异常黑胆质性哮喘ECP、IgE、FEV_1和β_2-AR、IL-4、IL-13基因多态性及血栓前状态分子标志物的研究
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摘要
目的
随着现代免疫学、分子生物学与现代科学的发展使哮喘病的研究在病因学、发病机制、免疫学、诊断和治疗水平等方面有了很大的进展,但哮喘作为复杂性疾病,其发病机理依然不够明确。目前认为哮喘是一种慢性非特异性炎症,是由多种细胞及细胞组份参与的慢性气道炎症,先天遗传的特应性和后天形成的变态反应是发生哮喘的基础,也可能与调节气道功能的神经、受体间平衡失调有关。治疗主要以糖皮质激素、气管扩张剂、白三烯调节剂等药物为主。能有效的控制哮喘的发作,但不能完全根除此病。因此进一步探求哮喘的发病机理,寻求有效的治疗手段是我们面临的挑战,尤其在中国传统医学中去探索、寻求,具有较大的现实意义。
维吾尔医学是祖国医学的重要组成部分,对哮喘的认识独特,疗效显著。维医将哮喘辩证分型为:乃孜来性哮喘、“野力”性哮喘、干性哮喘、异常粘液质性哮喘和异常黑胆质性哮喘。本课题组研究发现,在各种类型的哮喘中异常黑胆质性哮喘患者的年龄最大,病情程度最重,发病机理最为复杂。
本课题在以往工作的基础上拟探讨异常黑胆质性哮喘ECP、T-IgE、S-IgE、FEV_1、CD41、CD62P、ET-1、t-PA、PAI-1、FIB、APTT、PT、TT等指标的变化特点及哮喘发病的β_2-AR、IL-4、IL-13基因多态性与异常黑胆质性哮喘的关系,探索异常黑胆质性哮喘患者的遗传易感性,探究上述指标是否可作为判断异常黑胆质性哮喘的另外一部分微观指标,使维医异常黑胆质性哮喘的诊断更加客观化,临床上更能准确把握,同时为维吾尔医治疗异常黑胆质性哮喘寻找靶位,从而为哮喘的维西医结合治疗与研究的提升和发展提供新的思路。
材料和方法
病例来源第一、第二部分为2006年11月至2007年6月在新疆和田地区收集支气管哮喘患者共76例,正常对照组89例。第三部分为2006年3月～2006年7月在新疆医科大学附属中医医院收集支气管哮喘患者共67例,正常对照组33例。所有哮喘患者均符合中华医学会呼吸病学分会哮喘学组(2003年)制订的“支气管哮喘防治指南(支气管哮喘的定义、诊断、治疗及教育和管理方案)”的诊断分级标准,并按维吾尔医体液论进行辨证分型。正常对照组为经体检无心、肺、肝、肾及血液等疾病的健康人。对所研究对象进行以下方面的测定:用荧光酶联免疫法检测ECP、T-IgE、S-IgE;用肺功能仪测FEV_1;用聚合酶链反应方法检测β_2-AR、IL-4、IL-13基因多态性;用流式细胞仪测定患者血小板表面CD41,CD62p;用放射免疫法检测血清ET-1;用ELAISA方法检测血浆t-PA,PAI-1;全自动血凝分析仪检测凝血四项即血浆纤维蛋白原(FIB)水平、活化部分凝血活酶时间(APTT)、凝血酶原时间(PT)、凝血酶时间(TT)。统计学方法:所有实验数据采用SPSS15.0统计软件处理,用均数±标准差( x±s)表示;采用单因素方差分析,两组间比较采用t检验,P<0.05有统计学意义。
结果
1)血清ECP水平变化在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间有显著性差异(P<0.01),异常黑胆质性哮喘组和非异常黑胆质性哮喘组明显高于正常对照组(P<0.01),异常黑胆质性哮喘组明显高于非异常黑胆质性哮喘组(P<0.01)。血清T-IgE水平变化在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间有显著性差异(P<0.01),异常黑胆质性哮喘组和非异常黑胆质性哮喘组明显高于正常对照组(P<0.01),其中以异常黑胆质性哮喘组的T-IgE含量最高(P<0.01)。血清S-IgE阳性率在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间有显著性差异(P<0.01),异常黑胆质性哮喘组和非异常黑胆质性哮喘组血清S-IgE阳性率明显高于正常对照组(P<0.01),其中以异常黑胆质性哮喘组的S-IgE阳性率最高(P<0.01),FEV_1水平变化在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间有显著性差异(P<0.01),异常黑胆质性哮喘组和非异常黑胆质性哮喘组低于正常对照组(P<0.01),其中异常黑胆质性哮喘组降低最为明显(P<0.01)。
2)β_2-AR基因16位点多态性在异常黑胆质性哮喘组甘氨酸/甘氨酸(Gly/Gly)纯合子基因型频率分布明显高于非异常黑胆质性哮喘组和正常对照组(P<0.01)。β_2-AR基因16位点等位基因频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组及正常对照组间比较,差异无显著性(P>0.05)。β_2-AR基因27位点基因型频率分布及等位基因频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间比较,差异无显著性(P>0.05)。
IL-4基因启动子区-589(C/T)位点CT基因型频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组及正常对照组间比较有显著性差异(P<0.01)。异常黑胆质性哮喘组CT基因型频率分布明显高于非异常黑胆质性哮喘组和正常对照组差异有显著性(P<0.01)。非异常黑胆质性哮喘组CT基因型频率分布高于正常对照组(P<0.05)。而CC、TT基因型及等位基因频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间无显著性差异(P>0.05)。
IL-13基因intron3+1923位点多态性变化在异常黑胆质性哮喘组TT、TC基因型频率分布明显高于非异常黑胆质性哮喘组及正常对照组(P<0.01),非异常黑胆质性哮喘组TT、TC基因型频率分布高于正常对照组(P<0.05),而正常对照组CC基因型频率分布明显高于异常黑胆质性哮喘组(P<0.01),也高于非异常黑胆质性哮喘组(P<0.05),非异常黑胆质性哮喘组高于异常黑胆质性哮喘组(P<0.05)。该位点T等位基因频率分布异常黑胆质性哮喘组高于非异常黑胆质性哮喘组(P<0.05),明显高于正常对照组(P<0.01),C等位基因频率分布异常黑胆质性哮喘组低于非异常黑胆质性哮喘组(P<0.05),明显低于正常对照组(P<0.01)。IL-13基因+2044位点基因型频率分布和等位基因频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间比较,差异无显著性(P>0.05)。
