DA trend analysis, gastric cancer group and healthy control group samples have separate trend of stomach With control group sample separation group and health. And through the VIP map to find the differences between the three groups of urine metabolites in 11, and screen out the difference between the 8 kinds of metabolites were significant, respectively is: fucose, phosphocreatine, hippuric acid, glycerol, trigonelline, taurine, trimethylamine oxide, n- phenylacetylglycine. Based on the SSDH syndrome group (a+c group) and control group (Group D) urine metabonomic analysis detection, the PCA score plot can be seen in the spleen and stomach damp heat syndrome group and healthy control group samples have separate trend. Further can be seen in the PLS-DA score plot, spleen stomach damp heat syndrome group samples and healthy control group the sample was separated, the metabolic profile differences. And through the VIP map to find the differences between the two groups of urine metabolites in 12, finally screened potential biomarkers for 8 metabolites of spleen stomach damp heat syndrome: hippuric acid, taurine, fucose, glycerol , trigonelline, trimethylamine oxide, creatine phosphate, glucose. Compared with healthy control group, the difference in metabolite up-regulated in splenogastric damp heat syndrome is: taurine, fucose, glycerol, trimethylamine, oxidation of glucose. The difference is: cut the metabolites of hippuric acid, trigonelline, phosphocreatine. Conclusion: 1, from the research of febrile disease the classics and modern Chinese scholars summarize, pathogenesis of Hp associated gastritis of damp heat transfer has the same trend in general: Long Yun Qi, damp heat, blood stasis and toxin damage, getting.2, HP as pathogenic factors can be attributed to wet heat volt gas, Hp associated gastritis easier formation of spleen stomach damp heat syndrome, HP attack toxin gene type and its related, also with the host body is closely related to Yang deficiency, Qi deficiency, phlegm dampness, damp heat patients more prone to the disease, HP gastropathy development and heat of the poison and blood stasis, Qi depletion of.3, spleen and stomach damp heat syndrome The metabolism of group and healthy control group studies suggest that the difference of spleen stomach damp heat syndrome of the existence of objective material basis. Metabolic chronic gastritis with spleen stomach damp heat syndrome of spleen stomach damp heat syndrome differentiation of gastric cancer showed that the two diseases are not the same, also shows that the particularity of the pathogenesis of disease. The pathogenesis of transformation often early in the performance of the.4 card the advantage of traditional Chinese medicine, the disease occurrence and development of the overall, permanent change of cognition and individual differences in patient treatment. To reveal the pathogenesis of the disease, especially the disease transformation rules, in order to find the key node treatment has important clinical value.

【学位授予单位】：湖北中医药大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R259

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