本文關(guān)鍵詞：胃萎清治療慢性萎縮性胃炎的臨床療效及作用機(jī)制研究　出處：《廣州中醫(yī)藥大學(xué)》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 胃萎清 慢性萎縮性胃炎 臨床療效 作用機(jī)制 JAK2/STAT3

【摘要】：背景:慢性萎縮性胃炎是慢性胃炎的一種類型,是指胃黏膜固有腺體出現(xiàn)萎縮,可伴有腸上皮化生及異型增生,帶來嚴(yán)重的公共衛(wèi)生及社會(huì)問題,嚴(yán)重影響患者社會(huì)工作能力及生存質(zhì)量。慢性萎縮性胃炎是慢性淺表性胃炎和胃癌之間的"橋梁",是胃黏膜惡性轉(zhuǎn)變的關(guān)鍵階段,通過對(duì)慢性萎縮性胃炎機(jī)制的深入研究,不僅可以一定程度揭示炎癥導(dǎo)致炎性腫瘤的發(fā)病機(jī)理,更能實(shí)施針對(duì)性預(yù)防措施,降低胃癌的發(fā)病率及死亡率。胃萎清是我們臨床治療慢性萎縮性胃炎的經(jīng)驗(yàn)方,該方由北芪,白術(shù),半枝蓮,莪術(shù),五指毛桃,枳殼組成,共奏健脾理氣,化瘀解毒的功效,以促進(jìn)臟腑功能恢復(fù),改善患者的臨床癥狀為首務(wù)。JAK2/STAT3信號(hào)通路和細(xì)胞增殖凋亡密切相關(guān),活化的STAT3可以誘導(dǎo)Bcl-2、Bcl-xL基因的表達(dá),從而抑制胃黏膜細(xì)胞的凋亡,促進(jìn)胃黏膜慢性炎癥相關(guān)的胃癌發(fā)生,因此抑制JAK2/STAT3信號(hào)通路提供了一種防治胃癌發(fā)生的可能。本研究旨在評(píng)估胃萎清顆粒治療慢性萎縮性胃炎的臨床有效性及安全性,同時(shí)以JAK2/STAT3信號(hào)通路為切入點(diǎn),分析胃萎清對(duì)慢性萎縮性胃炎(CAG)大鼠的作用機(jī)制,進(jìn)一步揭示胃萎清改善慢性萎縮性胃炎病理的分子生物學(xué)機(jī)制。目的:(1)評(píng)估胃萎清顆粒治療慢性萎縮性胃炎患者的臨床有效性及安全性。(2)本實(shí)驗(yàn)用MNNG配合饑飽失常建立慢性萎縮性胃炎的大鼠模型,觀察胃萎清顆粒對(duì)慢性萎縮性胃炎大鼠一般情況的影響,同時(shí)胃萎清對(duì)慢性萎縮性胃炎大鼠腺體萎縮、腸上皮化生的治療效果。(3)探討通過觀察JAK2/STAT3信號(hào)通路在慢性萎縮性胃炎中的表達(dá)情況,探討胃萎清顆粒對(duì)JAK2/STAT3信號(hào)通路關(guān)鍵因子的調(diào)控作用。方法:(1)臨床研究:納入慢性萎縮性胃炎患者,隨機(jī)分為胃萎清組和葉酸組,胃萎清組予胃萎清顆粒劑,1次1包,1日3次。葉酸組予葉酸片,1次5mg,1日3次。給藥24周后復(fù)查胃鏡及病理,評(píng)估組間胃黏膜萎縮、腸化、異型增生、慢性炎癥、活動(dòng)性的治療前后改變。并且評(píng)估組間上腹(胃脘)疼痛、上腹(胃脘)脹悶、上腹(胃脘)堵悶、燒心、反酸、噯氣、食欲減退、食量減少各單項(xiàng)癥狀積分及癥狀總積分的治療前后改變情況。(2)實(shí)驗(yàn)研究:70-80天SPF級(jí)SD雄性大鼠94只,體重170-200克,適應(yīng)性喂養(yǎng)1周后,隨機(jī)分為2組,即:空白組,慢性萎縮性胃炎模型組�？瞻捉M14只,慢性萎縮性胃炎模型組80只�？瞻捉M給予正常飲食,自由飲水。慢性萎縮性胃炎模型組予180μg/mL的MNNG飲用液自由飲用,結(jié)合饑飽失常法復(fù)制慢性萎縮性胃炎大鼠模型,連續(xù)造模至第14周,隨機(jī)抽取2只慢性萎縮性胃炎模型組老鼠,進(jìn)行胃黏膜病理形態(tài)組學(xué)檢查,兩只大鼠病理結(jié)果均顯示為胃黏膜固有腺體萎縮伴腸上皮化生,表明造模成功。造模成功后將慢性萎縮性胃炎模型組隨機(jī)分為5組:模型組,胃萎清高劑量組,胃萎清中劑量組,胃萎清低劑量組,葉酸組。正常對(duì)照組和模型對(duì)照組給予生理鹽水灌胃。胃萎清高、中、低劑量組灌胃給藥濃度分別為15.6g/kg/d、7.8g/kg/d、3.9g/kg/d。葉酸組給藥濃度為1.46mg/kg/d。灌胃容積10ml/kg,每日1次,連續(xù)灌胃10周。實(shí)驗(yàn)結(jié)束后取小彎側(cè)胃體—竇交界處胃黏膜,制備胃黏膜上皮組織切片。HE染色法觀察各組大鼠胃黏膜上皮萎縮、腸上皮化生情況。AB-PAS染色法觀察各組大鼠胃黏膜上皮腸上皮化生病變范圍;刮取剩余大鼠胃黏膜,Western Blot法檢測(cè)JAK2、STAT3、p-STAT3 的表達(dá)。RT-PCR 法檢測(cè) Bcl-2、Bcl-xL 的表達(dá)。結(jié)果:(1)臨床研究:本試驗(yàn)共入組64例,治療組34例,對(duì)照30例。其中2例治療組患者脫落,總共62例患者參與數(shù)據(jù)分析。①病理方面,胃萎清對(duì)慢性炎癥積分改善的效果優(yōu)于葉酸組。②在主要癥狀積分改善方面,治療組在改善上腹(胃脘)疼痛方面效果優(yōu)于對(duì)照組,對(duì)照組在治療上腹(胃脘)脹滿方面效果優(yōu)于治療組,其它方面積分治療組與對(duì)照組對(duì)比,差異無統(tǒng)計(jì)學(xué)意義。(2)實(shí)驗(yàn)研究:①HE染色顯示模型組胃黏膜腺體大部分萎縮消失,粘膜肌層增厚,間質(zhì)內(nèi)有炎性細(xì)胞浸潤,淋巴濾泡形成,可見腸上皮化生。有不同程度的變性或壞死的脫落細(xì)胞,粘膜層變薄,腺體細(xì)胞排列紊亂,腺體呈囊狀擴(kuò)張,上皮細(xì)胞形態(tài)大小不一,間質(zhì)水腫、充血。胃黏膜全層出現(xiàn)腸上皮化生,可見大量杯狀細(xì)胞。葉酸組大鼠胃黏膜呈粉紅色,光澤度差,胃黏膜變薄、皺襞紊亂,見大量炎細(xì)胞浸潤。間質(zhì)水腫、充血、炎細(xì)胞浸潤,區(qū)域粘膜可見大量腸上皮化生。胃萎清三個(gè)劑量組病理介于葉酸與空白組之間,其中以胃萎清高劑量組病理改善最明顯,胃萎清中劑量組次之,胃萎清低劑量組病理改善效果不明顯。AB-PAS染色顯示正常組大鼠胃黏膜上皮無藍(lán)色或紫色腸上皮化生灶;模型組出現(xiàn)彌漫性腸上皮化生,胃萎清治療后,則主要集中在胃腔側(cè)的細(xì)胞,其中以胃萎清高劑量組和中劑量組改善最明顯,葉酸組改善不明顯;②JAK2蛋白在模型組的表達(dá)最高,其中胃萎清高劑量組和胃萎清中劑量組表達(dá)較模型組降低。STAT3蛋白在模型組的表達(dá)最高,胃萎清三個(gè)劑量組表達(dá)較模型組降低,其中高劑量組降低最明顯。p-STAT3蛋白在模型組的表達(dá)最高,胃萎清三個(gè)劑量組表達(dá)較模型組降低,其中胃萎清高劑量組較模型組降低最明顯。和模型組比較,胃萎清高劑量組Bcl-2mRNA表達(dá)下降,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。和模型組比較,胃萎清高劑量組Bcl-xL mRNA表達(dá)下降,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。結(jié)論:(1)胃萎清可改善患者病理的慢性炎癥積分。同時(shí)胃萎清可改善上腹(胃脘)疼痛。這為胃萎清治療慢性萎縮性胃炎提供臨床證據(jù)。(2)本次研究采用MNNG溶液自由飲用、饑飽失常法的綜合造模方法,成功復(fù)制了慢性萎縮性胃炎大鼠模型。(3)胃萎清能在一定程度上緩解大鼠胃黏膜萎縮、腸上皮化生。(4)慢性萎縮性胃炎階段JAK2/STAT3的激活可能是促進(jìn)黏膜細(xì)胞過度增殖,參與胃黏膜惡性轉(zhuǎn)變過程的重要步驟,胃萎清可一定程度抑制JAK2/STAT3信號(hào)通路的活化。
