摘要
目的
1.观察冠心病患者临床流行病学特点,研究冠心病患者的中医证型分布特点,并探讨前炎性因子TNF-α以及粘附分子E-selectin、ICAM-1在冠心病不同中医证候中的表达,分析它们之间的相关性,从中医证候的角度,为生物标志物对冠心病病情评估提供参考。
2.通过TNF-α刺激人微血管内皮细胞(HCMEC),模拟冠心病过程中的炎性反应,研究黄芪多糖对中性粒细胞与HCMEC之间粘附反应的作用,从蛋白表达、基因转录的角度探讨黄芪对内皮细胞炎性反应的保护作用。
方法
1.对243例冠心病患者进行中医证候调查,观察患者各中医证候分布情况。观察患者的血凝、血脂等理化指标变化规律,并测定冠心病各中医证候患者血清中炎性生物标志物TNF-α和E-selectin、ICAM-1的水平,运用医学统计学的方法,对各证候间TNF-a、E-selectin、ICAM-1的水平进行统计分析,探讨它们之间的差异性。同时,探讨TNF-α、E-selectin、ICAM-1与冠心病患者中医证候、血凝、血脂之间的相关性。
2.应用细胞分子生物学方法探讨黄芪多糖对TNF-α诱导的中性粒细胞与HCMEC粘附反应的影响及作用机制：制备外周血中性粒细胞,用TNF-α刺激诱导中性粒细胞与HCMEC之间的粘附反应,并以黄芪多糖对该粘附反应进行干预,测定细胞粘附率,探讨黄芪多糖对粘附反应的影响。运用Western-blot方法测定HCMEC细胞内粘附分子E-selectin、ICAM-1的蛋白表达。运用RT-PCR方法,测定HCMEC细胞内E-selectin、 p38MAPK、ATF-2的mRNA表达,从蛋白、基因角度探讨黄芪多糖对粘附分子、细胞信号转导通路的影响,从而了解黄芪多糖对细胞粘附反应干预作用的机制。
结果
1.入选243例冠心病患者的主要证候分布按人数多少排列顺序是：血瘀证>气虚证>痰浊证>气滞证>阴虚证>阳虚证>寒凝证。气虚血瘀证是冠心病的基本证候(占患者总人数的58.03%)。
2.冠心病中医证候与血脂的关系：气虚证组与非气虚证组比较血脂水平均无显著性差异(P>0.05)。血瘀证组TC、LDL-C水平显著高于非血瘀证组,而HDL-C水平显著低于非血瘀证组(P<0.05)。气虚血瘀证组HDL-C水平显著低于非气虚血瘀证组(P<0.05)。血瘀证与LDL正相关。气虚血瘀证与HDL-C负相关。痰浊证与TC、TC正相关,与HDL-C负相关。
3. TNF-α、sICAM-1、sE-selectin水平与冠心病亚型、年龄分层、中医证候的关系：冠心病患者各亚型TNF-α水平均高于正常组,UAP组、AMI组显著高于SAP组(P<0.05)。冠心病患者各亚型sICAM-1、sE-selectin水平均高于正常组,UAP组、AMI组显著高于SAP组。(P<0.01,P<0.05)。冠心病老年组、年轻老年组TNF-α水平显著高于青年组、中年组(P<0.01,P<0.05)。高龄老年组、年轻老年组sICAM-1、sE-selectin水平显著高于青年组、中年组(P<0.01)。气虚证组、血瘀证组、气虚血瘀证组患者血清中TNF-α、sICAM-1、sE-selectin水平均高于正常组(P<0.01)；气虚证组与非气虚证组TNF-a水平有显著性差异(P<0.05),血瘀证组TNF-α水平明显高于非血瘀证组(P<0.05)。血瘀证组sICAM-1、sE-selectin水平明显高于非血瘀证组(P<0.05)。血瘀证与TNF-α存在极显著相关性(P<0.01),血瘀证与sE-selectin、sICAM-1有显著相关性(P<0.05)。气虚证与TNF-α、sICAM-1、sE-selectin有显著相关性(P<0.05)。气虚血瘀证与TNF-α、sICAM-1、sE-selectin有极显著相关性(P<0.01,)。
4.粘附分子与血凝、血脂的相关性：sICAM-1与FIB、LDL-C正相关,与HDL-C负相关(P<0.05)；sE-selectin与FIB、LDL-C正相关(P<0.05)。
5.TNF-α与sICAM-1、sE-selectin的相关性：TNF-α与sICAM-1、sE-selectin存在显著性相关(P<0.05)。
6.APS对TNF-α诱导的中性粒细胞(PMN)与HCMEC粘附反应的影响：模型组心脏微血管内皮细胞(HCMEC)出现皱缩、重叠,细胞大片脱落,出现炎性损伤。APS高、中、低剂量组细胞炎性损伤的程度明显低于模型组。模型组HCMEC与PMN的粘附比正常对照组明显增加(P<0.01)。APS能降低HCMEC与PMN之间的粘附,其中APS高、中剂量组及P38MAPK抑制剂组的PMN粘附数量与模型组比较差异极显著(P<0.01),APS低剂量组PMN粘附数量与模型组比较差异显著(P<0.05),实验结果提示高、中、低浓度的APS可明显降低前炎性因子TNF-α诱导的HCMEC与PMN之间的粘附作用。
7. APS对HCMEC细胞E-selectin、ICAM-1蛋白表达的影响：与正常对照组比较,模型组E-selectin、ICAM-1蛋白表达明显增加(P<0.01)；与模型组比较,黄芪多糖高剂量组、p38MAPK抑制剂组E-selectin、ICAM-1蛋白表达显著降低(P<0.01)。
8.APS对HCMEC细胞p38MAPK、ATF-2、E-selectin基因表达的影响：与正常对照组比较,模型组HCMEC中p38MAPK和E-selectin mRNA表达明显增加(P<0.01), ATF-2mRNA表达也明显增加(P<0.05)；与模型组比较,APS高、低剂量组与p38MAPK抑制剂组组的p38MAPK、ATF-2、E-selectin mRNA表达显著降低(P<0.05)。
结论
1.冠心病证候要素以血瘀证、气虚证最多见,证候特点以组合证候多见,三证相兼的最多见,气虚血瘀证是冠心病的基本证候。冠心病不同中医证候之间血脂水平差异显著,血瘀证、气虚证、气虚血瘀证与血脂存在显著相关性。不同中医证候之间炎性生物标志物TNF-α、sICAM-1、sE-selectin的水平差异显著,提示不同中医证候存在不同的生物学基础。血瘀证、气虚证、气虚血瘀证与TNF-α、sICAM-1、sE-selectin具有显著相关性,提示冠心病血瘀证、气虚证、气虚血瘀证发生过程中与炎症反应关系密切炎性标志物TNF-α、sICAM-1、sE-selectin的水平与冠心病病情轻重程度相关,对临床诊疗具有一定的参考价值。