3)与正常对照组相比较,异常黑胆质性哮喘组和非异常黑胆质性哮喘组CD41阳性表达率无明显差异(P>0.05);CD62P阳性表达率均升高(P<0.05),且异常黑胆质性哮喘组CD62P水平高于非异常黑胆质性哮喘组(P<0.05);与正常对照组相比较,异常黑胆质性哮喘组和非异常黑胆质性哮喘组ET-1水平均升高(P<0.05),且异常黑胆质性哮喘组ET-1水平高于非异常黑胆质性哮喘组(P<0.05);与正常对照组相比较,异常黑胆质性哮喘组和非异常黑胆质性哮喘组t-PA含量均下降(P<0.05),以异常黑胆质性哮喘组下降明显;PAI-1含量均升高(P<0.05)在异常黑胆质性哮喘组升高明显;与正常对照组相比较,异常黑胆质性哮喘组和非异常黑胆质性哮喘组FIB含量明显升高(P<0.01),且异常黑胆质性哮喘组FIB含量高于非异常黑胆质性哮喘组(P<0.05),APTT、PT时间缩短(P<0.05), TT的变化无差异(P>0.05)。
结论
1)ECP是嗜酸性粒细胞活性的特异性指标,能反映气道炎症程度的发生和发展。IgE介导的Ⅰ型变态反应是形成气道慢性炎症反应的主要原因之一,而变应原是气道慢性炎症的主要致病因素,T-IgE、S-IgE水平升高,既是特应症的主要识别标志,也是气道慢性炎症的主要特征。本研究显示,血清ECP、T-IgE、S-IgE水平在异常黑胆质性哮喘患者中最高。因此可推测,血清ECP、T-IgE、S-IgE可能是异常黑胆质性哮喘的潜在的决定因素,其对预测和判断异常黑胆质性哮喘的活动性均有一定的临床意义。
2)FEV_1与小气道阻力有关系,它能更好的反映小气道阻塞的情况,是判断气道阻塞的及其严重性的可靠指标。FEV_1降低表明有气道阻塞存在。本研究表明与非异常黑胆质性哮喘组比较FEV_1在异常黑胆质性哮喘组中最低,由此可提出异常黑胆质性哮喘患者气道阻塞更明显。
3)β_2-AR基因16位点具有甘氨酸/甘氨酸(Gly/Gly)纯合子基因型的人群异常黑胆质性哮喘的危险性高于正常人群。我们认为,当甘氨酸/精氨酸(Gly/Arg)杂合子个体内的精氨酸突变为甘氨酸时,此个体患异常黑胆质性哮喘的危险性增加。即Gly/Gly基因型可能是异常黑胆质性哮喘发病的内在危险因素之一,β_2-AR基因16位点多态性与异常黑胆质性哮喘关联。
4)IL-4基因启动子区-589C/T位点,具有CT杂合子基因型的个体与异常黑胆质性哮喘易感性相关,提示IL-4基因启动子区-589C/T位点多态性可能是异常黑胆质性哮喘易感性的一个重要候选基因。
5)IL-13基因intron3+1923位点TT及TC基因可能与异常黑胆质性哮喘的发生相关,为异常黑胆质性哮喘的易感基因。该位点T等位基因可能为异常黑胆质性哮喘的易感基因,C等位基因可能为异常黑胆质性哮喘的抵抗基因。具有T等位基因的人群在受到环境因素刺激后,如反复过敏原接触,长期生活于污染严重的环境中,其发生异常黑胆质性哮喘哮的可能性将大于具有C等位基因者。因而这部分具有IL-13基因intron3+1923位点T等位基因的正常人群可能是进行维医异常黑胆质性哮喘预防的重点人群。
6)研究发现血栓前状态可能是异常黑胆质性哮喘的病理生理基础之一,也可能是致病因素,异常黑胆质性哮喘患者的血小板、血管内皮细胞、凝血血和纤溶功能发生紊乱,表现在血小板活化、血管内皮细胞损伤、血液粘度增高、纤溶功能降低,提示异常黑胆质性哮喘患者处于血栓前状态,且这种状态较非异常黑胆质性哮喘更为突出。
总之,维医异常黑胆质性哮喘病情较重,发病机理较为复杂,结合以往研究结果,我们认为在诊断异常黑胆质性哮喘时,基于维医的辩证分型标准,同时应考虑患者免疫功能紊乱、内源性皮质醇降低、血清ECP、T-IgE、S-IgE水平肺功能FEV_1及β_2-AR,IL-4、IL-13基因多态性和CD62P、PAI-1、t-PA、FIB、APTT、PT的改变,并应将这些指标作为维医治疗异常黑胆质性哮喘判断疗效的部分微观指标。
Object:
With the rapid development of modern medicine, the development of modern immunology, molecular biology contributed a lot to the etiology, pathogenesis, immunology, diagnosis and treatment of asthma. As far as the complexity of asthma concerned, its pathogenesis is still not clear enough. It is generally believed that, asthma is a chronic non-specific inflammation. A variety of cells and cell groups participate in the chronic airway inflammation. Innate congenital specialty and acquired allergic significance are the basis of asthmatic development. The imbalance between the nerves and their receptors which regulates the function of bronchitis may also be related to the formation of asthma. The main treatment methods of asthma are the usage of glucocorticoid, expansion of tracheal and leukotriene regulating agents. Although such treatment methods are effective in controlling of asthma, they cannot significantly reduce the mortality, cannot completely eradicate the disease itself. So in order to explore the pathogenesis of asthma and to seek an effective treatment method is the challenge that we are currently facing. Looking for a treatment method from the Traditional Chinese Medicine has even greater significance.