[Abstract]:Background: chronic atrophic gastritis is a type of chronic gastritis, refers to gastric glands atrophy, intestinal metaplasia and dysplasia, bring social and public health problem is serious, serious impact on social work ability and life quality of patients with chronic atrophic gastritis, chronic superficial gastritis and gastric cancer between the "bridge", is the key stage of gastric malignant transformation, through in-depth study of the mechanism of chronic atrophic gastritis, can not only reveal the degree of inflammation pathogenesis of inflammatory tumor, it can implement the preventive measures to reduce the incidence and mortality of gastric cancer. Gastric atrophy is the experience of chronic atrophy gastritis treated in our clinic, the side from Beiqi, Atractylodes, Scutellaria barbata, rhizoma curcumae, Radix Fici Hirtae, Fructus aurantii, played a total of Jianpiliqi, removing blood stasis detoxification, to promote viscera function recovery, improve patients The clinical symptoms of the first.JAK2/STAT3 signal pathway and proliferation and apoptosis is closely related to the activation of STAT3 can induce Bcl-2, Bcl-xL gene expression, thereby inhibiting the apoptosis of gastric mucosal cells, promote gastric mucosa of chronic inflammation related, the inhibition of JAK2/ STAT3 signaling pathway provides a gastric cancer prevention. This research to evaluate the clinical efficacy and safety of Wei Wei Qing granule in the treatment of chronic atrophic gastritis, and the JAK2/STAT3 pathway as a starting point, analysis of Wei Wei Qing on chronic atrophic gastritis (CAG) rats, to further reveal the molecular mechanism of Wei Wei Qing to improve the pathology of chronic atrophic gastritis. Objective: (1) to assess the clinical efficacy and safety of Wei Wei Qing granule in the treatment of patients with chronic atrophic gastritis (2). The experiment used MNNG with the establishment of chronic atrophic gastritis hunger The rat model, to observe the effect of Weiwei Granule on chronic atrophic gastritis rats in general, at the same time, Wei Wei Qing on chronic atrophic gastritis rats glandular atrophy, intestinal metaplasia (3) to investigate the effect of treatment. By observing the expression of JAK2/STAT3 signaling pathway in chronic atrophic gastritis, to explore the regulation effect of Wei Wei Qing Granule on the key factors of the JAK2/STAT3 signaling pathway. Methods: (1) clinical research: in patients with chronic atrophic gastritis, gastric atrophy were randomly divided into clear group and folic acid group, Weiwei group, Qing Wei Wei Qing granules, 1 Pack 1 times 1, 3 times a day. The folic acid group to Folic Acid Tablets. The 1 time 5mg, 1 3 times a day. Review of gastroscope and pathology after treatment for 24 weeks, the evaluation group of gastric atrophy, intestinal metaplasia, dysplasia, chronic