【摘要】：慢性支氣管炎是由感染、過敏等因素引起的氣管、支氣管黏膜及其周圍組織的慢性非特異性炎癥,臨床以咳嗽、咳痰或伴喘息為主要特征,是臨床常見的一種呼吸系統(tǒng)疾病。近年來,伴隨人口老齡化進(jìn)程和環(huán)境污染的加劇,我國慢性支氣管炎患病人數(shù)日趨增多。本病具有典型的病程長、易復(fù)發(fā)等特征,伴隨疾病的進(jìn)展可并發(fā)阻塞性肺氣腫、肺動脈高壓、肺源性心臟病等,嚴(yán)重危害人類健康,甚至影響患者的勞動能力和生存質(zhì)量。當(dāng)前,慢性阻塞性肺疾病已居世界死亡原因第四位,且發(fā)病率仍呈上升趨勢。因此,對慢性支氣管炎的有效防治具有非常重要的社會意義。“冬病夏治”穴位貼敷療法防治慢性支氣管炎以其療效明顯、操作簡便、副作用小等優(yōu)勢越來越被患者接受和認(rèn)可。諸多學(xué)者對中藥穴位貼敷療法的機(jī)制進(jìn)行了初步研究,一般認(rèn)為是藥物的透皮吸收與經(jīng)絡(luò)系統(tǒng)對人體調(diào)節(jié)的雙重效應(yīng)。但目前中藥的藥效成分及經(jīng)絡(luò)調(diào)節(jié)機(jī)制尚未清楚,尋找其它途徑的研究方法對于揭示穴位貼敷療法的機(jī)制意義重大。故本研究首先通過觀察“冬病夏治”穴位貼敷治療前后慢性支氣管炎患者發(fā)作時主要癥狀單項積分、生存質(zhì)量等指標(biāo)的變化,明確“冬病夏治”穴位貼敷法治療慢性支氣管炎的臨床療效;其次,通過觀察免疫球蛋白、炎癥細(xì)胞因子、神經(jīng)遞質(zhì)的變化,一方面佐證穴位貼敷法治療慢支的療效,另一方面從神經(jīng)-炎癥-免疫的角度,綜合解釋“冬病夏治”穴位貼敷法治療慢支的作用機(jī)制;第三,利用基于液相-質(zhì)譜聯(lián)用(LC/MS)技術(shù)的代謝組學(xué)研究方法,將代謝組學(xué)技術(shù)應(yīng)用到“冬病夏治”穴位貼敷療法的整體療效評價以及作用機(jī)制研究,分析穴位貼敷治療前后患者的血漿代謝圖譜,并通過觀察治療所引起的內(nèi)源性代謝物的變化,推測體內(nèi)生化狀態(tài)的變化,進(jìn)而探討該療法的作用機(jī)制;尋找反映治療前后機(jī)體變化的代謝標(biāo)志物,利用代謝物的終端性信息,為尋找或闡明藥物作用的靶點或受體奠定前期基礎(chǔ)。本論文的研究內(nèi)容主要包括以下三個部分:觀察第一部分“冬病夏治”穴位貼敷法治療緩解期慢性支氣管炎的臨床療效目的:觀察“冬病夏治”穴位貼敷法治療緩解期慢性支氣管炎患者的臨床療效。方法:選擇符合納入標(biāo)準(zhǔn)的緩解期慢性支氣管炎患者50例作為慢支組,分別于頭伏、二伏、末伏的第一天給予穴位貼敷治療,共3次。30天為1個療程。采取樣本治療前后自身對照的方法進(jìn)行對比分析。將患者治療前1年(2013年7月~2014年6月)的癥狀,與治療后1年(2014年7月~2015年6月)的癥狀做比較。參照《中藥新藥臨床研究指導(dǎo)原則》對慢支癥狀分級量化表評分,記錄治療前后觀察期內(nèi)咳嗽、咳痰、咳喘等各單項癥狀的嚴(yán)重程度及持續(xù)時間(以天數(shù)為記錄單位),并評定療效;采用圣喬治醫(yī)院呼吸問卷(SGRQ),從癥狀的頻率和嚴(yán)重程度(癥狀部分)、會造成氣促或受疾病限制的活動(活動部分)以及疾病導(dǎo)致的社會能力損害和心理問題(對日常生活的影響)三個方面綜合評價穴位貼敷治療前后慢支患者的生存質(zhì)量。結(jié)果:“冬病夏治”穴位貼敷法可顯著改善慢支患者臨床癥狀:治療后1年患者咳嗽癥狀積分明顯低于治療前(P0.05);咳痰癥狀積分與治療前比較差異有統(tǒng)計學(xué)意義(P0.05);咳喘癥狀積分較治療前明顯降低(P0.05);臨床中醫(yī)證候療效明顯,總有效率72%;該療法可明顯改善慢支患者的生存質(zhì)量,治療后1年癥狀部分評分、活動部分評分、影響部分評分及SGRQ總評分較治療前均明顯降低,差異有統(tǒng)計學(xué)意義(P0.05)。第二部分“冬病夏治”穴位貼敷法對緩解期慢性支氣管炎患者神經(jīng)-炎癥-免疫系統(tǒng)調(diào)控影響的研究目的:通過免疫球蛋白、炎癥細(xì)胞因子、神經(jīng)遞質(zhì)的觀察,在明確“冬病夏治”穴位貼敷療法治療慢支療效的基礎(chǔ)上,探討該療法的作用機(jī)制,從神經(jīng)-炎癥-免疫整體的角度探討其作用靶點和作用途徑。方法:選擇符合納入標(biāo)準(zhǔn)的緩解期慢性支氣管炎患者50例,設(shè)為慢支組(chronic bronchitis,CB)。給予“三伏天”穴位貼敷治療,30天作為一個療程。同時設(shè)50例健康志愿者作為對照組(control)。檢測對照組以及慢支病人治療前(pre-treatment,Pre)、治療后(post-treatment,Post)、治療后冬季(winter)血清免疫球蛋白(Ig A、Ig G、Ig M、Ig E),炎癥細(xì)胞因子(TNF-α、IL-4、IL-8、IL-10),血漿P物質(zhì)(SP),血管活性腸肽(VIP)等指標(biāo)。比較慢支組治療后、治療后冬季免疫球蛋白、炎癥細(xì)胞因子以及神經(jīng)遞質(zhì)與治療前的差異,并將慢支組治療前、治療后、治療后冬季的相應(yīng)指標(biāo)與對照組進(jìn)行比較,從神經(jīng)-炎癥-免疫角度,探討“冬病夏治”穴位貼敷療法對慢支患者炎癥的改善以及對機(jī)體的保護(hù)機(jī)制。結(jié)果:與對照組比較,慢支組治療前、治療后以及治療后冬季Ig A、Ig G、Ig M、IL-10、VIP水平下降,差異有統(tǒng)計學(xué)意義(P0.05);Ig E、IL-4、IL-8、TNF-α、SP水平升高,除慢支組治療后IL-8之外,與對照組比較差異均有統(tǒng)計學(xué)意義(P0.05);慢支組治療后Ig A、Ig G、Ig M、IL-10、VIP水平較治療前升高,差異有統(tǒng)計學(xué)意義(P0.05);Ig E、IL-4、IL-8、SP水平較治療前下降,差異有統(tǒng)計學(xué)意義(P0.05);治療后TNF-α較治療前有下降趨勢,但差異無統(tǒng)計學(xué)意義(P0.05)。慢支組治療后冬季Ig A、Ig G、Ig M、IL-10、VIP水平較治療前升高,差異有統(tǒng)計學(xué)意義(P0.05);Ig E、IL-4、IL-8、SP水平較治療前下降,差異有統(tǒng)計學(xué)意義(P0.05);治療后冬季TNF-α較治療前有下降趨勢,但差異無統(tǒng)計學(xué)意義(P0.05)。與慢支組治療后比較,治療后冬季Ig M、IL-10、VIP水平下降,差異有統(tǒng)計學(xué)意義(P0.05);IL-8、SP水平升高,差異有統(tǒng)計學(xué)意義(P0.05);治療后冬季Ig A、Ig G、TNF-α水平有下降趨勢,但差異無統(tǒng)計學(xué)意義(P0.05);Ig E、IL-4水平有上升趨勢,但差異無統(tǒng)計學(xué)意義(P0.05)。第三部分基于血漿代謝組學(xué)的“冬病夏治”穴位貼敷法治療緩解期慢性支氣管炎的機(jī)制研究目的:基于現(xiàn)代生物質(zhì)譜技術(shù),運用代謝組學(xué)方法研究“冬病夏治”穴位貼敷治療前后慢支患者的血漿代謝組學(xué)特征,通過治療前后潛在生物標(biāo)志物變化,探討“冬病夏治”穴位貼敷療法防治慢支的機(jī)理,并利用代謝物的終端性信息,為尋找或闡明藥物作用的靶點或受體奠定前期基礎(chǔ)。方法:選擇符合納入標(biāo)準(zhǔn)的緩解期慢支患者50例,設(shè)為慢支組,給予“三伏天”穴位貼敷療法,30天作為一個療程。同時設(shè)50例健康志愿者作為對照組(control)。分別采集對照組及慢支組治療前(Pre)、治療后(Post)、治療后冬季(winter)血液樣品,并采用高效液相色譜-質(zhì)譜聯(lián)用儀(HPLC-MS)進(jìn)行檢測。