Being an indispensable part of Traditional Chinese Medicine, Uyghur Medicine has its unique recognition and effective treatments for asthma. Asthma is divided asthma with abnormal Kan, asthma with abnormal Balgam, asthma with abnormal Sapra and asthma with abnormal Savda in Uyghur Medicine. In the previous studies, our research group discovered that, the asthmatic patients with abnormal Savda have the oldest age, most severe symptoms and most complex pathogenesis of asthma. In an asthma attack, compared to the other types of asthma in Uyghur Medicine, the value of CDllb, CDllb/CDl8 and rate of lymphocyte apoptosis in asthmatic patients with abnormal Savda was the highest, the value of CS, ACTH and CRH was the lowest in asthmatic patients with abnormal Savda. From above results, we assume that immune dysfunction, reduced endogenous cortisol and infection are the probable factors which largely contribute to the formation of asthma with abnormal Savda. We also discovered that there is a correlation ship in asthma with abnormal Savda in Uyghur Medicine, deficieacy asthma of traditional chinese medicine and the severe asthma in Western medicine. There is commonness in the level of CDllb/CDl8, lymphocyte apoptosis and the level of endogenous cortisol in these three types of asthma. There is a significant change in the metabolic group model between asthma with abnormal Savda and the other types of asthma in Uyghur Medicine.
Based on the results of previous research, this study will discuss the changes of ECP、T-IgE、S-IgE、FEV_1、CD41、CD62P、ET-1、t-PA、PAI-1、FIB、APTT、PT、TT in asthma with abnormal Savda and the relationship betweenβ_2-AR IL-4, IL-13, gene polymorphism and the asthma with abnormal Savda. By studying the genetic susceptibility of asthmatic patients with abnormal Savda and analyzing whether the above indicators can be used as part of the macro diagnostic indexes of asthma, this study will try to grasp more accuracy in the diagnosis of asthma and making the diagnosis even more objective.at the same time., this study will also look for the probable targets of treating asthma with abnormal Savda in Uyghur Medicine.
Materials and Methods
Patients:, There were 76 cases of asthmatic Uyghur patients in first and second group who were hospitalized from November 2006 to June 2007 in Hotan district of Xinjiang. There were 67 cases of asthmatic patients in the third group who were hospitalized from February 2006 to October 2006 in Traditional Chinese Medicine hospital in Urumqi. All patients were diagnosed according to the criteria of Uyghur Medicine and the Western medicine asthma diagnosis. 89 cases of healthy individuals,they have all been checked to make sure that they do not have hypertension, diabetes or other heart, liver, kidney and blood diseases. All individuals have been checked for following indicators: ECP, T-IgE, S-IgE were tested by using immuno fluorescence detection, FEV_1 was checked by using lung function testing machine,β_2-AR, IL-4, IL-13, gene polymorphism were measured by polymerase chain reaction method. The expression of CD62p on platelets, the level of plasma tissue plasminogen activator (t-PA)and its inhibiter(PAI-1), the level of endothelin-1(ET-1), Activated partial thromboplastin time (APTT), Fibrinogen ( FIB), Prothrombin time ( PT) and Thrombin time (TT) were tested by using Flow Cytometer, ELASA method, radioimmunoassay method and auto coagulometer. Statistical analysis: SPSS11.5 was used in the study. The data was expressed as means±standard deviation (SD). Statistical significance of a comparison was determined by using ANOVA. The difference between means was considered to be statistically significant if p<0.05.
Results:
1)Compared to normal control group, level of serum ECP was significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01),the level of ECP was significantly higher in asthma with abnormal Savda group than that of the asthma with non abnormal Savda group and the normal control group(P<0.01). Compared to normal control group, level of serum T-IgE was significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01),the level of T-IgE was significantly higher in asthma with abnormal Savda group and asthma with non abnormal Savda group than that of the normal control group(P<0.01). The level of T-IgE had no statistical difference between asthma with abnormal Savda and asthma with non abnormal Savda group(P>0.05)。Compared to normal control group, level of serum S-IgE significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01),the level of S-IgE was significantly higher in asthma with abnormal Savda group and asthma with non abnormal Savda group than that of the normal control group(P<0.01),The level of S-IgE had no statistical difference between asthma with abnormal Savda and asthma with non abnormal Savda group(P>0.05). Compared to normal control group, level of FEV_1 was significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01), the level of FEV_1 was significantly decreased in asthma with abnormal Savda and asthma with non abnormal Savda group than that of the normal control group(P<0.01).
2)Asthma with abnormal Savdaβ_2-AR gene polymorphism in 16 points (Gly / Gly) homozygous genotype frequency distribution was significantly higher than that of the asthma with non abnormal Savda group and the normal control group(P<0.01)。There was no statistical difference inβ_2-AR gene polymorphism in 16 points (Gly / Gly) homozygous genotype distribution frequency between these three groups(P>0.05). There was no statistical difference inβ_2-AR gene 27 points genotype frequency distributions and allele frequency distribution between these three groups(P>0.05). Compared to normal control group, IL-4 gene promoter -589 (C / T) sites CT genotype frequency distribution was significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01)(P<0.01). IL-4 gene promoter -589 (C / T) sites CT genotype frequency distribution was significantly higher in asthma with abnormal Savda group than that of the asthma with non abnormal Savda group and the normal control group(P<0.01). IL-4 gene promoter -589 (C / T) sites CT genotype frequency distribution was significantly higher in asthma with non abnormal Savda group than that of the normal control group(P<0.05). There was no statistical difference in CC, TT genotype and allele frequency distribution between these three groups(P>0.05).