inflammation, activity changes before and after treatment and between groups were evaluated. The abdomen (stomach pain), abdomen (stomach fullness), abdomen (stomach) plugging heartburn, acid regurgitation and belching. , loss of appetite, reduce food intake changes before and after the treatment of each single symptom score and total symptom score. (2) experimental study: 70-80 days SPF 94 male SD rats, weighing 170-200 grams, after 1 weeks of feeding, were randomly divided into 2 groups: control group, chronic atrophic gastritis model group. The blank group 14, model of chronic atrophic gastritis group 80. Control group were given normal diet, free drinking drinking drinking liquid. The MNNG model of chronic atrophic gastritis group received 180 g/mL, combined with the hunger to copy the chronic atrophic gastritis rat model, continuous modeling to fourteenth weeks, random selected 2 rats model of chronic atrophic gastritis rats, gastric mucosa were pathological examination group, two rats pathological results showed gastric glands atrophy with intestinal metaplasia, showed that the model was successful. After a successful modeling of chronic atrophic gastritis were randomly divided into model group 5 Group: model group, high dose group, Wei Wei, Wei Wei Qing Wei Wei Qing middle dose group, low dose group, folic acid group and normal control group and model control group were given normal saline. Wei Wei Gao, in the low dose group, gavage concentration were 15.6g/kg/d, 7.8g/kg/d, 3.9g/kg/d. folic acid group. The drug dosage was 1.46mg/kg/d. intragastric volume 10ml/kg, 1 times daily, 10 weeks after the end of the experiment. The lesser curvature of gastric body and antrum junction of gastric mucosa, preparation of gastric epithelial tissue sections were observed by.HE in rat gastric mucosa atrophy and intestinal metaplasia staining, observe condition.AB-PAS pathological changes of gastric mucosa epithelial range of intestinal epithelial rats staining; gastric mucosal scraping the remaining rats, detection of JAK2, Western Blot STAT3, Bcl-2 p-STAT3 method to detect the expression of.RT-PCR, the expression of Bcl-xL. Results: (1) clinical research: this experiment into the group of 64 cases, 34 cases in the treatment group and the control 30 Cases. The treatment group of 2 cases of patients off a total of 62 patients participated in the data analysis. The pathology of gastric atrophy, cleaning effect is better than that of the folic acid group of chronic inflammation. The main points to improve the improvement of symptoms, the treatment group in improving abdominal pain (stomach) is better than the effect of the control group, the control group in the treatment of the abdomen (stomach fullness) is better than the treatment group, the other scores of the treatment group compared with the control group, the difference was not statistically significant. (2) experimental study: 1. HE staining showed that the model group of gastric mucosa gland atrophy mostly disappeared, muscularis mucosa thickening, interstitial inflammatory cell infiltration, lymph follicle formation, visible