络风宁1号方治疗不稳定性心绞痛的临床观察及其对巨噬细胞炎症因子的影响
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摘要
背景
动脉粥样硬化(AS)引发的急性心脑血管病是一种严重威害人们生命和健康的疾病,如何防治AS成为全球医学界研究的焦点之一。中医药通过辨证论治和整体调节人体功能在防治AS方面有着独特的优势,并取得了显著的临床效果。但研究表明,即使积极干预心血管危险因素,仍有60%以上患者的AS斑块在进展,最终引发急性心脑血管疾病。导师王显教授在学习和总结古今医家理论及经验的基础上,对动脉粥样硬化的病因病机及其中西医结合防治策略进行创新性思考和探索,提出动脉粥样硬化“络风内动”学说,指出“络风内动”乃急性冠脉综合征的重要病机之一,并创制络风宁1号方用于冠心病不稳定性心绞痛的治疗。
目的
本课题从络风宁1号治疗冠心病不稳定性心绞痛临床疗效观察及其对巨噬细胞炎症因子的影响两方面进行研究,以期能佐证动脉粥样硬化“络风内动”学说的科学内涵。
方法
1临床研究
依据随机对照的原则,将60例不稳定性心绞痛的合格病例分为治疗组(基础治疗+络风宁1号颗粒剂)和对照组(基础治疗+匹伐他汀钙),服药4周后,观察两组患者心绞痛发作情况、中医症状积分及心电图的变化情况,同时使用ELISA i去检测患者用药前后血清炎症因子IL-6、MMP-9的浓度变化
2实验研究
(1)单核细胞(THP-1)的培养：经过对THP-1细胞的复苏、培养、传代,建立稳定的细胞实验平台。
(2)MTT试验法确定佛波酯(PMA)对正常培养的THP-1细胞最佳诱导浓度：通过检测细胞活性变化,观察正常培养下的THP-1细胞经不同浓度、不同时间的PMA处理后细胞的分化情况,以确定安全有效的诱导浓度。
(3)MTT试验法确定络风宁1号含药血清最佳作用浓度：通过检测细胞活性变化,观察THP-1源性巨噬细胞经不同浓度含药血清处理后细胞的增殖情况,以确定安全有效的作用浓度。
(4) THP-1源性巨噬细胞炎性损伤模型的建立：通过检测细胞活性变化,观察THP-1源性巨噬细胞经不同浓度脂多糖(LPS)刺激后的细胞增殖情况,以确定最佳造模浓度。
(5)络风宁1号含药血清对THP-1源性巨噬细胞炎症因子的影响：通过实时荧光定量PCR(real-t ime quant itat ive PCR)实验对TLR4mRNA、MyD88mRNA、 NF-KBp65mRNA进行相对定量,同时以ELISA法检测细胞上清液中炎症因子IL-6,TNF-α,MMP-9的浓度,观察络风宁1号含药血清对巨噬细胞炎症因子的影响。
结果
1、治疗组可明显改善患者心绞痛发作情况及中医症状,与对照组相比,P<0.05,且总体疗效优于对照组(P<0.05)。
2、刚复苏的THP-1单核细胞为非贴壁形式生长,体积较小,为圆形；培养48h后,细胞体积逐渐变大,细胞密度也增大。
3、诱导24h或48h,PMA80组与对照组均有显著性差异(P<0.01)；且诱导24h时的A均值明显高于诱导48h时的A均值(P<0.05)；故以PMA80nmol/L诱导24小时为最佳诱导条件。
4、10%浓度的中药血清可抑制细胞增殖,与对照组相比,P<0.01；15%与20%浓度的空白血清与5%的空白血清相比,则显示出血清对细胞的毒性,P<0.01；故以10%浓度的含药血清为最佳浓度。
5、LPS可刺激细胞增殖,与对照组相比,1μg/ml组与对照组相比有明显增殖作用,且P<0.01。
6、TLR4mRNA与MyD88mRNA表达有相同的趋势,模型组低于空白组(P<0.01)；NF-κBP65mRNA的表达：空白组明显低于与模型组(P<0.05),中药血清高浓度组及西药血清组低于模型组(P<0.05)；随着中药各组含药血清浓度的增加,NF-κBP65RNA的表达逐渐降低(P<0.01或0.05)。
7、炎症因子IL-6,TNF-α, MMP-9蛋白表达量有相同的趋势,模型组明显高于空白组(P<0.01或0.05),中药血清高浓度组及西药血清组低于模型组(P<0.05)随着中药各组含药血清浓度的增加,3种炎症因子的表达均逐渐降低(P<0.05)。
结论
1、络风宁1号颗粒剂治疗不稳定性心绞痛有一定的临床疗效。
2、络风宁1号含药血清呈剂量依赖型抑制NF-κBp65mRNA的表达。
3、络风宁1号含药血清呈剂量依赖型抑制TNF-α、MMP-9与IL-6的表达。
Background
Atherosclerosis (AS) which can bring about the acute cerebrovascular disease has been a serious threat to human lives and health. So how to control AS has become one of the focus of global medical research. By means of syndrome differentiation and overall adjustment the function of the body,Traditional Chinese medicine has a unique advantage in the prevention and treatment of AS. In recent years, Professor Wang put forward the hypothesis that: endogenous collateral wind is, one of the important pathogenesis of acute coronary syndrome, and create a formula which is called Luofengning-1(LFN-1) for the treatment of unstable angina.