利用主成分分析法(principal component analysis,PCA)和正交偏最小二乘法判別分析(orthogonal partial least squares-discriminant analysis,OPLS-DA)進(jìn)行數(shù)據(jù)統(tǒng)計學(xué)處理,比較各組血漿代謝組學(xué)原始圖譜和數(shù)據(jù)。結(jié)果:各組血漿代謝物圖譜均呈現(xiàn)聚類型分布,慢支組在治療前與對照組的代謝譜存在明顯不同。穴位貼敷治療后,慢支組治療后以及治療后冬季的代謝譜均向?qū)φ战M回歸,與對照組代謝成分接近。初步推測膽堿、組氨酸、維生素B6、甲硫氨酸、生物喋呤等為慢支治療前區(qū)分對照組的潛在標(biāo)志物,在發(fā)病和復(fù)發(fā)中發(fā)揮重要作用。其中,組氨酸、甲硫氨酸在各組比較中均發(fā)揮重要作用,且呈現(xiàn)治療后組氨酸降低、甲硫氨酸升高的趨勢。結(jié)論:1“冬病夏治”穴位貼敷法治療緩解期慢性支氣管炎療效確切,值得在臨床繼續(xù)深化和推廣。該觀察結(jié)果也為深入研究“冬病夏治”穴位貼敷療法的作用機(jī)制提供了堅實的臨床數(shù)據(jù)支持。2“冬病夏治”穴位貼敷法能改善機(jī)體的免疫狀態(tài),協(xié)調(diào)免疫平衡,增強(qiáng)機(jī)體防病抗病能力;能調(diào)節(jié)炎癥細(xì)胞因子的釋放,降低炎癥發(fā)生的程度;能通過神經(jīng)遞質(zhì)的調(diào)節(jié),對免疫和炎癥反應(yīng)發(fā)揮良性調(diào)節(jié)作用。這可能是其預(yù)防慢支復(fù)發(fā)、減輕癥狀的協(xié)同機(jī)制。3通過對人體血漿的代謝組學(xué)研究,發(fā)現(xiàn)慢支患者存在與對照組明顯不同的代謝圖譜。慢支組治療后及治療后冬季代謝圖譜向?qū)φ战M的回歸,證實了“冬病夏治”穴位貼敷法治療慢支的療效;初步闡釋了“冬病夏治”穴位貼敷療法防治慢支的代謝組學(xué)機(jī)制,可能集中在糾正氨基酸、維生素代謝紊亂、調(diào)節(jié)細(xì)胞因子的產(chǎn)生和釋放等方面。研究結(jié)果對采用現(xiàn)代生物科學(xué)技術(shù)探討傳統(tǒng)中醫(yī)藥理論有一定的啟發(fā)作用。
[Abstract]:Chronic bronchitis is a chronic nonspecific inflammation of trachea, bronchial mucosa and its surrounding tissues caused by infection, allergy and other factors. It is a common respiratory disease clinically characterized by cough, sputum or wheezing. Chronic obstructive pulmonary disease (COPD) is the leading cause of death in the world. With the development of COPD, obstructive pulmonary emphysema, pulmonary hypertension, pulmonary heart disease and so on, it seriously endangers human health and even affects the working ability and quality of life of patients. Therefore, it is of great social significance for the effective prevention and treatment of chronic bronchitis. Acupoint application therapy of "treating winter diseases in summer" has been accepted and recognized by patients more and more for its obvious curative effect, simple operation and less side effects. The mechanism of this method has been preliminarily studied, generally believed to be the dual effects of drug transdermal absorption and meridian system on human body regulation. However, the pharmacodynamic components of traditional Chinese medicine and the mechanism of meridian regulation are still unclear. It is of great significance to find other ways to reveal the mechanism of acupoint application therapy. The clinical effect of acupoint sticking therapy of "treating winter disease in summer" on chronic bronchitis was clarified. Secondly, the changes of immunoglobulin, inflammatory cytokines and neurotransmitters were observed, which supported the evidence on the one hand. On the other hand, the mechanism of Acupoint Application in treating chronic bronchitis is comprehensively explained from the angle of nerve-inflammation-immunity. Thirdly, the metabolomics research method based on liquid chromatography-mass spectrometry (LC/MS) technology is applied to acupoint application in treating chronic bronchitis. Methods To evaluate the overall efficacy and study the mechanism of action, analyze the plasma metabolic map of patients before and after acupoint sticking therapy, and by observing the changes of endogenous metabolites caused by treatment, infer the changes of biochemical state in vivo, and then explore the mechanism of action of this therapy; to find metabolic markers reflecting the changes of the body before and after treatment. The research contents of this paper mainly include the following three parts: the first part observes the clinical effect of acupoint sticking therapy of treating chronic bronchitis in remission period; the second