参七消痞颗粒对MNNG负荷多因素致大鼠慢性萎缩性胃炎的干预作用及机制探讨
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摘要
第一部分MNNG负荷多因素致慢性萎缩性胃炎大鼠模型的建立
目的：目前常用的MNNG建立大鼠慢性萎缩性胃炎动物模型,普遍存在耗时长、费用大、造模剂量不统一、出现病理改变时间不同等问题,且普遍缺乏停止造模后是否自我恢复的观察,故本实验欲建立MNNG同时负荷雷尼替丁、乙醇刺激、饥饱失常多因素致大鼠实验性慢性萎缩性胃炎(CAG)模型,动态探究慢性萎缩性胃炎的病变过程,确定不同病变阶段的造模时间,同时观察成模后停止造模4周和8周模型动物的自我恢复情况。
方法：①观察高低两个不同浓度MNNG溶液同时负荷多因素致大鼠CAG病变情况：将雄性Wistar大鼠随机分成正常对照组(Control),模型1组(80μg/mLMNNG组)和模型2组(150μg/mLMNNG组);Control组大鼠常规饲养,自由进食饮水,模型1、2组大鼠每日自由饮用MNNG溶液(模型1组：80μg/mL;模型2组：150μg/mL),同时负荷每日灌胃给药雷尼替丁0.03g/kg大鼠体重,每周禁食一次,每次14-16小时,禁食第二天灌胃45%乙醇1mL/只,当天不再灌胃雷尼替丁。连续造模16周。
②观察停止造模后模型大鼠的自我恢复情况：16周后模型1组大鼠再随机分为停止造模后恢复组(M1-A组)和继续造模组(M1-B组),模型2组大鼠也再随机分为停止造模后恢复组(M2-A组)和继续造模组(M2-B组)。第20周各组随机小样本取材,HE染色观察各组大鼠病变情况。第24周正式取材,HE染色,分析病理结果。
③动态监测各组大鼠不同时间段的病变情况：每周观察各组大鼠的进食饮水量及活动状态；在第12、16和20周各组大鼠随机取材,收集胃液,测定胃酸分泌情况,胃组织泡于10%的福尔马林液,HE染色,分析病理结果。24周实验结束,正式取材,仍观测胃酸分泌情况和胃黏膜病理变化。
结果：①模型1组和模型2组大鼠在造模期间进食饮水量均明显减少体重增长较缓。②模型1、2组大鼠在12周已出现慢性萎缩性胃炎病变,模型2病变程度较模型1明显。③模型1、2组大鼠在16周萎缩性胃炎病变明显,模型2组部分伴有肠化生,模型1、2继续造模组大鼠20周、24周病变继续加重,多伴有肠化生。④恢复4周和8周,M1-A组和M2-A组大鼠胃黏膜病变未见明显恢复现象。恢复8周,M1-A组大鼠体重增长较明显,接近空白组体重,M2-A组大鼠体重与空白组仍有差异。⑤12、16、24周大鼠胃酸测定由于测定方法掌握不成熟,结果不能反映真实情况,具体见实验一讨论部分
结论：①MNNG负荷多因素可复制大鼠CAG模型。②大鼠饮用80μg/mLMNNG和150μg/mLMNNG溶液同时负荷其它因素12周可形成慢性萎缩性胃炎,饮用150μg/mLMNNG溶液同时负荷其它因素16周可出现肠化生20周至24周可形成胃癌前病变。③MNNG负荷多因素致大鼠CAG模型造模16周后停止造模胃黏膜病理变化未见明显自我恢复,只是低浓度80μg/mLMNNG溶液致大鼠CAG模型组停止造模恢复8周后,体重增长有明显恢复,高浓度150μg/mLMNNG溶液致大鼠CAG模型组停止造模恢复8周后体重增长未见明显恢复。
第二部分参七消痞颗粒对慢性萎缩性胃炎大鼠模型的干预作用
目的：参七消痞颗粒为董建华教授的经验方,原为东方医院院内制剂,临床用于治疗慢性萎缩性胃炎。该方由党参、三七等9味中药组成,具有益气养阴,活血消癞、清热解毒功能。复方现经过现代中药工艺制成颗粒剂。本实验参照第一部分方法建立实验性慢性萎缩性胃炎大鼠模型,观察参七消痞颗粒对模型大鼠的干预作用,为其临床疗效和新药申报提供实验基础数据。
方法：参照第一部分方法,大鼠自由饮用120μg/mLMNNG溶液同时负荷灌胃雷尼替丁、乙醇加上饥饱失常14周复制慢性萎缩性胃炎大鼠模型,之后将造模大鼠随机分为模型组,参七消痞颗粒(SQ)18、9和4.5mg/kg组,阳性药摩罗丹4.05g/kg组和叶酸(Folacin)2mg/kg组；另从实验开始即设正常对照组(Control);治疗组动物从第15周开始灌胃给药8周,模型组和正常对照组灌胃生理盐水；每周监测各组大鼠体重、进食量、饮水量；22周取材,观察各组大鼠胃酸分泌情况,胃组织作常规HE染色,计算胃黏膜厚度/黏膜肌层厚度(L1/L2)。
结果：①造模大鼠体重明显偏轻,参七消痞颗粒低剂量组和叶酸组对模型大鼠的体重增长有一定的恢复作用。②参七消痞颗粒各剂量组可明显改善慢性萎缩性胃炎大鼠的胃黏膜病变,胃壁较模型组厚,弹性较好,对肠化生及异型增生有一定的逆转作用；降低黏膜肌层厚度,升高胃黏膜厚度/黏膜肌层厚度比值(同模型组比较P<0.05、0.01)。③参七消痞颗粒高剂量组能增加胃酸酸度(同模型组比较P<0.05),参七消痞颗粒各剂量组能提高胃蛋白酶活性(同模型组比较P<0.05、0.01),促进消化。
结论：参七消痞颗粒对MNNG负荷多因素致大鼠CAG模型胃黏膜病变有显著改善作用,降低黏膜肌层厚度,提高胃黏膜厚度/黏膜肌层厚度比值,抑制胃黏膜萎缩；提高模型大鼠胃液酸度,增加胃蛋白酶活性,提示参七消痞颗粒对慢性萎缩性胃炎模型大鼠具有明显的干预作用,有很好的药效作用。
第三部分参七消痞颗粒抗慢性萎缩性胃炎大鼠模型的机制研究