Purpose
In order to elaborate the connotation of the hypothesis of endogenous collateral wind, we'll study on this topic from two methods:first, we observe the clinical effect of LFN-1;and then we explore the impact which the formula make on Macrophage inflammatory factors.
Methods
1. Clinical study
According to the random, positive-control principle, all the eligible patients were divided into treatment group (routine treatment and LFN-1) and the control group (routine treatment and pitavastatin calcium).After4weeks, we compared the change of TCM symptoms and ECG, and observed the state of this illness. At the same time, the changes of serum inflammatory factors, such as IL-6, MMP-9were detected with ELISA method before and after the treatment.
2. Experimental study
(1) The culture of THP-1cells:
After the recovery, training, passages of THP-1cells, we had established a stable cell experiment platform.
(2) Determined the best concentration of PMA which differentiated the THP-1cells into macrophages:
By means of detecting the change of cells activity, we observed the state of normal cultured THP-1cells which were treated with PMA under different concentrations and time, and then determined the best effective concentration.
(3) Determined the best working concentration of the LFN-1medicated serum:
Through detecting changes in cells activity, we observed the proliferation of the THP-1derived macrophages which were treated with medicated serum of different concentration,and then determined the most safe and effective concentration.
(4) Established the inflammatory injury model of the THP-1derived macrophages: By the aid of detecting changes in cells activity, we observed the proliferation of the THP-1derived macrophages which were treated with different concentration of lipopolysaccharide (LPS),and then determine the best concentration for molding.
(5) Effect of LFN-1medicated serum on macrophage inflammatory factors: TLR4mRNA, MyD88mRNA, NF-KBp65mRNA were analysed relatively and quantitatively by means of RT-PCR. At the same time, the inflammatory factors such as IL-6, TNF-α, MMP-9in cell supernatant were detected by ELISA assay.
Results
1. The Treatment group can obviously reduce the attacks of angina (P<0.05), and the overall effect was better than the control group (P<0.05). At the same time, the treatment group can better improve the symptoms of TCM, and there was a significant difference between the two groups (P<0.05).
2. The THP-1cells were non-adherent, smaller and round at the beginning of the recovery; but after48h incubation, cell volume becomes larger and the density of the cells increased too.
3. The best induced condition was PMA of80nmol/L for24h.
4. The best concentration of the LFN-1medicated serum was10%.
5. The most suitable concentration of LPS for modeling was lμg/ml.
6. The expression of NF-κBp65mRNA was significantly lower than that in the model group while the expression of TLR4mRNA and MyD88mRNA was higher than the control group.Compared with the model group, the expression of NF-κBp65mRNA had been gradually reduced with the increasing concentration of LFN-1medicated serum.
7. The concentration of TNF-α、MMP-9and IL-6in control group was significantly lower than that in the model group,and the difference was statistically significant (P<0.01or0.05).The expression of three cytokines in TCM groups were significantly decreased compared with the model group. And furthermore, the expression of the three cytokines had been gradually reduced with the increasing concentration of LFN-1medicated serum.
