慢性阻塞性肺疾病患者糖皮质激素受体表达与激素疗效相关性的研究
发布时间：2018-05-24 05:44
本文选题：慢性阻塞性肺疾病 + 糖皮质激素 ； 参考：《吉林大学》2012年硕士论文
【摘要】：背景：慢性阻塞性肺疾病（chronic obstructive pulmonary disease,COPD）是以不完全可逆、呈进行性发展的慢性气流受限为特征的疾病，多与肺部对有毒颗粒和气体的异常炎症反应有关。它是一种严重危害人类健康的全球性疾病，其死亡率及致残率也在逐年上升。2002年，COPD为世界第五大致死原因，但据世界卫生组织（World Health Organization,WHO）估计，至2030年COPD可能上升为第三位致死原因，其致残率也将上升到第五位。糖皮质激素（glucocorticoids, GC）（以下简称激素）是目前临床上应用广泛且有效的抗炎症药物，它已经成为治疗极重度COPD的重要药物之一，在COPD治疗中发挥着举足轻重的作用。但在临床上，与同属于气道慢性炎症性疾病的支气管哮喘相比，COPD对抗炎症药物的敏感性较差，COPD患者对激素的疗效不及以哮喘为基础病的COPD患者。长期的激素治疗，不但不能有效的改善肺功能，反而引起某些患者对激素的长期依赖性，甚至可能出现所谓的“糖皮质激素抵抗”现象，这也同时增加了激素副作用的发生。目前，对于激素抵抗机制尚不完全清楚，但学者们普遍认为糖皮质激素受体（glucocorticoid receptor, GR），尤其是GRα及GRβ在激素抵抗中起着至关重要的作用。GRα作为激素的功能性受体发挥着对靶基因的转录激活作用，而GRβ则被认为是GRα的内源性抑制因子对GRα起着负性调节作用，并与激素抵抗有关。那么，GRα、GRβ数量的多少及二者比值的大小则可用来初步预测激素的作用效果。本研究主要是通过对COPD患者外周血单个核细胞（peripheral blood mononuclear cells,PBMCs）中GRα及GRβ蛋白表达水平及细胞核内GRβ/GRα比值等情况的分析，初步寻找一种潜在的、有效的检测指标来预测激素对COPD患者的治疗效果。 目的：观察COPD急性加重期患者使用激素治疗过程中GRα及GRβ蛋白表达含量的变化，探讨激素受体蛋白表达水平与激素疗效的相关性，试图建立在激素治疗前预测激素疗效及指导激素剂量的实验室检测指标。 方法：研究对象为42例COPD急性加重期患者，将其分为激素治疗组（22例）、非激素治疗组（20例）；以8例健康者为对照组；激素治疗组给予适当剂量的激素治疗及常规治疗，非激素治疗组给予除激素之外的常规治疗，，在激素治疗前及治疗3天、治疗8天后晨时抽取患者外周静脉血，分别提取PBMCs中细胞浆和细胞核蛋白质，并通过ELISA方法分别测定PBMCs中GRα和GRβ的蛋白表达含量。 结果： 1.COPD患者各年龄、性别及病程组的GRα、GRβ蛋白表达量及细胞核GRβ/GRα比值情况之间无明显统计学差异（P0.05）；但COPD吸烟组GRα蛋白表达量显著低于COPD不吸烟组及健康组，差异均有统计学意义（P0.05）；各组之间GRβ蛋白表达量及细胞核GRβ/GRα比值无明显统计学差异（P0.05）。提示，吸烟的COPD患者对激素耐受的可能性更大。 2.COPDⅡ级组、COPDⅢ级组、COPDⅣ级组及健康组各组之间GRα、GRβ的蛋白表达量均无明显统计学差异（P0.05）；COPDⅣ级组细胞核GRβ/GRα比值明显低于其他三组，差异有统计学意义（P0.05）。提示，COPD患者的肺功能分级与GRα、GRβ蛋白表达量无明显相关性。 3.COPD组GRα蛋白表达量显著低于哮喘合并COPD组及健康组,差异有统计学意义（P0.05）；COPD组、哮喘合并COPD组及健康组各组之间GRβ蛋白表达量均无明显统计学差异（P0.05）；COPD组及健康组的细胞核GRβ/GRα比值显著高于哮喘合并COPD组，差异有统计学意义(P0.05)。提示，激素对COPD患者的疗效较以哮喘为基础病的COPD患者疗效差，可能与COPD患者GRα蛋白的低表达有关。 4.COPD患者激素治疗3天后与激素治疗前相比GRα蛋白表达量降低,但差异无明显统计学意义（P0.05）；激素治疗3天后与激素治疗前相比GRβ蛋白表达量及细胞核GRβ/GRα比值均显著升高，差异有统计学意义（P0.05）。提示，短期激素治疗，可以使GRβ的蛋白表达量升高，影响激素的作用效果。 5.COPD患者激素治疗8天后与激素治疗3天后相比GRα、GRβ蛋白表达量均明显降低，差异有统计学意义（P0.05）；COPD患者激素治疗8天后与激素治疗3天后相比细胞核GRβ/GRα比值无明显统计学差异（P0.05）。提示，随着激素使用时间的延长，可进一步抑制GRα及GRβ的蛋白表达量，影响激素的作用效果。 6.激素治疗前，不同剂量组的GRα、 GRβ蛋白表达量及细胞核GRβ/GRα比值之间无明显统计学差异(P0.05)。激素治疗3天后，GRα、GRβ蛋白表达量在小剂量组㧐中、大剂量组，差异有统计学意义（P0.05）；GRα蛋白表达量在中、大剂量组均明显低于激素治疗前水平（P0.05）；GRβ蛋白表达量在中、大剂量组均明显高于激素治疗前水平(P0.05)；细胞核GRβ/GRα比值在各组之间无明显统计学差异(P0.05)，但均高于激素治疗前水平(P0.05)。提示，随着激素使用剂量的增加，可进一步抑制GRα及GRβ的蛋白表达量，影响激素的作用效果。 结论： 1.吸烟可能是COPD患者对激素敏感性差的危险因素之一。 2.COPD患者对激素的敏感性差与PBMCs中GRα蛋白含量的低表达、GRβ蛋白含量的高表达及细胞核GRβ/GRα比值的升高具有一定的相关性。 3.在一定剂量范围内，激素使用时间的延长或剂量的增加可导致激素受体数量的进行性减少，激素疗效与激素本身并不呈时间及剂量依赖性。 4.激素治疗过程中，PBMCs中的GRα、GRβ蛋白含量及细胞核GRβ/GRα比值，可能成为预测激素治疗效果及指导激素使用剂量的实验室检测指标。
[Abstract]:Background: chronic obstructive pulmonary disease (chronic obstructive pulmonary disease, COPD) is a disease characterized by incomplete and reversible, progressive development of chronic airflow, which is related to the abnormal inflammatory response of the lungs to toxic particles and gases. It is a global disease that seriously endangers human health and its mortality and disability. The rate is also rising year by year, and COPD is the