目的：慢性萎缩性胃炎的病因病机至今未尚未明确,西医目前仍没有特别有效的治疗方法和特效药。中药对慢性萎缩性胃炎的临床治疗目前虽取得可喜的进展,但由于中医是辩证治疗,针对不同证型采取不同方药治则,治疗机制亦不同。本课题综合文献资料,从胃肠激素细胞因子和COX-2通路两方面探讨参七消痞颗粒抗慢性萎缩性胃炎大鼠模型的机制。
方法：实验动物及分组给药同第二部分
①放免法检测PGE2,SS,CCK,MTL,GAS,VIP胃肠激素和IL-1,GH,EGF细胞因子。胃肠激素是人体内最大的激素系统,胃肠道的每一功能几乎都受到胃肠激素的调节。其中有营养胃、保护胃黏膜的PGE2、GAS；调节胃肠道分泌功能的GAS、SS、CCK；调节胃肠运动功能的MTL、VIP、CCK、SS；细胞因子EGF、GH促进胃黏膜细胞更新修复,保护胃黏膜作用；IL-1不仅是重要的促炎因子,而且是目前已知最强的胃酸分泌抑制剂。
②酶免法检测反映胃黏膜屏障功能的胃蛋白原PGI和PG II。
③免疫组化法检测COX-2、Bcl-2、IL-10、PCNA等蛋白表达情况。COX-2调控花生四烯酸的代谢过程,在萎缩性胃炎、胃癌疾病的发生发展中扮演重要角色。COX-2主要通过调控其通路上相关的信号因子如Bcl-2、IL-10、PCNA等发挥作用。其中Bcl-2为抑制细胞凋亡蛋白；PCNA反映细胞的增殖状态；IL-10为免疫抑制因子
结果：①参七消痞颗粒各剂量组可提高血清EGF水平,能促进胃黏膜上皮细胞生长,增加胃黏膜血流量,对胃黏膜起到保护作用；②提高血清GH水平能促进萎缩胃黏膜的修复生长；③提高血清CCK水平,调节协调胃肠活动,并能促进多种消化酶的分泌；④降低血清GAS水平；⑤模型组COX-2、Bcl-2均过表达,参七消痞颗粒各剂量组能显著抑制COX-2、Bcl-2的表达(P<0.05、0.01)。
结论：参七消痞颗粒对胃肠激素及COX-2通路有明显调节干预作用,提示可能是参七消痞颗粒干预萎缩性胃炎大鼠胃黏膜病变的途径,抑制萎缩性胃炎向癌前病变甚至癌变方向发展的机制。
1. Establishment of experimental chronic atrophic gastritis rats model by MNNG and other factors
Objective At present commonly used MNNG to establish chronic atrophic gastritis model in rats exists generally time consuming, big cost, formed model dose not unified, different time of appearing pathological changes and other issues, and all most lack of observation whether it can recover after stoping making model. This experiment try to establish experimental chronic atrophic gastritis (CAG) model in rats by given MNNG, ranitidine, alcohol and hunger satiety disorders. Explore the process dynamically by MNNG and other factors.Dynamic observing the pathological process of chronic atrophic gastritis and the self recovery situation after stoping making model4weeks and8weeks.
Methods①Observing high and low two different concentrations MNNG solution loading multiple factors to build CAG rats model:Male Wistar rats were randomLy divided into3groups, including the control group, model1group (80μg/mLMNNG group) and model2group (150μg/mLMNNG group). Rats in the control group were fed with normal food, while rats in the model1and model2groups were given MNNG solution (modell:80μg/mLMNNG, model2:150ug/mL MNNG) every day;ig ranitidine0.03g/kg rats body weight; rats fasting14-16hours1times a week, ig45%alcohol after fasting,not given ranitidine that day.Continuous modeling for16weeks.
