本文選題：慢性阻塞性肺疾病 + 糖皮質(zhì)激素　； 參考：《吉林大學(xué)》2012年碩士論文

【摘要】：背景：慢性阻塞性肺疾�。╟hronic obstructive pulmonary disease,COPD）是以不完全可逆、呈進行性發(fā)展的慢性氣流受限為特征的疾病，多與肺部對有毒顆粒和氣體的異常炎癥反應(yīng)有關(guān)。它是一種嚴重危害人類健康的全球性疾病，其死亡率及致殘率也在逐年上升。2002年，COPD為世界第五大致死原因，但據(jù)世界衛(wèi)生組織（World Health Organization,WHO）估計，至2030年COPD可能上升為第三位致死原因，其致殘率也將上升到第五位。糖皮質(zhì)激素（glucocorticoids, GC）（以下簡稱激素）是目前臨床上應(yīng)用廣泛且有效的抗炎癥藥物，它已經(jīng)成為治療極重度COPD的重要藥物之一，在COPD治療中發(fā)揮著舉足輕重的作用。但在臨床上，與同屬于氣道慢性炎癥性疾病的支氣管哮喘相比，COPD對抗炎癥藥物的敏感性較差，COPD患者對激素的療效不及以哮喘為基礎(chǔ)病的COPD患者。長期的激素治療，不但不能有效的改善肺功能，反而引起某些患者對激素的長期依賴性，甚至可能出現(xiàn)所謂的“糖皮質(zhì)激素抵抗”現(xiàn)象，這也同時增加了激素副作用的發(fā)生。目前，對于激素抵抗機制尚不完全清楚，但學(xué)者們普遍認為糖皮質(zhì)激素受體（glucocorticoid receptor, GR），尤其是GRα及GRβ在激素抵抗中起著至關(guān)重要的作用。GRα作為激素的功能性受體發(fā)揮著對靶基因的轉(zhuǎn)錄激活作用，而GRβ則被認為是GRα的內(nèi)源性抑制因子對GRα起著負性調(diào)節(jié)作用，并與激素抵抗有關(guān)。那么，GRα、GRβ數(shù)量的多少及二者比值的大小則可用來初步預(yù)測激素的作用效果。本研究主要是通過對COPD患者外周血單個核細胞（peripheral blood mononuclear cells,PBMCs）中GRα及GRβ蛋白表達水平及細胞核內(nèi)GRβ/GRα比值等情況的分析，初步尋找一種潛在的、有效的檢測指標來預(yù)測激素對COPD患者的治療效果。 目的：觀察COPD急性加重期患者使用激素治療過程中GRα及GRβ蛋白表達含量的變化，探討激素受體蛋白表達水平與激素療效的相關(guān)性，試圖建立在激素治療前預(yù)測激素療效及指導(dǎo)激素劑量的實驗室檢測指標。 方法：研究對象為42例COPD急性加重期患者，將其分為激素治療組（22例）、非激素治療組（20例）；以8例健康者為對照組；激素治療組給予適當劑量的激素治療及常規(guī)治療，非激素治療組給予除激素之外的常規(guī)治療，，在激素治療前及治療3天、治療8天后晨時抽取患者外周靜脈血，分別提取PBMCs中細胞漿和細胞核蛋白質(zhì)，并通過ELISA方法分別測定PBMCs中GRα和GRβ的蛋白表達含量。 結(jié)果： 1.COPD患者各年齡、性別及病程組的GRα、GRβ蛋白表達量及細胞核GRβ/GRα比值情況之間無明顯統(tǒng)計學(xué)差異（P0.05）；但COPD吸煙組GRα蛋白表達量顯著低于COPD不吸煙組及健康組，差異均有統(tǒng)計學(xué)意義（P0.05）；各組之間GRβ蛋白表達量及細胞核GRβ/GRα比值無明顯統(tǒng)計學(xué)差異（P0.05）。提示，吸煙的COPD患者對激素耐受的可能性更大。 2.COPDⅡ級組、COPDⅢ級組、COPDⅣ級組及健康組各組之間GRα、GRβ的蛋白表達量均無明顯統(tǒng)計學(xué)差異（P0.05）；COPDⅣ級組細胞核GRβ/GRα比值明顯低于其他三組，差異有統(tǒng)計學(xué)意義（P0.05）。提示，COPD患者的肺功能分級與GRα、GRβ蛋白表達量無明顯相關(guān)性。 3.COPD組GRα蛋白表達量顯著低于哮喘合并COPD組及健康組,差異有統(tǒng)計學(xué)意義（P0.05）；COPD組、哮喘合并COPD組及健康組各組之間GRβ蛋白表達量均無明顯統(tǒng)計學(xué)差異（P0.05）；COPD組及健康組的細胞核GRβ/GRα比值顯著高于哮喘合并COPD組，差異有統(tǒng)計學(xué)意義(P0.05)。提示，激素對COPD患者的療效較以哮喘為基礎(chǔ)病的COPD患者療效差，可能與COPD患者GRα蛋白的低表達有關(guān)。 4.COPD患者激素治療3天后與激素治療前相比GRα蛋白表達量降低,但差異無明顯統(tǒng)計學(xué)意義（P0.05）；激素治療3天后與激素治療前相比GRβ蛋白表達量及細胞核GRβ/GRα比值均顯著升高，差異有統(tǒng)計學(xué)意義（P0.05）。提示，短期激素治療，可以使GRβ的蛋白表達量升高，影響激素的作用效果。 5.COPD患者激素治療8天后與激素治療3天后相比GRα、GRβ蛋白表達量均明顯降低，差異有統(tǒng)計學(xué)意義（P0.05）；COPD患者激素治療8天后與激素治療3天后相比細胞核GRβ/GRα比值無明顯統(tǒng)計學(xué)差異（P0.05）。提示，隨著激素使用時間的延長，可進一步抑制GRα及GRβ的蛋白表達量，影響激素的作用效果。 6.激素治療前，不同劑量組的GRα、 GRβ蛋白表達量及細胞核GRβ/GRα比值之間無明顯統(tǒng)計學(xué)差異(P0.05)。激素治療3天后，GRα、GRβ蛋白表達量在小劑量組㧐中、大劑量組，差異有統(tǒng)計學(xué)意義（P0.05）；GRα蛋白表達量在中、大劑量組均明顯低于激素治療前水平（P0.05）；GRβ蛋白表達量在中、大劑量組均明顯高于激素治療前水平(P0.05)；細胞核GRβ/GRα比值在各組之間無明顯統(tǒng)計學(xué)差異(P0.05)，但均高于激素治療前水平(P0.05)。提示，隨著激素使用劑量的增加，可進一步抑制GRα及GRβ的蛋白表達量，影響激素的作用效果。 結(jié)論： 1.吸煙可能是COPD患者對激素敏感性差的危險因素之一。 2.COPD患者對激素的敏感性差與PBMCs中GRα蛋白含量的低表達、GRβ蛋白含量的高表達及細胞核GRβ/GRα比值的升高具有一定的相關(guān)性。 3.在一定劑量范圍內(nèi)，激素使用時間的延長或劑量的增加可導(dǎo)致激素受體數(shù)量的進行性減少，激素療效與激素本身并不呈時間及劑量依賴性。 4.激素治療過程中，PBMCs中的GRα、GRβ蛋白含量及細胞核GRβ/GRα比值，可能成為預(yù)測激素治療效果及指導(dǎo)激素使用劑量的實驗室檢測指標。
[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.
Result錛

本文編號：1927899