part observes the acupoint sticking therapy of treating chronic bronchitis in winter and summer Methods: Fifty patients with chronic bronchitis in remission period were selected as the chronic bronchitis group. They were treated with acupoint sticking therapy on the first day of headrest, second volt and last volt respectively. The treatment course was 3 times and 30 days. The symptoms of the patients in the first year before treatment (July 2013-June 2014) were compared with those in the first year after treatment (July 2014-June 2015). The SGRQ was used to evaluate acupoint patches comprehensively from three aspects: frequency and severity of symptoms (symptoms), activities (activities) that may cause shortness of breath or be restricted by disease, social impairment and psychological problems (effects on daily life) caused by disease. Results: Acupoint sticking therapy of "treating winter disease in summer" can significantly improve the clinical symptoms of patients with chronic bronchitis: one year after treatment, the score of cough symptoms was significantly lower than that before treatment (P 0.05); the score of cough symptoms was significantly lower than that before treatment (P 0.05); the score of cough and asthma symptoms was significantly lower than that before treatment (P 0.05); the score of cough and asthma symptoms was (P 0.05); the curative effect of TCM syndromes was obvious, the total effective rate was 72%; the treatment can significantly improve the quality of life of patients with chronic bronchitis, one year after treatment symptoms partial score, activity partial score, influence partial score and SGRQ total score were significantly lower than before treatment, the difference was statistically significant (P 0.05). The second part of the "winter disease summer treatment" acupoint application method. Objective: To investigate the effect of acupoint sticking therapy on chronic bronchitis in remission stage by observing immunoglobulin, inflammatory cytokines and neurotransmitters, and to explore the mechanism of acupoint sticking therapy on chronic bronchitis from the perspective of nerve-inflammation-immunity. Methods: Fifty patients with chronic bronchitis in remission period were selected and assigned to the chronic bronchitis group (CB) according to the inclusion criteria. Serum immunoglobulin (Ig A, Ig G, Ig M, Ig E), inflammatory cytokines (TNF-alpha, IL-4, IL-8, IL-10), plasma substance P (SP), vasoactive intestinal peptide (VIP) were measured before and after treatment, and in winter after treatment. Compared with the control group, the corresponding indexes in winter after treatment were compared. From the angle of nerve-inflammation-immunity, the improvement of inflammation and the protective mechanism of acupoint sticking therapy for treating chronic bronchitis in winter were discussed. The levels of Ig A, Ig G, Ig M, IL-10 and VIP were significantly lower before and after treatment than before treatment (P 0.05), while the levels of Ig E, IL-4, IL-8, TNF-a and SP were significantly higher than those before treatment (P 0.05), except for IL-8 in the chronic bronchitis group, the levels of Ig A, Ig G, Ig M, IL-10 and VIP were significantly higher than those before treatment. The levels of Ig E, IL-4, IL-8 and SP were significantly lower than those before treatment (P 0.05). After treatment, the levels of TNF-alpha decreased, but there was no significant difference (P 0.05). After treatment, the levels of Ig A, Ig G, Ig M, IL-10 and VIP in the chronic bronchitis group were significantly higher than those before treatment (P 0.05). The levels of IL-8 and SP were significantly lower than those before treatment (P 0.05). After treatment, the levels of TNF-a in winter had a downward trend, but there was no significant difference (P 0.05). After treatment, the levels of Ig M, IL-10 and VIP in winter were significantly lower than those in CMB group (P 0.05). The levels of IL-8 and SP were significantly higher than those before treatment (P 0.0). 