②Observe the CAG rats gastric mucosa lesions recovery situation after stoping making model:16weeks later,model1group and model2group rats were randomLy divided into2groups each, including model A group (Recovery group) and model B group(keep modeling group). In the20week killed part of each group rats, removed the gastric mucosa tissue and soaked in10%formalin liquid, HE staining, analysis the pathological results. In the24week, killed all rats, removed the gastric mucosa tissue and soaked in10%formalin liquid, HE staining, observed the gastric mucosa lesions.
〥ynamic monitoring of gastric mucosa lesions in different period of CAG in rats:weekly observation each group rats eating, drinking and activity status; observe the rats gastric acid secretion and gastric mucosa lesions by HE staining in12,16,20and24week.
Results①Model1and model2group rats eating and drinking during modeling were significantly decreased, weight growth was slower.②In12week model1and model2group rats had appeared atrophic gastritis pathological changes, model2rats got more serious lesions than modell rats.③In16week model1and model2group rats were markedly atrophic gastritis pathological changes, parts associated with intestinal metaplasia in the model2groups. Model B group rats gastric mucosa lesions continued to worsen,accompanied by intestinal metaplasia in20-.24week.④Recovery4weeks and8weeks,M1-A and M2-A group rats gastric mucosal lesions did not see obvious self-healing phenomenon,M2-B group rats associated with intestinal metaplasia and hyperlasis. Recovery8weeks M1-A group rats body weight growth obviously, close to the control group.⑤In12,16,24week, the rats gastric acid results can't reflect the real situation due to the measurement method not mastered.Specific see experiment1discussion section.
Conclusion①In summary, experimental chronic atrophic gastritis rats model can be established by MNNG with other factors.②Rats drink80μg/mL MNNG and150μg/mL MNNG solution can form chronic atrophic gastritis at the12week,drink150μg/mL MNNG solution with other factors can emerge intestinal metaplasia at the16week,and gastic precancerous lesions at the20-24week.③The CAG rats model gastric mucosa pathological changes did not see obvious recovery when stop making model for4weeks and8weeks.Only80μg/mL MNNG CAG model group rats weight growth had obvious recovery but not150μg/mL MNNG CAG model group.
