摘要
目的:通过观察大黄黄连泻心汤、理中丸对消炎痛型胃溃疡寒、热证模型相关性的影响,探讨该模型的形成机制,阐明寒、热性质不同方剂对消炎痛型胃溃疡寒、热证模型的作用机理及方证相应规律,为规范临床评价标准提供可靠的实验依据。
方法:采用消炎痛注射法复制大鼠胃溃疡模型,同时施加“寒、热”因素(冰水+0.3%氢氧化钠、8%干辣椒粉+60%乙醇混合液)建立消炎痛型胃溃疡寒、热证模型,并观察寒、热方剂大黄黄连泻心汤、理中丸对其影响。检测相关微观指标:酶免法检测模型血清ET、PDGF、PAF、MOT含量;硝酸还原酶法检测模型血清NO含量;酶免法检测模型胃组织TGF-a、EGF含量;酶免法检测下丘脑组织5-HT、NE含量;免疫组化法观察Bax、Bcl-2灰度值并进行密度定量分析。结果:1、在ET方面,与空白组比较,各模型组均明显升高,有显著性差异(P<0.01),尤以寒消组升高明显,理中丸干预后,寒消理组与寒消组、单寒理组与单寒组比较含量明显降低,有统计学意义(P<0.01或P<0.05);2、在NO方面,与空白组比较,单消组、寒消组、单寒组含量明显降低,热消组、单热组含量明显升高,有统计学意义(P<0.01或P<0.05)。大黄黄连泻心汤干预后,热消大组与热消组、单热大组与单热组比较含量降低,有统计学意义(P<0.01或P<0.05);3、在PAF、PDGF方面,与空白组比较,模消组、寒消组、单寒组、热消组、单热组均可使PAF、PDGF明显升高(P<0.01或P<0.05),尤以热消组、单热组升高明显,有统计学意义(P<0.05);大黄黄连泻心汤干预后,热消大组与热消组、单热大组与单热组比较,PAF含量降低,PDGF含量明显升高,有统计学意义(P<0.01或P<0.05);理中丸干预后,寒消理组与寒消组、单寒理组与单寒组比较,PDGF含量明显升高,有统计学意义(P<0.01或P<0.05)。4、在EGF、TGF-a方面,与空白组比较,模消组、寒消组、单寒组、热消组、单热组均有不同程度的下降,有统计学意义(P<0.01),其中热消组、寒消组EGF含量下降明显,有统计学意义(P<0.01或P<0.05),理中丸干预后,寒消理组与寒消组、单寒理组与单寒组比较,EGF、TGF-a含量明显升高,有统计学意义(P<0.01),大黄黄连泻心汤干预后,热消大组与热消组、单热大组与单热组比较,EGF、TGF-a含量明显升高,有统计学意义(P<0.01或P<0.05)5、在MOT方面,与空白组比较,模消组、寒消组、热消组、单热组比较明显升高,尤以热消组升高明显,有统计学意义(P<0.01)。大黄黄连泻心汤干预后,热消大与热消、单热大与单
热比较,MOT含量明显降低,有统计学意义。6、在5-HT方面,与空白组比较,寒消组、单寒组明显升高,与热消组比较差异明显,有统计学意义(P<0.01),理中丸干预后,寒消理组与寒消组、单寒理组与单寒组比较含量明显降低,有统计学意义(P<0.01或P<0.05)7、在NE方面,与空白组比较,除单寒组外,各模型组均有同程度的升高,尤以热消组升高明显,有统计学意义(P<0.01或P<0.05),大黄黄连泻心汤干预后后,热消大组与热消组、单热大组与单热组比较含量降低,有统计学意义(P<0.01或P<0.05)。8、在Bcl-2方面,寒消组与空白组比较,阳性表达增强;寒消理与寒消比表达更强;单寒组与空白组比较表达减弱;单寒理与单寒比表达增强;热消组与空白组比较,阳性表达增强;热消大与热消比表达增强;单热与空白比表达减弱;单热大与单热比表达增强。在Bax方面,各模型组与空白组比较,灰度值降低,阳性表达增强;寒消理与寒消、热消大与热消比较,灰度值升高,阳性表达减弱,有显著性差异。
结论:
1、本课题采用消炎痛注射与寒(冰水、氢氧化钠)、热(辣椒+乙醇)因素结合,成功建立了胃溃疡寒、热证模型;寒、热因素可加重胃溃疡的形成与损伤。
2、ET、5-HT可作为胃溃疡寒证模型的微观指标NO、MOT、PAF、PDGF、NE、TGF-a、EGF可作为胃溃疡热证的微观指标。
3、理中丸对相应寒证模型有选择性,通过下调ET、5-HT含量;上调EGF、TGF-a、PDGF含量,改善抗氧化能力和调节炎性因子释放,可能是理中丸治疗胃溃疡寒证的作用机制,体现了方证相应的证治规律。
4、大黄黄连泻心汤对相应热证模型有选择性,通过下调NO、MOT、NE、PAF含量,升高EGF、TGF-a、PDGF含量,调节胃肠激素、抑制炎症反应、调节炎性因子释放,可能是大黄黄连泻心汤治疗胃溃疡热证的作用机制,体现了方证相应的证治规律。
5、大黄黄连泻心汤与理中丸通过上调Bcl-2和下调Bax表达,进而抑制胃溃疡模型细胞凋亡的表达,这可能是促进胃溃疡损伤黏膜修复机制之一。
Objective: Through observing Dahuang huanglian xiexin decoction and li zhong pill `s influence on indomethacin gastric ulcer model cold or heat types` relativity, we intend to explore the mechanism of the model, understand cold or heat different prescriptions` mechanism of action and orderliness for gastric ulcer model induced by indomethacin, in order to provide credible experimental evidences for clinical practice evaluation criteria.
Methods: The gastric ulcer models were copied by Indomethacin injection method, at the same time imposing "cold or hot" factor (ice water +0.3% NaOH, 8% dried chili powder +60% ethanol mixture). Establish the cold or heat syndrome modles of indomethacin ulcer model, and to observe the impact of cold or heat prescription Dahuang huanglian xiexin decoction and Lizhong pill. Detect the Related micro-target: The content of model serum ET, PDGF, PAF, MOT was detected by enzyme immunoassay; the content of model serum NO by Nitrate reductase; the content of model gastric tissue TGF-a, EGF by enzyme immunoassay;content; the content of hypothalamus 5-HT and NE by enzyme immunoassay. Besides, The gray value of Bax and Bc1-2 was detected and analyzed in density.