5) After treatment, the levels of Ig A, Ig G and TNF-alpha decreased in winter, but there was no significant difference (P 0.05); Ig E and IL-4 levels increased, but there was no significant difference (P 0.05). The third part based on plasma metabolomics, "winter disease summer treatment" acupoint sticking therapy for chronic bronchitis in remission mechanism research purposes: based on modern health Material spectrum technique was used to study the plasma metabolomic characteristics of patients with chronic bronchitis before and after acupoint sticking therapy of "Winter Disease Treated in Summer". The mechanism of acupoint sticking therapy of "Winter Disease Treated in Summer" for prevention and treatment of chronic bronchitis was discussed through the changes of potential biomarkers before and after treatment, and the terminal information of metabolites was used to find or elucidate drugs. Methods: Fifty patients with chronic bronchitis in remission period were selected as the chronic bronchitis group, and treated with Acupoint Application Therapy of "three-dog days" for 30 days as a course of treatment. T. Blood samples in winter after treatment were analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS). Data were analyzed by principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). Results: The plasma metabolite profiles of each group showed clustering distribution, and the metabolite profiles of the CMB group were significantly different from those of the control group before treatment. It is speculated that choline, histidine, vitamin B6, methionine and biopterin are the potential markers to distinguish the control group before CB treatment and play an important role in the pathogenesis and recurrence. The observation also provides a solid clinical data support for the further study of the mechanism of acupoint application therapy. 2 The acupoint application method of "treating winter diseases in summer" can improve the body's immune symptoms. It can regulate the release of inflammatory cytokines and reduce the degree of inflammation. It can play a benign role in regulating immune and inflammation through the regulation of neurotransmitters. This may be the synergistic mechanism of preventing relapse of chronic bronchitis and alleviating symptoms. The results showed that the metabolic Atlas of patients with chronic bronchitis were significantly different from those of the control group. The regression of the metabolic Atlas of patients with chronic bronchitis in winter after treatment and after treatment to the control group confirmed the curative effect of acupoint sticking therapy for treating chronic bronchitis by "treating winter diseases in summer"; and preliminarily explained the metabolomic mechanism of acupoint sticking therapy for treating chronic bronchitis by "treating winter diseases in summer", which might be a collection. The results of this study will be helpful to the application of modern biotechnology in the study of traditional Chinese medicine.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R246.1