intestinal metaplasia. There are different degrees of degeneration or necrosis of exfoliated cells, mucous layer thinning, glandular cell disorder, gland cystic dilatation, epithelial cell size, interstitial edema and hyperemia. Gastric mucosal full-thickness intestinal on Metaplasia, showing a large number of goblet cells. The folic acid group in rat gastric mucosa was pink, gloss, gastric mucosa thinning, fold disorder, see a large number of inflammatory cells infiltration. Interstitial edema, hyperemia, inflammatory cell infiltration, mucous membrane area shows a large number of intestinal metaplasia. Between the Wei Wei Qing three dose group between pathology folic acid with the control group, the high dose of Weiwei group improved the most obvious pathological, Wei Wei Qing middle dose group, low dose group of Wei Wei Qing improved the pathological.AB-PAS staining showed that the effect is not obvious in normal group in rat gastric mucosa without blue or purple intestinal metaplasia lesions; diffuse intestinal metaplasia model Wei Wei Qing group, after treatment, mainly concentrated in the stomach cavity side of the cell, the Wei Wei Gao dose group and medium dose group improved the most obvious improvement is not obvious, the folic acid group; the JAK2 protein expression in the highest model group, high dose group, and the Wei Wei Wei Wei In the dose group was lower than model group.STAT3 protein expression in the model group the highest, Wei Wei Qing three dose group was lower than the model group, the high dose group decreased most significantly in the model group, the highest.P-STAT3 protein expression, Wei Wei Qing three dose group was lower than that of model group, the gastric atrophy high dose group than in the model group decreased most significantly. Compared with the model group, decreased expression of Wei Wei high dose group Bcl-2mRNA, the difference was statistically significant (P0.05). Compared with the model group, high dose group, Bcl-xL Wei Wei the expression of mRNA decreased, the difference was statistically significant (P0.05). Conclusion: (1) chronic stomach inflammation score Wei Qing can improve the patient pathology. At the same time, Wei Wei Qing (stomach) can improve abdominal pain. This is Wei Wei Qing to provide clinical evidence for the treatment of chronic atrophic gastritis (2). This study uses MNNG solution free drinking, the comprehensive modelling method into hunger method. Work to build the model of chronic atrophic gastritis rats. (3) Weiwei cleanergy to some extent alleviate rat gastric mucosal atrophy, intestinal metaplasia, chronic atrophic gastritis (4) stage of the activation of JAK2/STAT3 may promote proliferation of mucosal cells in gastric mucosa malignant transformation is an important step of the stomach Wei Qing can effectively inhibit the activation of JAK2/STAT3 signaling pathway.

【學(xué)位授予單位】：廣州中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R259

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1 宋廣艷;幽門螺桿菌感染致炎癥微環(huán)境改變?cè)谖s性胃炎及胃癌中作用的研究[D];山東大學(xué);2013年

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