IL-13 gene polymorphism loci intron 3 +1923 in asthma with abnormal Savda TT, TC genotype frequency distribution was significantly higher than that of the asthma with non abnormal Savda group and the normal control group(P<0.01),asthma with non abnormal Savda group TT, TC genotype frequency distribution was significantly higher than that of the normal control group(P<0.05),CC genotype frequency distribution in normal control group was significantly higher than that of the asthma with abnormal Savda group (P<0.05)and asthma with non abnormal Savda group(P<0.01). T allele frequency distribution of this site in asthma with abnormal Savda group was significantly higher than that of the normal control group(P<0.01),C allele frequency distribution of this site in normal control group was significantly higher than that of the asthma with abnormal Savda group(P<0.05). There was no statistical difference in IL-13 gene loci +2044 genotype frequency distributions and allele frequency distribution between these three groups(P>0.05).
3)Compared to normal control group, there was no significance on the expression of asthma with abnormal Savda group and asthma with non abnormal Savda group(P>0.05);the expression of CD62P in all three groups(P<0.05),among them the expression of CD62P in asthma with abnormal Savda group was significantly higher than that of the asthma with non abnormal Savda group(P<0.05). Compared to normal control group, level of serum ET-1 was significantly higher in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.05),the level of ET-1 was significantly higher in asthma with abnormal Savda group than that of the asthma with non abnormal Savda group and the normal control group(P<0.01). Compared to normal control group, level of plasma t-PA was significantly lower in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.05);Compared to normal control group, level of serum PAI-1 was significantly higher in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.05). Compared to normal control group, level of plasma FIB was significantly higher in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.05), the level of plasma FIB was significantly higher in asthma with abnormal Savda group than that of the asthma with non abnormal Savda group and the normal control group. Compared to normal control group, level of APTT、PTwas significantly shortened in asthma with abnormal Savda and asthma with non abnormal Savda groups (P<0.05); There was no significance on TT between these three groups(P>0.05).
Conclusion:
1)ECP is a specific indicator of eosinophil activity, it reflects the degree of airway inflammation in the development. IgE-mediated allergic reaction is one of the main reasons of airway chronic inflammatory reaction. High level of T-IgE、S-IgE is not only the main recognition factors of atopic disease but also the main characteristic of airway chronic inflammation. The result of this study showed that, the level of serum ECP、T-IgE and S-IgE was significantly higher in asthmatic patients with abnormal Savda. From this result we assume that the high level of serum ECP、T-IgE and S-IgE might be the potential deciding factor if asthma with abnormal Savda. Therefore, judgement and assessment of these factors might have certain clinical significance in assessing the activity of asthma with abnormal Savda .
2)FEV_1 is related to the small airway resistance. FEV_1 is a reliable indicator of the degree and severity of airway obstruction. Decreased FEV_1 indicates the existence of airway obstruction. Our research result showed that the level of FEV_1 was significantly lower in asthmatic patients with abnormal Savda than that of the asthmatic patients with non abnormal Savda, indicates that airway obstruction is most obvious in asthmatic patients with abnormal Savda.
3)Individuals who haveβ_2-AR gene with 16 points glycine / glycine (Gly / Gly) homozygotes have a higher risk in developing asthma with abnormal Savda compared to individual who do not have it. We assume that when glycine arginine (Gly / Arg) heterozygous in individuals mutates to arginine, glycine, these individuals will have a higher risk in developing asthma with abnormal Savda. Gly/Gly genotype might be the inherent risk factor of asthma with abnormal Savda. There might be a correlation between theβ_2-AR gene polymorphism with 16 loci and asthma with abnormal Savda. 4)Individuals who have IL-4 gene promoter -589 (C/T) site with CT heterozygous genotype is related to the susceptibility of asthma with abnormal Savda, implies that IL-4 gene promoter -589 (C/T) site with CT polymorphism maybe an important candidate gene of asthma with abnormal Savda susceptibility.
5)IL-13intron 3 +1923 siteand TT and TC gene may be related to the pathogeneses of asthma with abnormal Savda. It is the susceptibility gene of asthma with abnormal Savda. The T allele of this site may be the susceptibility gene of asthma with abnormal Savda, C allele of this site may be the resistance gene of asthma with abnormal Savda. Individual With the T allele who are stimulated by environmental factors, such as repeated allergen exposure, long-term living in seriously polluted environment, are the ones who will have a higher chance of developing asthma with abnormal Savda than those with C allele. Therefore, individuals who have IL-13 intron3 +1923 site with T allele may be the important focus groups of asthma with abnormal Savda prevention in peacekeeping and medical abnormal biliary asthma prevention in Uyghur Medicine.
6)Studies found that prethromboitic state may be one of the pathological basis of asthma with abnormal Savda, and may also be pathogenic factors. There is platelet, vascular endothelial cells, blood coagulation and fibrinolytic function disorder , and in asthmatic patients with abnormal Savda, expressed in the activation of platelets, vascular endothelial cell damage, increased blood viscosity and reduced fibrinolytic function. Above results imply asthmatic patients with abnormal Savda are in a prothrombotic state, which is more prominent than asthmatic patients with non-abnormal Savda.
In short, the pathogenesis of asthma with abnormal Savda in Uyghur Medicine is heavier and more complex. Combined with the results of previous studies, we believe that in the diagnosis of asthma with abnormal Savda, while complying to the diagnostic methods in Uyghur Medicine, it is also important to consider the patient's immune dysfunction, endogenous cortisol decrease, the changes of serum ECP, T-IgE, S-IgE, FEV_1 lung function andβ_2-AR, IL-4, IL-13 gene polymorphism and CD62P, t-PA, PAI-1, FIB , APTT, PT. We should also consider these indicators as the micro indicators of asthma with abnormal Savda. These results will provide a new target for treating asthma with abnormal Savda in Uyghur Medicine, also it provides a thingking for the development and progresss of combined Uyghur, Western Medicine treatment of asthma.