2. The experimental research of SQ granule on the treatment of chronic atrophic gastritis
Objective SQ granules were professor Jianhua-Dong's experience prescription, was hospital preparations and clinical used in the treatment of chronic atrophic gastritis.It made up of9taste traditional Chinese medicine.Now it was made into granules throμ gh modern medicine technology.The purpose of this part is to establish experimental chronic atrophic gastritis(CAG) model in rats refer to the first part and explore the effect of SQ granules on rats general condition,gastric mucosal lesions, provide the basis experimental data for its clinical curative and new drug application.
Methods CAG model was established by120ug/mL MNNG solution MNNG and other factors for14weeks with reference to the first part.Then the model rats were divided into6groups randomLy, which were ig administered with saline, Moluodan,folic acid,SQ granules18、9and4.5mg/kg,respectively,taking normal rats as control group at the beginning of modeling.Monitoring each group rats general conditions.In22week, gastric tissue for routine HE staining, calculation of mucous membrane thickness/muscle layer thickness (L1/L2).
Results①The CAG rats'weight were obviously lighter than the control group, the SQ granules and folic acid group could increase the body weight of CAG rats.②SQ granules in each dose group could obviously improve the elimination of chronic atrophic gastritis rats gastric mucosa pathological changes, stomach wall thicker, flexibility was better, had a reverse effect in intestinal metaplasia and dysplasia hyperplasia,decreased the thickness of the mucosal muscularis,increased the mucous membrane of the gastric mucosa thickness/muscle layer thickness ratio.③SQ granules in each dose group could improve the gastric acid secretion and Pepsin activity.
Conclusion SQ granules had a significantly effect on improving gastric mucosa lesions of CAG model rats. It decreased the thickness of the mucosal muscularis, increased the mucous membrane of the gastric mucosa thickness/muscle layer thickness ratio, improve the gastric acid secretion and Pepsin activity. Indicated that SQ granules had obvious intervention effect for chronic atrophic gastritis, showed a good therapeutic effects.
3. The mechanism research of SQ granules on CAG rats
Objective Etiology and pathogenesis of chroic atrophic gastritis were not clear yet, and there were still no very effective treatment methods and specific western medicine. Traditional Chinese medicine had made gratifying progress for clinical treatment of CAG, but different treatment methods, treatment mechanism is also different.In this part,review the latest literatures, try to discuss the mechanism of SQ granules cureing chronic atrophic gastritis through gastrointestinal hormone, cytokines and COX-2pathway.
Methods Grouping of experimental animals and dosing see the second part.
〥etected the gastrointestinal hormone PGE2, SS, CCK, MTL, GAS, VIP and cytokines IL-1, GH, EGF by radioimmunoassay; GAS、SS、CCK have have the function of nutrion, protect the gastric mucosa; MTL、VIP、CCK、SS have the function of adjusting gastrointestinal tract secretion; GAS、SS、CCK have the function of adjusting gastric bowel movement;cytokines EGFand GH can promote gastric mucosa cell update repair, protect the gastric mucosa;IL-1is not only the important proinflammatory factor,and it is the strongest gastric acid secretion inhibitor.
②Detected PGI and PG II by enzyme immunoassay; PGI/PG II reflect the gastric mucosal barrier function.
③Detected COX-2、Bcl-2、IL-10and PCNA by immunohistochemistry. COX-2regulates the prcess of arachidonic acid metabolism and plays an important role in the development of CAG and GC. COX-2regulates the relevant signal factors on its path such as Bcl-2, IL-10and PCNA. Bcl-2inhibitor the cell apoptosis, PCNA reflects the cells proliferation status, IL-10is an immune inhibitory factor.
Results①SQ granules in each dose group could improve the level of serum EGF, promote gastric mucosa epithelial cell growth, increase the gastric mucosal blood flow, protect gastric mucosa;②Improve the level of serum GH, promote the mucosal repair;③Improve the level of serum cck, regulate the movement of the gastrointestinal tract, and promote the secretion of various digestive enzymes;④Reduce the levels of serum GAS.⑤Model group rats cox-2,bcl-2were higher expressed,and SQ granules each dose group could significantly inhibit cox-2,bcl-2expression.