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 陳阿浮;王瑞麗;張驕瀅;;天灸聯(lián)合左氧氟沙星治療慢性支氣管炎療效觀察[J];上海針灸雜志;2015年12期

2 張彩芬;;冬病夏治FBP方案治療慢性支氣管炎臨床觀察[J];世界最新醫(yī)學(xué)信息文摘;2015年27期

3 唐冬梅;張賽;王昊;陳紅;;利肺片配合冬病夏治哮喘膏治療肺腎兩虛型慢性支氣管炎的臨床觀察[J];中華中醫(yī)藥雜志;2015年08期

4 耿雨作;王廣洋;任現(xiàn)志;;代謝組學(xué)在紫癜性腎炎中醫(yī)分型研究中的應(yīng)用前景[J];遼寧中醫(yī)藥大學(xué)學(xué)報;2015年07期

5 丁新華;;蘇子降氣湯配合穴位貼敷治療慢性支氣管炎60例臨床觀察[J];新中醫(yī);2015年06期

6 林燕;王亞利;王鑫國;張明泉;王文智;耿立梅;孫玉鳳;曹文利;師旭亮;;反復(fù)上呼吸道感染肺衛(wèi)氣虛證的血漿代謝組學(xué)特征及玉屏風(fēng)顆粒干預(yù)的臨床療效[J];中醫(yī)雜志;2015年15期

7 杜佳;雷撼;胡蕓;吳怡;梁永;;SGRQ、CAT和CCQ問卷在COPD患者生活質(zhì)量中的評估價值比較[J];現(xiàn)代生物醫(yī)學(xué)進(jìn)展;2015年12期

8 黃艷芳;尹玲;朱藎雯;;天灸聯(lián)合扶正化痰湯治療慢性支氣管炎復(fù)發(fā)隨機(jī)平行對照研究[J];實用中醫(yī)內(nèi)科雜志;2015年04期

9 田巍;田冀虹;;穴位注射配合穴位貼敷治療慢性支氣管炎80例[J];中國中醫(yī)藥現(xiàn)代遠(yuǎn)程教育;2015年07期

10 田愛平;趙輝;張麗;季輝;;膏方聯(lián)合穴位貼敷治療慢性支氣管炎的療效觀察[J];針灸臨床雜志;2015年03期

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