2.经TNF-α活化后,中性粒细胞与HCMEC粘附增加,TNF-α参与了细胞间的炎性损伤和粘附反应。APS能够减轻细胞间的粘附反应,降低经TNF-α活化后HCMEC细胞内粘附分子E-selectin、ICAM-1的蛋白表达和基因转录。同时,还能抑制P38MAPK及其转录因子ATF-2的基因转录。
本研究表明气虚血瘀证是冠心病的基本中医证型,气虚证、血瘀证、气虚血瘀证与炎性生物标志物具有显著相关性,且与病情程度相一致,说明炎症反应参与了冠心病的发展过程,炎症标志物能够在一定程度上评估患者的炎症反应程度,对病情评估有一定参考作用。黄芪多糖对炎性细胞与血管内皮细胞的粘附反应具有一定的抑制作用,其机制可能是药物通过抑制P38信号通路的激活,减少其下游转录因子ATF-2的基因转录,从而降低粘附分子E-selectin、ICAM-1的蛋白表达和基因转录。研究结果提示黄芪多糖对细胞炎性损伤具有一定的保护作用。
Background
Inflammation is the main pathology in the Coronary sclerosis.Inflammation biomarkers take part in many patho-physiological course such as inflammation,their levels in the blood can evaluate and predict the inflammate action in coronary sclerosis plaque. TNF-a, E-selectin and ICAM-1are very important to the adhesion between inflammatory cells and endothelium cells.
Objecitve
1.To observe the clinical epidemiology of CHD,research CHD's differentiation of symptoms features, test the levels of TNF-a, E-selectin and ICAM-1in different symptoms of CHD,discuss the correlation between them,from the angle of Chinese medicine,provide reference to evaluate condition of CHD by inflammation biomarkers.
2.Stimulate HCMEC by TNF-a,produce an inflammatory condition to observe the effects of APS on adhesion between neutrophils and HCMEC,from the angles of protein and gene expression,discuss the effects of APS on endothelium cells inflammatory.
Methods
1.Investigate243CHD Chinese medicine differentiation syndromes distribution.Observe the change pattern of blood fat and blood coagulation.Test the level of TNF-a,E-selectin and ICAM-1in patients'serum of different syndromes,using medicial statistics methods to investigate those biomarkers diviosion between different Chinese medicine syndromes.Discuss the correlation between TNF-a,E-selectin and ICAM-1and different syndromes,blood fat and blood coagulation.
2.Effects of APS on adhesion between neutrophils and endothelium cells and its mechanism:Separate neutrophils from human blood,using TNF-a stimulate adhesion between neutrophils and endothelium cells.using APS to affect this adhesion action.test amount of adhesion cells.discuss the effects of APS on adhesion action.Using Western-blot method to test protein expression of adhesion molecules E-selectin、ICAM-1.Using RT-PCR method to test mRNA of E-selectin,P38and ATF-2.Discuss the effects of APS on adhesion molecules and cells signal transduction,as a result to find the mechanism of APS intervene molecules adhesion.