Conclusion SQ granules have obvious intervention role of gastrointestinal hormone and cox-2pathway, inhibit atrophic gastritis to develop in the direction of precancerous lesions and even canceration.
目的：目前常用的MNNG建立大鼠慢性萎缩性胃炎动物模型,普遍存在耗时长、费用大、造模剂量不统一、出现病理改变时间不同等问题,且普遍缺乏停止造模后是否自我恢复的观察,故本实验欲建立MNNG同时负荷雷尼替丁、乙醇刺激、饥饱失常多因素致大鼠实验性慢性萎缩性胃炎(CAG)模型,动态探究慢性萎缩性胃炎的病变过程,确定不同病变阶段的造模时间,同时观察成模后停止造模4周和8周模型动物的自我恢复情况。
方法：①观察高低两个不同浓度MNNG溶液同时负荷多因素致大鼠CAG病变情况：将雄性Wistar大鼠随机分成正常对照组(Control),模型1组(80μg/mLMNNG组)和模型2组(150μg/mLMNNG组);Control组大鼠常规饲养,自由进食饮水,模型1、2组大鼠每日自由饮用MNNG溶液(模型1组：80μg/mL;模型2组：150μg/mL),同时负荷每日灌胃给药雷尼替丁0.03g/kg大鼠体重,每周禁食一次,每次14-16小时,禁食第二天灌胃45%乙醇1mL/只,当天不再灌胃雷尼替丁。连续造模16周。
②观察停止造模后模型大鼠的自我恢复情况：16周后模型1组大鼠再随机分为停止造模后恢复组(M1-A组)和继续造模组(M1-B组),模型2组大鼠也再随机分为停止造模后恢复组(M2-A组)和继续造模组(M2-B组)。第20周各组随机小样本取材,HE染色观察各组大鼠病变情况。第24周正式取材,HE染色,分析病理结果。
③动态监测各组大鼠不同时间段的病变情况：每周观察各组大鼠的进食饮水量及活动状态；在第12、16和20周各组大鼠随机取材,收集胃液,测定胃酸分泌情况,胃组织泡于10%的福尔马林液,HE染色,分析病理结果。24周实验结束,正式取材,仍观测胃酸分泌情况和胃黏膜病理变化。
结果：①模型1组和模型2组大鼠在造模期间进食饮水量均明显减少体重增长较缓。②模型1、2组大鼠在12周已出现慢性萎缩性胃炎病变,模型2病变程度较模型1明显。③模型1、2组大鼠在16周萎缩性胃炎病变明显,模型2组部分伴有肠化生,模型1、2继续造模组大鼠20周、24周病变继续加重,多伴有肠化生。④恢复4周和8周,M1-A组和M2-A组大鼠胃黏膜病变未见明显恢复现象。恢复8周,M1-A组大鼠体重增长较明显,接近空白组体重,M2-A组大鼠体重与空白组仍有差异。⑤12、16、24周大鼠胃酸测定由于测定方法掌握不成熟,结果不能反映真实情况,具体见实验一讨论部分
结论：①MNNG负荷多因素可复制大鼠CAG模型。②大鼠饮用80μg/mLMNNG和150μg/mLMNNG溶液同时负荷其它因素12周可形成慢性萎缩性胃炎,饮用150μg/mLMNNG溶液同时负荷其它因素16周可出现肠化生20周至24周可形成胃癌前病变。③MNNG负荷多因素致大鼠CAG模型造模16周后停止造模胃黏膜病理变化未见明显自我恢复,只是低浓度80μg/mLMNNG溶液致大鼠CAG模型组停止造模恢复8周后,体重增长有明显恢复,高浓度150μg/mLMNNG溶液致大鼠CAG模型组停止造模恢复8周后体重增长未见明显恢复。
第二部分参七消痞颗粒对慢性萎缩性胃炎大鼠模型的干预作用
目的：参七消痞颗粒为董建华教授的经验方,原为东方医院院内制剂,临床用于治疗慢性萎缩性胃炎。该方由党参、三七等9味中药组成,具有益气养阴,活血消癞、清热解毒功能。复方现经过现代中药工艺制成颗粒剂。本实验参照第一部分方法建立实验性慢性萎缩性胃炎大鼠模型,观察参七消痞颗粒对模型大鼠的干预作用,为其临床疗效和新药申报提供实验基础数据。
方法：参照第一部分方法,大鼠自由饮用120μg/mLMNNG溶液同时负荷灌胃雷尼替丁、乙醇加上饥饱失常14周复制慢性萎缩性胃炎大鼠模型,之后将造模大鼠随机分为模型组,参七消痞颗粒(SQ)18、9和4.5mg/kg组,阳性药摩罗丹4.05g/kg组和叶酸(Folacin)2mg/kg组；另从实验开始即设正常对照组(Control);治疗组动物从第15周开始灌胃给药8周,模型组和正常对照组灌胃生理盐水；每周监测各组大鼠体重、进食量、饮水量；22周取材,观察各组大鼠胃酸分泌情况,胃组织作常规HE染色,计算胃黏膜厚度/黏膜肌层厚度(L1/L2)。