fifth leading cause of death in the world, but according to the WHO (World Health Organization, WHO), it is estimated that by 2030 COPD may rise to third fatal causes and the rate of disability will rise to fifth. Extensive and effective anti inflammatory drugs, which have become one of the most important drugs for the treatment of extremely severe COPD, play an important role in the treatment of COPD, but in clinical, COPD is less sensitive to inflammatory drugs than bronchial asthma that belongs to chronic inflammatory diseases of the airway, and the effect of COPD on hormone is less than that of asthma. The long-term hormone therapy not only can not effectively improve the lung function, but also causes the long-term dependence of some patients on the hormone, even the so-called "glucocorticoid resistance" phenomenon, which also increases the occurrence of hormone side effects. The mechanism of hormone resistance is not completely clear, but the mechanism of hormone resistance is not completely clear before COPD. Scholars generally believe that glucocorticoid receptor (GR), especially GR A and GR beta play an important role in hormone resistance,.GR alpha acts as a functional receptor for hormone, which plays a role in the transcription of the target gene, while GR beta is considered as a negative regulator of the endogenous inhibitory factor of GR a to GR a. The number of GR alpha, GR beta and the size of the two ratio can be used to preliminarily predict the effect of hormones. This study is mainly through the expression of GR and GR beta protein in the peripheral blood mononuclear cells of the COPD patients (peripheral blood mononuclear cells, PBMCs) and the GR beta /GR alpha ratio in the nucleus. In order to predict the therapeutic effect of hormone on COPD patients, a potential and effective detection index was initially searched.
Objective: To observe the changes in the expression of GR alpha and GR beta protein during the treatment of COPD in patients with acute exacerbation, and to explore the correlation between the level of hormone receptor protein expression and the effect of hormone, and try to establish a laboratory test for predicting the effect of hormone and guiding the dose of hormone before hormone therapy.
Methods: the subjects were 42 patients with acute exacerbation of COPD, which were divided into hormone therapy group (22 cases), non hormone treatment group (20 cases) and 8 healthy subjects as control group; hormone treatment group was given appropriate dose of hormone therapy and routine treatment, non hormone treatment group was given routine treatment except hormone treatment before hormone treatment and 3 days of treatment. The peripheral venous blood of the patients was extracted 8 days after treatment, and the cytoplasm and nuclear proteins in PBMCs were extracted respectively. The protein expression of GR A and GR beta in PBMCs was measured by ELISA method respectively.
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