Results: 1.In the ET side, compared with the control group, the model group were significantly higher, there was significant difference (P <0.01), especially in Hanxiao groups, after the intervention of Lizhong pill, Hanxiaoli compared with Hanxiao group while Danhanli group compared with Danhan group, the content of ET is significantly lower, with statistical significance (P <0.01 or P <0.05); 2, In the NO side, compared with the control group, the model group were significantly lower, with statistically significant (P <0.01 or P <0.05), especially in Rexiao group was decreased significantly, after the intervention of Dahuang huanglian xiexin decoction, Rexiaoda group compared with Rexiao group while Danreda group compared with Danre group the content of NO decreased, with statistically significant (P <0.01 or P <0.05); 3, In the PAF, PDGF side, comparison with the control group, Moxiao Hanxiao Danhan Rexiao Danre groups can increased significantly (P <0.01 or P <0.05), especially in Rexiao Danre groups, with statistical significance(P <0.05); after the intervention of Dahuang huanglian xiexin decoction, Rexiaoda group compared with Rexiao group while Danreda group compared with Danre group, PAF decreased and PDGF were significantly higher, with statistically significant (P <0.01 or P <0.05); after the intervention of Lizhong pill, Hanxiaoli group compared with Hanxiao group while Danhanli group compared with Danhan group, PDGF were significantly higher, with statistically significant (P <0.01 or P <0.05).4. Considering EGF, TGF-a, Moxiao group, Rexiao group, Hanxiao group, Danre group and Danhan group decreased in different degree compared with the Kongbai group with the statistical significance (P <0.01). And the content of EGF of Rexiao group and Hanxiao group decreased significantly with the statistical significance (P <0.01, or P <0.05). After the intervention of Lizhong pill, the content of EGF and TGF-a of Hanxiaoli group and Danhanli group increased significantly compared with Hanxiao group and Danhan group with the statistical significance (P <0.01). After the intervention of Dahuang huanglian xiexin decoction, the content of EGF and TGF-a of Rexiaoda group and Danreda group increased significantly compared with Rexiao group and Danre group with the statistical significance (P <0.01, or P <0.05). 5. The Moxiao group, Hanxiao group, Rexiao group and Danre group increased significantly in MOT compared to Kongbai group, especially the Rexiao group with the statistical significance (P <0.01). After the intervention of Dahuang huanglian xiexin decoction, the content of MOT of Rexiaoda group and Danreda group decreased significantly compared to Rexiao group and Danre group with the statistical significance. 