Conclusion
1. The method of expelling wind and wet is effective to a certain extent in the treatment of unstable angina.
2. The expression of NF-κBp65mRNA was gradually reduced dependent on the concentration of LFN-1medicated serum.
3. The expression of TNF-α、MMP-9and IL-6was gradually reduced dependent on the concentration of LFN-1medicated serum.
动脉粥样硬化(AS)引发的急性心脑血管病是一种严重威害人们生命和健康的疾病,如何防治AS成为全球医学界研究的焦点之一。中医药通过辨证论治和整体调节人体功能在防治AS方面有着独特的优势,并取得了显著的临床效果。但研究表明,即使积极干预心血管危险因素,仍有60%以上患者的AS斑块在进展,最终引发急性心脑血管疾病。导师王显教授在学习和总结古今医家理论及经验的基础上,对动脉粥样硬化的病因病机及其中西医结合防治策略进行创新性思考和探索,提出动脉粥样硬化“络风内动”学说,指出“络风内动”乃急性冠脉综合征的重要病机之一,并创制络风宁1号方用于冠心病不稳定性心绞痛的治疗。
目的
本课题从络风宁1号治疗冠心病不稳定性心绞痛临床疗效观察及其对巨噬细胞炎症因子的影响两方面进行研究,以期能佐证动脉粥样硬化“络风内动”学说的科学内涵。
方法
1临床研究
依据随机对照的原则,将60例不稳定性心绞痛的合格病例分为治疗组(基础治疗+络风宁1号颗粒剂)和对照组(基础治疗+匹伐他汀钙),服药4周后,观察两组患者心绞痛发作情况、中医症状积分及心电图的变化情况,同时使用ELISA i去检测患者用药前后血清炎症因子IL-6、MMP-9的浓度变化
2实验研究
(1)单核细胞(THP-1)的培养：经过对THP-1细胞的复苏、培养、传代,建立稳定的细胞实验平台。
(2)MTT试验法确定佛波酯(PMA)对正常培养的THP-1细胞最佳诱导浓度：通过检测细胞活性变化,观察正常培养下的THP-1细胞经不同浓度、不同时间的PMA处理后细胞的分化情况,以确定安全有效的诱导浓度。
(3)MTT试验法确定络风宁1号含药血清最佳作用浓度：通过检测细胞活性变化,观察THP-1源性巨噬细胞经不同浓度含药血清处理后细胞的增殖情况,以确定安全有效的作用浓度。
(4) THP-1源性巨噬细胞炎性损伤模型的建立：通过检测细胞活性变化,观察THP-1源性巨噬细胞经不同浓度脂多糖(LPS)刺激后的细胞增殖情况,以确定最佳造模浓度。
(5)络风宁1号含药血清对THP-1源性巨噬细胞炎症因子的影响：通过实时荧光定量PCR(real-t ime quant itat ive PCR)实验对TLR4mRNA、MyD88mRNA、 NF-KBp65mRNA进行相对定量,同时以ELISA法检测细胞上清液中炎症因子IL-6,TNF-α,MMP-9的浓度,观察络风宁1号含药血清对巨噬细胞炎症因子的影响。
结果
1、治疗组可明显改善患者心绞痛发作情况及中医症状,与对照组相比,P<0.05,且总体疗效优于对照组(P<0.05)。
2、刚复苏的THP-1单核细胞为非贴壁形式生长,体积较小,为圆形；培养48h后,细胞体积逐渐变大,细胞密度也增大。
3、诱导24h或48h,PMA80组与对照组均有显著性差异(P<0.01)；且诱导24h时的A均值明显高于诱导48h时的A均值(P<0.05)；故以PMA80nmol/L诱导24小时为最佳诱导条件。
4、10%浓度的中药血清可抑制细胞增殖,与对照组相比,P<0.01；15%与20%浓度的空白血清与5%的空白血清相比,则显示出血清对细胞的毒性,P<0.01；故以10%浓度的含药血清为最佳浓度。
5、LPS可刺激细胞增殖,与对照组相比,1μg/ml组与对照组相比有明显增殖作用,且P<0.01。
6、TLR4mRNA与MyD88mRNA表达有相同的趋势,模型组低于空白组(P<0.01)；NF-κBP65mRNA的表达：空白组明显低于与模型组(P<0.05),中药血清高浓度组及西药血清组低于模型组(P<0.05)；随着中药各组含药血清浓度的增加,NF-κBP65RNA的表达逐渐降低(P<0.01或0.05)。
7、炎症因子IL-6,TNF-α, MMP-9蛋白表达量有相同的趋势,模型组明显高于空白组(P<0.01或0.05),中药血清高浓度组及西药血清组低于模型组(P<0.05)随着中药各组含药血清浓度的增加,3种炎症因子的表达均逐渐降低(P<0.05)。
结论
1、络风宁1号颗粒剂治疗不稳定性心绞痛有一定的临床疗效。
2、络风宁1号含药血清呈剂量依赖型抑制NF-κBp65mRNA的表达。
3、络风宁1号含药血清呈剂量依赖型抑制TNF-α、MMP-9与IL-6的表达。
Background
Atherosclerosis (AS) which can bring about the acute cerebrovascular disease has been a serious threat to human lives and health. So how to control AS has become one of the focus of global medical research. By means of syndrome differentiation and overall adjustment the function of the body,Traditional Chinese medicine has a unique advantage in the prevention and treatment of AS. In recent years, Professor Wang put forward the hypothesis that: endogenous collateral wind is, one of the important pathogenesis of acute coronary syndrome, and create a formula which is called Luofengning-1(LFN-1) for the treatment of unstable angina.