Results
1. The distribution of CHD patients with differentiation syndromes orderly are:blood stagnation syndrome> qi deficiency syndrome> phlegm stasis syndrome> qi stasis syndrome> yin deficiency syndrome> yang deficiency syndrome> cold coagulation syndrome.The features of syndromes combination is that three syndromes combination are in the majority, among this, the largest amount is Qi deficiency and blood stagnation syndrome.The second is two syndromes combination. Qi deficiency and blood stagnation syndrome is the basic syndrome in CHD(58.03%of the total patients).
2.Correlation between Blood cholesterol and Chinese medicine differentiation syndromes:Blood cholesterol in qi dificency syndromes compare with other syndromes (non-qi dificency syndromes) statistical significance isn't obvious (P>0.05). TC、LDL-C level in blood stagnation syndrome group is higher than non-blood stagnation syndrome group,while HDL-C level is lower than non-blood stagnation syndrome (P<0.05). HDL-C level in qi deficiency and blood stagnation syndrome is lower than other syndromes (non-qi deficiency and blood stagnation syndrome)(P<0.05). Blood stagnation syndrome is correlated with LDL-C, qi deficiency and blood stagnation syndrome is correlated with HDL-C,phlegm syndrome is correlated with TG,TC and HDL-C.
3. Correlation between level of TNF-a、sICAM-1、sE-selectin in serum with CHD differentiation syndromes:TNF-a level of CHD each group is higher than normal group,UAP and AMI group is higher than SAP group(P<0.05). sICAM-1、sE-selectin level of CHD each group is higher than normal group,UAP and AMI group is higher than SAP group (P<0.01). TNF-a,sICAM-1and sE-selectin level of qi deficiency syndrome group,blood stagnation syndrome group, qi deficiency and blood stagnation syndrome group are higher than normal group (P<0.01). TNF-a level in qi dificency syndromes compare with non-qi dificency syndromes statistical significance is obvious (P<0.05).sICAM-1、sE-selectin level in blood stagnation syndromes compare with non blood stagnation syndrome statistical significance is obvious (P<0.05). Correlation between TNF-a and blood stagnation syndrome is extremely obvious (P<0.01) correlation between blood stagnation syndrome and sICAM-1,sE-selectin is obvious(P<0.05). Correlation between qi dificency syndromes and TNF-a,sICAM-1and sE-selectin is obvious (P<0.05).while correlation between qi dificency and blood stagnation syndromes and TNF-a,sICAM-1and sE-selectin is extremely obvious (P<0.01)
4.Correlation between adhesion molecules and blood cholesterols and blood coagulation: correlation between sICAM-land FIB.LDL-C.HDL-C is obvious (P<0.05).Correlation between sE-selectin and FIB,LDL-C is obvious (P<0.05)
5.Correlation between TNF-a and sICAM-1, sE-selectin:Correlation between TNF-α and sICAM-1,sE-selectin is obvious (P<0.05)
6. Effects of APS on TNF-a stimulate adhesion action between neutrophils and HCMEC:HCMEC in modle group was shrinking,fall off,appeared to inflammatory injure.The inflammatory injure in APS group are much lighter than modle group.The adhesion cells amount between neutrophils and HCMEC in modle group is higher than normal group (P<0.01),while in APS group and inhibitor group are much lower than in modle group(P<0.01).
7. Effects of APS on TNF-a stimulate adhesion molecules protein expression in HCMEC: ICAM-1protein expression in modle group is much higher than in normal group (P< 0.01).Compare to modle group, ICAM-1protein expression in APS high dose group and inhibitor group is much lower (P<0.01)
8. Effects of APS on TNF-a stimulate adhesion molecules mRNA and P38signal pathway in HCMEC:P38and E-selectin mRNA in modle group are much higher than in normal group (P<0.01), ATF-2mRNA in modle group are higher than in normal group (P <0.05).Compare to modle group, P38,ATF-2and E-selectin mRNA in APS high dose group,low dose group and P38inhibitor group are lower (P<0.05)
Conclusion
This research found that Qi deficiency,blood stagnation and qi deficiency-blood stagnation syndrome is the most common syndrome. Qi deficiency and blood stagnation syndrome is the basic Chinese medicine syndrome in CHD.
Qi deficiency,blood stagnation and qi deficiency-blood stagnation syndrome is obviously correlated with blood cholesterol. Blood cholesterol level are obviously different in different syndrome. Qi deficiency,blood stagnation and qi deficiency-blood stagnation syndrome is obviously correlated with inflammatory biomarkers,which are in according with CHD's condition.
Inflammation take part in the development of CHD, inflammatory biomarkers can predict and evaluate the inflammatory condition of CHD,be reference to disease evaluation. APS can inhibit adhesion between inflammation cells and HCMEC,the mechanism are through the effects of inhibit activation of P38signal pathway,alleviate ATF-2mRNA,to reduce protein and mRNA expression of E-selectin, ICAM-1.
引文
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