6. The Hanxiao group and Danhan group increased significantly in 5-HT compared to Kongbai group with the statistical significance (P <0.01). After the intervention of Lizhong pill, the content of Danxiao group and Danhan group decreased significantly compared to Hanxiao group and Danhan group with the statistical significance(P <0.01, or P <0.05). 7. In the aspect of NE content, all groups increased differently compared to Kongbai group except Danhan group, especially the Rexiao group with the statistical significance(P <0.01, or P <0.05). After the intervention of Dahuang huanglian xiexin decoction, the content of MOT of Rexiaoda group and Danreda group decreased significantly compared to Rexiao group and Danre group with the statistical significance(P <0.01, or P <0.05). 8. In the Bc1-2 and Bax content, compared to Kongbai group, the model group decreased on Bax expression, Danhan group and Danre group of Bcl-2 expression increased significantly (P <0.01 or P <0.05). The expression of Hanxiao group, Rexiao group, Hanxiaoli group and Rexiaoda group increased especially the Hanxiaoli group and Rexiaoda group; the Danhan group, Danhanli group, Danreda group and Danre group decreased especially the Danhanli group and Danreda group with the statistical significance.
Conclusions:
1. This subject uses Indomethacin injection with the cold (ice water + NaOH) or heat (chilli + ethanol) factors established the cold or heat syndrome gastric ulcer disease model successfully. Cold or heat factors can increase the formation and injury of gastric ulcer model.
2, ET、5-HT can be a microcosmic indicator of cold syndrome gastric ulcer . NO, MOT, PAF, PDGF, NE, TGF-a, EGF can be used as microcosmic indicators of heat syndrome gastric ulcer.
3.Lizhong Pill is selective to the cold syndrome model, through making down the content of ET ,5-HT, PDGF, and making up the content of EGF, TGF-a, The mechanism of Lichong Pill to treat cold syndrome peptic ulcer disease may be improving the antioxidant capacity and regulation of inflammatory cytokine release, reflecting the law of Recipe corresponding to syndrome.
4. Dahuang huanglian xiexin decoction is selective to corresponding models, and is able to Regulate gastrointestinal hormones, inhibit inflammation and regulate inflammatory cytokine release by raising the content of EGF, TGF-a and reducing the content of NO, MOT, NE, PAF. This may be mechanism of Dahuang huanglian xiexin decoction on heat of ulcer disease, reflecting treatment of the corresponding square law of evidence.
5. Dahuang huanglian xiexin decoction and the Lizhong Pill can inhibit the expression of Gastric ulcer model cell death by raising Bc1-2 and reducing Bax. This may be one of Gastric mucosal repair mechanisms for damage.
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