结果：①造模大鼠体重明显偏轻,参七消痞颗粒低剂量组和叶酸组对模型大鼠的体重增长有一定的恢复作用。②参七消痞颗粒各剂量组可明显改善慢性萎缩性胃炎大鼠的胃黏膜病变,胃壁较模型组厚,弹性较好,对肠化生及异型增生有一定的逆转作用；降低黏膜肌层厚度,升高胃黏膜厚度/黏膜肌层厚度比值(同模型组比较P<0.05、0.01)。③参七消痞颗粒高剂量组能增加胃酸酸度(同模型组比较P<0.05),参七消痞颗粒各剂量组能提高胃蛋白酶活性(同模型组比较P<0.05、0.01),促进消化。
结论：参七消痞颗粒对MNNG负荷多因素致大鼠CAG模型胃黏膜病变有显著改善作用,降低黏膜肌层厚度,提高胃黏膜厚度/黏膜肌层厚度比值,抑制胃黏膜萎缩；提高模型大鼠胃液酸度,增加胃蛋白酶活性,提示参七消痞颗粒对慢性萎缩性胃炎模型大鼠具有明显的干预作用,有很好的药效作用。
第三部分参七消痞颗粒抗慢性萎缩性胃炎大鼠模型的机制研究
目的：慢性萎缩性胃炎的病因病机至今未尚未明确,西医目前仍没有特别有效的治疗方法和特效药。中药对慢性萎缩性胃炎的临床治疗目前虽取得可喜的进展,但由于中医是辩证治疗,针对不同证型采取不同方药治则,治疗机制亦不同。本课题综合文献资料,从胃肠激素细胞因子和COX-2通路两方面探讨参七消痞颗粒抗慢性萎缩性胃炎大鼠模型的机制。
方法：实验动物及分组给药同第二部分
①放免法检测PGE2,SS,CCK,MTL,GAS,VIP胃肠激素和IL-1,GH,EGF细胞因子。胃肠激素是人体内最大的激素系统,胃肠道的每一功能几乎都受到胃肠激素的调节。其中有营养胃、保护胃黏膜的PGE2、GAS；调节胃肠道分泌功能的GAS、SS、CCK；调节胃肠运动功能的MTL、VIP、CCK、SS；细胞因子EGF、GH促进胃黏膜细胞更新修复,保护胃黏膜作用；IL-1不仅是重要的促炎因子,而且是目前已知最强的胃酸分泌抑制剂。
②酶免法检测反映胃黏膜屏障功能的胃蛋白原PGI和PG II。
③免疫组化法检测COX-2、Bcl-2、IL-10、PCNA等蛋白表达情况。COX-2调控花生四烯酸的代谢过程,在萎缩性胃炎、胃癌疾病的发生发展中扮演重要角色。COX-2主要通过调控其通路上相关的信号因子如Bcl-2、IL-10、PCNA等发挥作用。其中Bcl-2为抑制细胞凋亡蛋白；PCNA反映细胞的增殖状态；IL-10为免疫抑制因子
结果：①参七消痞颗粒各剂量组可提高血清EGF水平,能促进胃黏膜上皮细胞生长,增加胃黏膜血流量,对胃黏膜起到保护作用；②提高血清GH水平能促进萎缩胃黏膜的修复生长；③提高血清CCK水平,调节协调胃肠活动,并能促进多种消化酶的分泌；④降低血清GAS水平；⑤模型组COX-2、Bcl-2均过表达,参七消痞颗粒各剂量组能显著抑制COX-2、Bcl-2的表达(P<0.05、0.01)。
结论：参七消痞颗粒对胃肠激素及COX-2通路有明显调节干预作用,提示可能是参七消痞颗粒干预萎缩性胃炎大鼠胃黏膜病变的途径,抑制萎缩性胃炎向癌前病变甚至癌变方向发展的机制。
1. Establishment of experimental chronic atrophic gastritis rats model by MNNG and other factors
Objective At present commonly used MNNG to establish chronic atrophic gastritis model in rats exists generally time consuming, big cost, formed model dose not unified, different time of appearing pathological changes and other issues, and all most lack of observation whether it can recover after stoping making model. This experiment try to establish experimental chronic atrophic gastritis (CAG) model in rats by given MNNG, ranitidine, alcohol and hunger satiety disorders. Explore the process dynamically by MNNG and other factors.Dynamic observing the pathological process of chronic atrophic gastritis and the self recovery situation after stoping making model4weeks and8weeks.