随着现代免疫学、分子生物学与现代科学的发展使哮喘病的研究在病因学、发病机制、免疫学、诊断和治疗水平等方面有了很大的进展,但哮喘作为复杂性疾病,其发病机理依然不够明确。目前认为哮喘是一种慢性非特异性炎症,是由多种细胞及细胞组份参与的慢性气道炎症,先天遗传的特应性和后天形成的变态反应是发生哮喘的基础,也可能与调节气道功能的神经、受体间平衡失调有关。治疗主要以糖皮质激素、气管扩张剂、白三烯调节剂等药物为主。能有效的控制哮喘的发作,但不能完全根除此病。因此进一步探求哮喘的发病机理,寻求有效的治疗手段是我们面临的挑战,尤其在中国传统医学中去探索、寻求,具有较大的现实意义。
维吾尔医学是祖国医学的重要组成部分,对哮喘的认识独特,疗效显著。维医将哮喘辩证分型为:乃孜来性哮喘、“野力”性哮喘、干性哮喘、异常粘液质性哮喘和异常黑胆质性哮喘。本课题组研究发现,在各种类型的哮喘中异常黑胆质性哮喘患者的年龄最大,病情程度最重,发病机理最为复杂。
本课题在以往工作的基础上拟探讨异常黑胆质性哮喘ECP、T-IgE、S-IgE、FEV_1、CD41、CD62P、ET-1、t-PA、PAI-1、FIB、APTT、PT、TT等指标的变化特点及哮喘发病的β_2-AR、IL-4、IL-13基因多态性与异常黑胆质性哮喘的关系,探索异常黑胆质性哮喘患者的遗传易感性,探究上述指标是否可作为判断异常黑胆质性哮喘的另外一部分微观指标,使维医异常黑胆质性哮喘的诊断更加客观化,临床上更能准确把握,同时为维吾尔医治疗异常黑胆质性哮喘寻找靶位,从而为哮喘的维西医结合治疗与研究的提升和发展提供新的思路。
材料和方法
病例来源第一、第二部分为2006年11月至2007年6月在新疆和田地区收集支气管哮喘患者共76例,正常对照组89例。第三部分为2006年3月～2006年7月在新疆医科大学附属中医医院收集支气管哮喘患者共67例,正常对照组33例。所有哮喘患者均符合中华医学会呼吸病学分会哮喘学组(2003年)制订的“支气管哮喘防治指南(支气管哮喘的定义、诊断、治疗及教育和管理方案)”的诊断分级标准,并按维吾尔医体液论进行辨证分型。正常对照组为经体检无心、肺、肝、肾及血液等疾病的健康人。对所研究对象进行以下方面的测定:用荧光酶联免疫法检测ECP、T-IgE、S-IgE;用肺功能仪测FEV_1;用聚合酶链反应方法检测β_2-AR、IL-4、IL-13基因多态性;用流式细胞仪测定患者血小板表面CD41,CD62p;用放射免疫法检测血清ET-1;用ELAISA方法检测血浆t-PA,PAI-1;全自动血凝分析仪检测凝血四项即血浆纤维蛋白原(FIB)水平、活化部分凝血活酶时间(APTT)、凝血酶原时间(PT)、凝血酶时间(TT)。统计学方法:所有实验数据采用SPSS15.0统计软件处理,用均数±标准差( x±s)表示;采用单因素方差分析,两组间比较采用t检验,P<0.05有统计学意义。
结果
1)血清ECP水平变化在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间有显著性差异(P<0.01),异常黑胆质性哮喘组和非异常黑胆质性哮喘组明显高于正常对照组(P<0.01),异常黑胆质性哮喘组明显高于非异常黑胆质性哮喘组(P<0.01)。血清T-IgE水平变化在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间有显著性差异(P<0.01),异常黑胆质性哮喘组和非异常黑胆质性哮喘组明显高于正常对照组(P<0.01),其中以异常黑胆质性哮喘组的T-IgE含量最高(P<0.01)。血清S-IgE阳性率在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间有显著性差异(P<0.01),异常黑胆质性哮喘组和非异常黑胆质性哮喘组血清S-IgE阳性率明显高于正常对照组(P<0.01),其中以异常黑胆质性哮喘组的S-IgE阳性率最高(P<0.01),FEV_1水平变化在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间有显著性差异(P<0.01),异常黑胆质性哮喘组和非异常黑胆质性哮喘组低于正常对照组(P<0.01),其中异常黑胆质性哮喘组降低最为明显(P<0.01)。
2)β_2-AR基因16位点多态性在异常黑胆质性哮喘组甘氨酸/甘氨酸(Gly/Gly)纯合子基因型频率分布明显高于非异常黑胆质性哮喘组和正常对照组(P<0.01)。β_2-AR基因16位点等位基因频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组及正常对照组间比较,差异无显著性(P>0.05)。β_2-AR基因27位点基因型频率分布及等位基因频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间比较,差异无显著性(P>0.05)。
IL-4基因启动子区-589(C/T)位点CT基因型频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组及正常对照组间比较有显著性差异(P<0.01)。异常黑胆质性哮喘组CT基因型频率分布明显高于非异常黑胆质性哮喘组和正常对照组差异有显著性(P<0.01)。非异常黑胆质性哮喘组CT基因型频率分布高于正常对照组(P<0.05)。而CC、TT基因型及等位基因频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间无显著性差异(P>0.05)。
IL-13基因intron3+1923位点多态性变化在异常黑胆质性哮喘组TT、TC基因型频率分布明显高于非异常黑胆质性哮喘组及正常对照组(P<0.01),非异常黑胆质性哮喘组TT、TC基因型频率分布高于正常对照组(P<0.05),而正常对照组CC基因型频率分布明显高于异常黑胆质性哮喘组(P<0.01),也高于非异常黑胆质性哮喘组(P<0.05),非异常黑胆质性哮喘组高于异常黑胆质性哮喘组(P<0.05)。该位点T等位基因频率分布异常黑胆质性哮喘组高于非异常黑胆质性哮喘组(P<0.05),明显高于正常对照组(P<0.01),C等位基因频率分布异常黑胆质性哮喘组低于非异常黑胆质性哮喘组(P<0.05),明显低于正常对照组(P<0.01)。IL-13基因+2044位点基因型频率分布和等位基因频率分布在异常黑胆质性哮喘组、非异常黑胆质性哮喘组和正常对照组间比较,差异无显著性(P>0.05)。