Purpose
In order to elaborate the connotation of the hypothesis of endogenous collateral wind, we'll study on this topic from two methods:first, we observe the clinical effect of LFN-1;and then we explore the impact which the formula make on Macrophage inflammatory factors.
Methods
1. Clinical study
According to the random, positive-control principle, all the eligible patients were divided into treatment group (routine treatment and LFN-1) and the control group (routine treatment and pitavastatin calcium).After4weeks, we compared the change of TCM symptoms and ECG, and observed the state of this illness. At the same time, the changes of serum inflammatory factors, such as IL-6, MMP-9were detected with ELISA method before and after the treatment.
2. Experimental study
(1) The culture of THP-1cells:
After the recovery, training, passages of THP-1cells, we had established a stable cell experiment platform.
(2) Determined the best concentration of PMA which differentiated the THP-1cells into macrophages:
By means of detecting the change of cells activity, we observed the state of normal cultured THP-1cells which were treated with PMA under different concentrations and time, and then determined the best effective concentration.
(3) Determined the best working concentration of the LFN-1medicated serum:
Through detecting changes in cells activity, we observed the proliferation of the THP-1derived macrophages which were treated with medicated serum of different concentration,and then determined the most safe and effective concentration.
(4) Established the inflammatory injury model of the THP-1derived macrophages: By the aid of detecting changes in cells activity, we observed the proliferation of the THP-1derived macrophages which were treated with different concentration of lipopolysaccharide (LPS),and then determine the best concentration for molding.
(5) Effect of LFN-1medicated serum on macrophage inflammatory factors: TLR4mRNA, MyD88mRNA, NF-KBp65mRNA were analysed relatively and quantitatively by means of RT-PCR. At the same time, the inflammatory factors such as IL-6, TNF-α, MMP-9in cell supernatant were detected by ELISA assay.
Results
1. The Treatment group can obviously reduce the attacks of angina (P<0.05), and the overall effect was better than the control group (P<0.05). At the same time, the treatment group can better improve the symptoms of TCM, and there was a significant difference between the two groups (P<0.05).
2. The THP-1cells were non-adherent, smaller and round at the beginning of the recovery; but after48h incubation, cell volume becomes larger and the density of the cells increased too.
3. The best induced condition was PMA of80nmol/L for24h.
4. The best concentration of the LFN-1medicated serum was10%.
5. The most suitable concentration of LPS for modeling was lμg/ml.
6. The expression of NF-κBp65mRNA was significantly lower than that in the model group while the expression of TLR4mRNA and MyD88mRNA was higher than the control group.Compared with the model group, the expression of NF-κBp65mRNA had been gradually reduced with the increasing concentration of LFN-1medicated serum.
7. The concentration of TNF-α、MMP-9and IL-6in control group was significantly lower than that in the model group,and the difference was statistically significant (P<0.01or0.05).The expression of three cytokines in TCM groups were significantly decreased compared with the model group. And furthermore, the expression of the three cytokines had been gradually reduced with the increasing concentration of LFN-1medicated serum.
Conclusion
1. The method of expelling wind and wet is effective to a certain extent in the treatment of unstable angina.
2. The expression of NF-κBp65mRNA was gradually reduced dependent on the concentration of LFN-1medicated serum.
3. The expression of TNF-α、MMP-9and IL-6was gradually reduced dependent on the concentration of LFN-1medicated serum.
引文
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