Methods①Observing high and low two different concentrations MNNG solution loading multiple factors to build CAG rats model:Male Wistar rats were randomLy divided into3groups, including the control group, model1group (80μg/mLMNNG group) and model2group (150μg/mLMNNG group). Rats in the control group were fed with normal food, while rats in the model1and model2groups were given MNNG solution (modell:80μg/mLMNNG, model2:150ug/mL MNNG) every day;ig ranitidine0.03g/kg rats body weight; rats fasting14-16hours1times a week, ig45%alcohol after fasting,not given ranitidine that day.Continuous modeling for16weeks.
②Observe the CAG rats gastric mucosa lesions recovery situation after stoping making model:16weeks later,model1group and model2group rats were randomLy divided into2groups each, including model A group (Recovery group) and model B group(keep modeling group). In the20week killed part of each group rats, removed the gastric mucosa tissue and soaked in10%formalin liquid, HE staining, analysis the pathological results. In the24week, killed all rats, removed the gastric mucosa tissue and soaked in10%formalin liquid, HE staining, observed the gastric mucosa lesions.
〥ynamic monitoring of gastric mucosa lesions in different period of CAG in rats:weekly observation each group rats eating, drinking and activity status; observe the rats gastric acid secretion and gastric mucosa lesions by HE staining in12,16,20and24week.
Results①Model1and model2group rats eating and drinking during modeling were significantly decreased, weight growth was slower.②In12week model1and model2group rats had appeared atrophic gastritis pathological changes, model2rats got more serious lesions than modell rats.③In16week model1and model2group rats were markedly atrophic gastritis pathological changes, parts associated with intestinal metaplasia in the model2groups. Model B group rats gastric mucosa lesions continued to worsen,accompanied by intestinal metaplasia in20-.24week.④Recovery4weeks and8weeks,M1-A and M2-A group rats gastric mucosal lesions did not see obvious self-healing phenomenon,M2-B group rats associated with intestinal metaplasia and hyperlasis. Recovery8weeks M1-A group rats body weight growth obviously, close to the control group.⑤In12,16,24week, the rats gastric acid results can't reflect the real situation due to the measurement method not mastered.Specific see experiment1discussion section.
Conclusion①In summary, experimental chronic atrophic gastritis rats model can be established by MNNG with other factors.②Rats drink80μg/mL MNNG and150μg/mL MNNG solution can form chronic atrophic gastritis at the12week,drink150μg/mL MNNG solution with other factors can emerge intestinal metaplasia at the16week,and gastic precancerous lesions at the20-24week.③The CAG rats model gastric mucosa pathological changes did not see obvious recovery when stop making model for4weeks and8weeks.Only80μg/mL MNNG CAG model group rats weight growth had obvious recovery but not150μg/mL MNNG CAG model group.