3)与正常对照组相比较,异常黑胆质性哮喘组和非异常黑胆质性哮喘组CD41阳性表达率无明显差异(P>0.05);CD62P阳性表达率均升高(P<0.05),且异常黑胆质性哮喘组CD62P水平高于非异常黑胆质性哮喘组(P<0.05);与正常对照组相比较,异常黑胆质性哮喘组和非异常黑胆质性哮喘组ET-1水平均升高(P<0.05),且异常黑胆质性哮喘组ET-1水平高于非异常黑胆质性哮喘组(P<0.05);与正常对照组相比较,异常黑胆质性哮喘组和非异常黑胆质性哮喘组t-PA含量均下降(P<0.05),以异常黑胆质性哮喘组下降明显;PAI-1含量均升高(P<0.05)在异常黑胆质性哮喘组升高明显;与正常对照组相比较,异常黑胆质性哮喘组和非异常黑胆质性哮喘组FIB含量明显升高(P<0.01),且异常黑胆质性哮喘组FIB含量高于非异常黑胆质性哮喘组(P<0.05),APTT、PT时间缩短(P<0.05), TT的变化无差异(P>0.05)。
结论
1)ECP是嗜酸性粒细胞活性的特异性指标,能反映气道炎症程度的发生和发展。IgE介导的Ⅰ型变态反应是形成气道慢性炎症反应的主要原因之一,而变应原是气道慢性炎症的主要致病因素,T-IgE、S-IgE水平升高,既是特应症的主要识别标志,也是气道慢性炎症的主要特征。本研究显示,血清ECP、T-IgE、S-IgE水平在异常黑胆质性哮喘患者中最高。因此可推测,血清ECP、T-IgE、S-IgE可能是异常黑胆质性哮喘的潜在的决定因素,其对预测和判断异常黑胆质性哮喘的活动性均有一定的临床意义。
2)FEV_1与小气道阻力有关系,它能更好的反映小气道阻塞的情况,是判断气道阻塞的及其严重性的可靠指标。FEV_1降低表明有气道阻塞存在。本研究表明与非异常黑胆质性哮喘组比较FEV_1在异常黑胆质性哮喘组中最低,由此可提出异常黑胆质性哮喘患者气道阻塞更明显。
3)β_2-AR基因16位点具有甘氨酸/甘氨酸(Gly/Gly)纯合子基因型的人群异常黑胆质性哮喘的危险性高于正常人群。我们认为,当甘氨酸/精氨酸(Gly/Arg)杂合子个体内的精氨酸突变为甘氨酸时,此个体患异常黑胆质性哮喘的危险性增加。即Gly/Gly基因型可能是异常黑胆质性哮喘发病的内在危险因素之一,β_2-AR基因16位点多态性与异常黑胆质性哮喘关联。
4)IL-4基因启动子区-589C/T位点,具有CT杂合子基因型的个体与异常黑胆质性哮喘易感性相关,提示IL-4基因启动子区-589C/T位点多态性可能是异常黑胆质性哮喘易感性的一个重要候选基因。
5)IL-13基因intron3+1923位点TT及TC基因可能与异常黑胆质性哮喘的发生相关,为异常黑胆质性哮喘的易感基因。该位点T等位基因可能为异常黑胆质性哮喘的易感基因,C等位基因可能为异常黑胆质性哮喘的抵抗基因。具有T等位基因的人群在受到环境因素刺激后,如反复过敏原接触,长期生活于污染严重的环境中,其发生异常黑胆质性哮喘哮的可能性将大于具有C等位基因者。因而这部分具有IL-13基因intron3+1923位点T等位基因的正常人群可能是进行维医异常黑胆质性哮喘预防的重点人群。
6)研究发现血栓前状态可能是异常黑胆质性哮喘的病理生理基础之一,也可能是致病因素,异常黑胆质性哮喘患者的血小板、血管内皮细胞、凝血血和纤溶功能发生紊乱,表现在血小板活化、血管内皮细胞损伤、血液粘度增高、纤溶功能降低,提示异常黑胆质性哮喘患者处于血栓前状态,且这种状态较非异常黑胆质性哮喘更为突出。
总之,维医异常黑胆质性哮喘病情较重,发病机理较为复杂,结合以往研究结果,我们认为在诊断异常黑胆质性哮喘时,基于维医的辩证分型标准,同时应考虑患者免疫功能紊乱、内源性皮质醇降低、血清ECP、T-IgE、S-IgE水平肺功能FEV_1及β_2-AR,IL-4、IL-13基因多态性和CD62P、PAI-1、t-PA、FIB、APTT、PT的改变,并应将这些指标作为维医治疗异常黑胆质性哮喘判断疗效的部分微观指标。
Object:
With the rapid development of modern medicine, the development of modern immunology, molecular biology contributed a lot to the etiology, pathogenesis, immunology, diagnosis and treatment of asthma. As far as the complexity of asthma concerned, its pathogenesis is still not clear enough. It is generally believed that, asthma is a chronic non-specific inflammation. A variety of cells and cell groups participate in the chronic airway inflammation. Innate congenital specialty and acquired allergic significance are the basis of asthmatic development. The imbalance between the nerves and their receptors which regulates the function of bronchitis may also be related to the formation of asthma. The main treatment methods of asthma are the usage of glucocorticoid, expansion of tracheal and leukotriene regulating agents. Although such treatment methods are effective in controlling of asthma, they cannot significantly reduce the mortality, cannot completely eradicate the disease itself. So in order to explore the pathogenesis of asthma and to seek an effective treatment method is the challenge that we are currently facing. Looking for a treatment method from the Traditional Chinese Medicine has even greater significance.