2. The experimental research of SQ granule on the treatment of chronic atrophic gastritis
Objective SQ granules were professor Jianhua-Dong's experience prescription, was hospital preparations and clinical used in the treatment of chronic atrophic gastritis.It made up of9taste traditional Chinese medicine.Now it was made into granules throμ gh modern medicine technology.The purpose of this part is to establish experimental chronic atrophic gastritis(CAG) model in rats refer to the first part and explore the effect of SQ granules on rats general condition,gastric mucosal lesions, provide the basis experimental data for its clinical curative and new drug application.
Methods CAG model was established by120ug/mL MNNG solution MNNG and other factors for14weeks with reference to the first part.Then the model rats were divided into6groups randomLy, which were ig administered with saline, Moluodan,folic acid,SQ granules18、9and4.5mg/kg,respectively,taking normal rats as control group at the beginning of modeling.Monitoring each group rats general conditions.In22week, gastric tissue for routine HE staining, calculation of mucous membrane thickness/muscle layer thickness (L1/L2).
Results①The CAG rats'weight were obviously lighter than the control group, the SQ granules and folic acid group could increase the body weight of CAG rats.②SQ granules in each dose group could obviously improve the elimination of chronic atrophic gastritis rats gastric mucosa pathological changes, stomach wall thicker, flexibility was better, had a reverse effect in intestinal metaplasia and dysplasia hyperplasia,decreased the thickness of the mucosal muscularis,increased the mucous membrane of the gastric mucosa thickness/muscle layer thickness ratio.③SQ granules in each dose group could improve the gastric acid secretion and Pepsin activity.
Conclusion SQ granules had a significantly effect on improving gastric mucosa lesions of CAG model rats. It decreased the thickness of the mucosal muscularis, increased the mucous membrane of the gastric mucosa thickness/muscle layer thickness ratio, improve the gastric acid secretion and Pepsin activity. Indicated that SQ granules had obvious intervention effect for chronic atrophic gastritis, showed a good therapeutic effects.
3. The mechanism research of SQ granules on CAG rats
Objective Etiology and pathogenesis of chroic atrophic gastritis were not clear yet, and there were still no very effective treatment methods and specific western medicine. Traditional Chinese medicine had made gratifying progress for clinical treatment of CAG, but different treatment methods, treatment mechanism is also different.In this part,review the latest literatures, try to discuss the mechanism of SQ granules cureing chronic atrophic gastritis through gastrointestinal hormone, cytokines and COX-2pathway.
Methods Grouping of experimental animals and dosing see the second part.
〥etected the gastrointestinal hormone PGE2, SS, CCK, MTL, GAS, VIP and cytokines IL-1, GH, EGF by radioimmunoassay; GAS、SS、CCK have have the function of nutrion, protect the gastric mucosa; MTL、VIP、CCK、SS have the function of adjusting gastrointestinal tract secretion; GAS、SS、CCK have the function of adjusting gastric bowel movement;cytokines EGFand GH can promote gastric mucosa cell update repair, protect the gastric mucosa;IL-1is not only the important proinflammatory factor,and it is the strongest gastric acid secretion inhibitor.
②Detected PGI and PG II by enzyme immunoassay; PGI/PG II reflect the gastric mucosal barrier function.
③Detected COX-2、Bcl-2、IL-10and PCNA by immunohistochemistry. COX-2regulates the prcess of arachidonic acid metabolism and plays an important role in the development of CAG and GC. COX-2regulates the relevant signal factors on its path such as Bcl-2, IL-10and PCNA. Bcl-2inhibitor the cell apoptosis, PCNA reflects the cells proliferation status, IL-10is an immune inhibitory factor.
Results①SQ granules in each dose group could improve the level of serum EGF, promote gastric mucosa epithelial cell growth, increase the gastric mucosal blood flow, protect gastric mucosa;②Improve the level of serum GH, promote the mucosal repair;③Improve the level of serum cck, regulate the movement of the gastrointestinal tract, and promote the secretion of various digestive enzymes;④Reduce the levels of serum GAS.⑤Model group rats cox-2,bcl-2were higher expressed,and SQ granules each dose group could significantly inhibit cox-2,bcl-2expression.
Conclusion SQ granules have obvious intervention role of gastrointestinal hormone and cox-2pathway, inhibit atrophic gastritis to develop in the direction of precancerous lesions and even canceration.
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