Being an indispensable part of Traditional Chinese Medicine, Uyghur Medicine has its unique recognition and effective treatments for asthma. Asthma is divided asthma with abnormal Kan, asthma with abnormal Balgam, asthma with abnormal Sapra and asthma with abnormal Savda in Uyghur Medicine. In the previous studies, our research group discovered that, the asthmatic patients with abnormal Savda have the oldest age, most severe symptoms and most complex pathogenesis of asthma. In an asthma attack, compared to the other types of asthma in Uyghur Medicine, the value of CDllb, CDllb/CDl8 and rate of lymphocyte apoptosis in asthmatic patients with abnormal Savda was the highest, the value of CS, ACTH and CRH was the lowest in asthmatic patients with abnormal Savda. From above results, we assume that immune dysfunction, reduced endogenous cortisol and infection are the probable factors which largely contribute to the formation of asthma with abnormal Savda. We also discovered that there is a correlation ship in asthma with abnormal Savda in Uyghur Medicine, deficieacy asthma of traditional chinese medicine and the severe asthma in Western medicine. There is commonness in the level of CDllb/CDl8, lymphocyte apoptosis and the level of endogenous cortisol in these three types of asthma. There is a significant change in the metabolic group model between asthma with abnormal Savda and the other types of asthma in Uyghur Medicine.
Based on the results of previous research, this study will discuss the changes of ECP、T-IgE、S-IgE、FEV_1、CD41、CD62P、ET-1、t-PA、PAI-1、FIB、APTT、PT、TT in asthma with abnormal Savda and the relationship betweenβ_2-AR IL-4, IL-13, gene polymorphism and the asthma with abnormal Savda. By studying the genetic susceptibility of asthmatic patients with abnormal Savda and analyzing whether the above indicators can be used as part of the macro diagnostic indexes of asthma, this study will try to grasp more accuracy in the diagnosis of asthma and making the diagnosis even more objective.at the same time., this study will also look for the probable targets of treating asthma with abnormal Savda in Uyghur Medicine.
Materials and Methods
Patients:, There were 76 cases of asthmatic Uyghur patients in first and second group who were hospitalized from November 2006 to June 2007 in Hotan district of Xinjiang. There were 67 cases of asthmatic patients in the third group who were hospitalized from February 2006 to October 2006 in Traditional Chinese Medicine hospital in Urumqi. All patients were diagnosed according to the criteria of Uyghur Medicine and the Western medicine asthma diagnosis. 89 cases of healthy individuals,they have all been checked to make sure that they do not have hypertension, diabetes or other heart, liver, kidney and blood diseases. All individuals have been checked for following indicators: ECP, T-IgE, S-IgE were tested by using immuno fluorescence detection, FEV_1 was checked by using lung function testing machine,β_2-AR, IL-4, IL-13, gene polymorphism were measured by polymerase chain reaction method. The expression of CD62p on platelets, the level of plasma tissue plasminogen activator (t-PA)and its inhibiter(PAI-1), the level of endothelin-1(ET-1), Activated partial thromboplastin time (APTT), Fibrinogen ( FIB), Prothrombin time ( PT) and Thrombin time (TT) were tested by using Flow Cytometer, ELASA method, radioimmunoassay method and auto coagulometer. Statistical analysis: SPSS11.5 was used in the study. The data was expressed as means±standard deviation (SD). Statistical significance of a comparison was determined by using ANOVA. The difference between means was considered to be statistically significant if p<0.05.
Results:
1)Compared to normal control group, level of serum ECP was significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01),the level of ECP was significantly higher in asthma with abnormal Savda group than that of the asthma with non abnormal Savda group and the normal control group(P<0.01). Compared to normal control group, level of serum T-IgE was significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01),the level of T-IgE was significantly higher in asthma with abnormal Savda group and asthma with non abnormal Savda group than that of the normal control group(P<0.01). The level of T-IgE had no statistical difference between asthma with abnormal Savda and asthma with non abnormal Savda group(P>0.05)。Compared to normal control group, level of serum S-IgE significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01),the level of S-IgE was significantly higher in asthma with abnormal Savda group and asthma with non abnormal Savda group than that of the normal control group(P<0.01),The level of S-IgE had no statistical difference between asthma with abnormal Savda and asthma with non abnormal Savda group(P>0.05). Compared to normal control group, level of FEV_1 was significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01), the level of FEV_1 was significantly decreased in asthma with abnormal Savda and asthma with non abnormal Savda group than that of the normal control group(P<0.01).
2)Asthma with abnormal Savdaβ_2-AR gene polymorphism in 16 points (Gly / Gly) homozygous genotype frequency distribution was significantly higher than that of the asthma with non abnormal Savda group and the normal control group(P<0.01)。There was no statistical difference inβ_2-AR gene polymorphism in 16 points (Gly / Gly) homozygous genotype distribution frequency between these three groups(P>0.05). There was no statistical difference inβ_2-AR gene 27 points genotype frequency distributions and allele frequency distribution between these three groups(P>0.05). Compared to normal control group, IL-4 gene promoter -589 (C / T) sites CT genotype frequency distribution was significantly changed in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.01)(P<0.01). IL-4 gene promoter -589 (C / T) sites CT genotype frequency distribution was significantly higher in asthma with abnormal Savda group than that of the asthma with non abnormal Savda group and the normal control group(P<0.01). IL-4 gene promoter -589 (C / T) sites CT genotype frequency distribution was significantly higher in asthma with non abnormal Savda group than that of the normal control group(P<0.05). There was no statistical difference in CC, TT genotype and allele frequency distribution between these three groups(P>0.05).
IL-13 gene polymorphism loci intron 3 +1923 in asthma with abnormal Savda TT, TC genotype frequency distribution was significantly higher than that of the asthma with non abnormal Savda group and the normal control group(P<0.01),asthma with non abnormal Savda group TT, TC genotype frequency distribution was significantly higher than that of the normal control group(P<0.05),CC genotype frequency distribution in normal control group was significantly higher than that of the asthma with abnormal Savda group (P<0.05)and asthma with non abnormal Savda group(P<0.01). T allele frequency distribution of this site in asthma with abnormal Savda group was significantly higher than that of the normal control group(P<0.01),C allele frequency distribution of this site in normal control group was significantly higher than that of the asthma with abnormal Savda group(P<0.05). There was no statistical difference in IL-13 gene loci +2044 genotype frequency distributions and allele frequency distribution between these three groups(P>0.05).
3)Compared to normal control group, there was no significance on the expression of asthma with abnormal Savda group and asthma with non abnormal Savda group(P>0.05);the expression of CD62P in all three groups(P<0.05),among them the expression of CD62P in asthma with abnormal Savda group was significantly higher than that of the asthma with non abnormal Savda group(P<0.05). Compared to normal control group, level of serum ET-1 was significantly higher in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.05),the level of ET-1 was significantly higher in asthma with abnormal Savda group than that of the asthma with non abnormal Savda group and the normal control group(P<0.01). Compared to normal control group, level of plasma t-PA was significantly lower in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.05);Compared to normal control group, level of serum PAI-1 was significantly higher in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.05). Compared to normal control group, level of plasma FIB was significantly higher in asthma with abnormal Savda and asthma with non abnormal Savda groups(P<0.05), the level of plasma FIB was significantly higher in asthma with abnormal Savda group than that of the asthma with non abnormal Savda group and the normal control group. Compared to normal control group, level of APTT、PTwas significantly shortened in asthma with abnormal Savda and asthma with non abnormal Savda groups (P<0.05); There was no significance on TT between these three groups(P>0.05).
Conclusion:
1)ECP is a specific indicator of eosinophil activity, it reflects the degree of airway inflammation in the development. IgE-mediated allergic reaction is one of the main reasons of airway chronic inflammatory reaction. High level of T-IgE、S-IgE is not only the main recognition factors of atopic disease but also the main characteristic of airway chronic inflammation. The result of this study showed that, the level of serum ECP、T-IgE and S-IgE was significantly higher in asthmatic patients with abnormal Savda. From this result we assume that the high level of serum ECP、T-IgE and S-IgE might be the potential deciding factor if asthma with abnormal Savda. Therefore, judgement and assessment of these factors might have certain clinical significance in assessing the activity of asthma with abnormal Savda .
2)FEV_1 is related to the small airway resistance. FEV_1 is a reliable indicator of the degree and severity of airway obstruction. Decreased FEV_1 indicates the existence of airway obstruction. Our research result showed that the level of FEV_1 was significantly lower in asthmatic patients with abnormal Savda than that of the asthmatic patients with non abnormal Savda, indicates that airway obstruction is most obvious in asthmatic patients with abnormal Savda.
3)Individuals who haveβ_2-AR gene with 16 points glycine / glycine (Gly / Gly) homozygotes have a higher risk in developing asthma with abnormal Savda compared to individual who do not have it. We assume that when glycine arginine (Gly / Arg) heterozygous in individuals mutates to arginine, glycine, these individuals will have a higher risk in developing asthma with abnormal Savda. Gly/Gly genotype might be the inherent risk factor of asthma with abnormal Savda. There might be a correlation between theβ_2-AR gene polymorphism with 16 loci and asthma with abnormal Savda. 4)Individuals who have IL-4 gene promoter -589 (C/T) site with CT heterozygous genotype is related to the susceptibility of asthma with abnormal Savda, implies that IL-4 gene promoter -589 (C/T) site with CT polymorphism maybe an important candidate gene of asthma with abnormal Savda susceptibility.
5)IL-13intron 3 +1923 siteand TT and TC gene may be related to the pathogeneses of asthma with abnormal Savda. It is the susceptibility gene of asthma with abnormal Savda. The T allele of this site may be the susceptibility gene of asthma with abnormal Savda, C allele of this site may be the resistance gene of asthma with abnormal Savda. Individual With the T allele who are stimulated by environmental factors, such as repeated allergen exposure, long-term living in seriously polluted environment, are the ones who will have a higher chance of developing asthma with abnormal Savda than those with C allele. Therefore, individuals who have IL-13 intron3 +1923 site with T allele may be the important focus groups of asthma with abnormal Savda prevention in peacekeeping and medical abnormal biliary asthma prevention in Uyghur Medicine.
6)Studies found that prethromboitic state may be one of the pathological basis of asthma with abnormal Savda, and may also be pathogenic factors. There is platelet, vascular endothelial cells, blood coagulation and fibrinolytic function disorder , and in asthmatic patients with abnormal Savda, expressed in the activation of platelets, vascular endothelial cell damage, increased blood viscosity and reduced fibrinolytic function. Above results imply asthmatic patients with abnormal Savda are in a prothrombotic state, which is more prominent than asthmatic patients with non-abnormal Savda.
In short, the pathogenesis of asthma with abnormal Savda in Uyghur Medicine is heavier and more complex. Combined with the results of previous studies, we believe that in the diagnosis of asthma with abnormal Savda, while complying to the diagnostic methods in Uyghur Medicine, it is also important to consider the patient's immune dysfunction, endogenous cortisol decrease, the changes of serum ECP, T-IgE, S-IgE, FEV_1 lung function andβ_2-AR, IL-4, IL-13 gene polymorphism and CD62P, t-PA, PAI-1, FIB , APTT, PT. We should also consider these indicators as the micro indicators of asthma with abnormal Savda. These results will provide a new target for treating asthma with abnormal Savda in Uyghur Medicine, also it provides a thingking for the development and progresss of combined Uyghur, Western Medicine treatment of asthma.
引文
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