本文選題：慢性阻塞性肺疾病 + 中醫(yī)��； 參考：《新疆醫(yī)科大學(xué)》2013年博士論文

【摘要】：目的： 選擇中醫(yī)藥治療COPD的常用治法,在運用系統(tǒng)評價和Meta分析確定中醫(yī)藥治療COPD有效和安全的基礎(chǔ)上,開展基于流行病學(xué)調(diào)查的新疆COPD和基于文獻研究的內(nèi)地COPD中醫(yī)發(fā)病特點的對比研究,揭示新疆COPD的中醫(yī)證型分布特點,找到特殊證型。在此基礎(chǔ)上建立新疆寒燥型COPD動物模型,并從實驗層面揭示寒燥型COPD的生物學(xué)基礎(chǔ),為COPD的方域化防治提供借鑒和參考。 方法： 利用系統(tǒng)評價和Meta分析的方法評價小青龍湯治療COPD發(fā)作期和中醫(yī)貼敷治療COPD穩(wěn)定期的療效性和安全性；利用中醫(yī)證候流行病學(xué)調(diào)查的方法揭示新疆COPD的發(fā)病特點,并將其和基于文獻的內(nèi)地COPD的發(fā)病特點進行對比研究,揭示新疆COPD的特殊證型�；诓∫蚰M-慢性應(yīng)激-生物表征-藥物反證的思路,利用氣管滴注彈性蛋白酶結(jié)合熏煙90天建立COPD模型,在此基礎(chǔ)上復(fù)合寒燥應(yīng)激建立寒燥型COPD模型,通過肺功能、肺部病理觀察和生物表征判斷模型的成功建立,利用ELISA、Real-time PCR、Western-blot等方法檢測模型內(nèi)在病理生理狀態(tài),揭示寒燥型COPD的生物學(xué)基礎(chǔ)。 結(jié)果： 1.小青龍湯聯(lián)合西藥內(nèi)服可提高單純西藥治療的有效率[MD=3.91,95%CI (2.50,6.12), P0.00001],小青龍湯內(nèi)服聯(lián)合有創(chuàng)通氣有效率優(yōu)于單純有創(chuàng)通氣組[MD=3.48,95%CI (1.45,8.32), P=0.005];對于Pa02的改善小青龍湯聯(lián)合西藥內(nèi)服優(yōu)于單純西藥組[MD=7.55,95%CI (1.41,13.68), P=0.02];對于PaCO2的改善小青龍湯聯(lián)合西藥內(nèi)服優(yōu)于單純西藥組[MD=-7.11,95%CI (-9.89,-4.33),P0.00001],小青龍湯內(nèi)服聯(lián)合有創(chuàng)通氣優(yōu)于單純有創(chuàng)通氣組[MD=-6.66,95%CI (-8.79,-4.54), P0.00001];對于FEV1的改善小青龍湯聯(lián)合西藥內(nèi)服優(yōu)于單純西藥組[MD=6.97,95%CI (3.60,10.34), P0.0001]。 2.所有加用中醫(yī)貼敷組的有效率均優(yōu)于未用中醫(yī)貼敷組[MD=3.63,95%CI(2.84,4.65),P0.00001]；對于FEV1,貼敷加西藥組優(yōu)于西藥組[MD=0.29,95%CI(0.06,0.52),P=0.01]；對于FEV1/FVC,貼敷加中藥優(yōu)于中藥組[MD=5.29,95%CI(2.52,8.07),P=0.0002]。 3.1)內(nèi)地COPD總體癥狀中出現(xiàn)頻次較多的是咳嗽(313,22.88%)、咳痰(204,14.91%)、氣喘(124,9.06%)、喘息(120,8.77%)、氣短(91,6.65%)、哮鳴音(54,3.95%)、胸悶(45,3.29%)、乏力(40,2.93%)、納差(38,2.78%)、氣促(36,2.63%)、自汗(28,2.05%)、易感冒(27,1.97%)；而新疆COPD出現(xiàn)頻次較多的癥狀是氣短(317次,4.43%),咳嗽(310例,4.33%),氣喘(288,4.02%),咽干口干(259,3.62%),神疲乏力(244,3.41%),咳痰(235,3.28%),胸悶(227,3.17%),健忘(226,3.16%),汗出(211,2.95%),咽癢(207,2.89%),畏寒(206,2.88%),乏力(206,2.88%)；其中“燥”的表現(xiàn)(咽干、口干、鼻燥)為259例,占到全部調(diào)查病例的63%；“寒”的表現(xiàn)(惡風(fēng)、畏寒、形寒怕冷、腰背冷痛、肢冷)為164例,占到全部調(diào)查病例的40%�！昂奔妗霸铩钡谋憩F(xiàn)同時出現(xiàn)的為110例,占到全部調(diào)查病例的27%。內(nèi)地COPD病位證素以肺(237,59.55%)、脾(81,20.35%)、腎(74,18.59%)為主,病性證素以痰(163,35.21%)、氣虛(92,19.87%)、熱(89,19.22%)、瘀(65,14.04%)、濕(14,3.02%)為主。證型主要以痰熱蘊肺(69,19.77%)、痰瘀阻肺(43,12.32%)、肺脾氣虛(33,9.46%)、肺。腎兩虛(24,6.88%)、痰濁阻肺(20,5.73%)為主；新疆COPD病位證素以肺(287,61.46%),腎(142,30.41%),脾(38,8.14%)為主；病性為氣虛(120,16.37%),寒(117,15.96%),陽虛(109,14.87%),痰(98,13.37%),陰虛(90,12.28%)為主。2)新疆和內(nèi)地COPD患者相比舌質(zhì)、舌苔和脈象總體分布不同。內(nèi)地舌質(zhì)瘀斑和舌質(zhì)淡的多于新疆(P0.01,P0.05)；新疆舌質(zhì)紫的則多于內(nèi)地(P0.01)；新疆舌質(zhì)少津的構(gòu)成比2.84%,內(nèi)地舌質(zhì)少津的構(gòu)成比0.56%,新疆多于內(nèi)地,但無統(tǒng)計學(xué)差異；內(nèi)地患者舌質(zhì)出現(xiàn)的胖、齒痕、絳、青則本次調(diào)查中新疆患者未見。內(nèi)地黃苔和膩苔多于新疆(P0.01),白苔和薄苔新疆多于內(nèi)地(P0.01),本次研究內(nèi)地患者出現(xiàn)的濁苔、厚苔,本次調(diào)查新疆患者則未見。內(nèi)地滑脈多于新疆(P0.01),沉脈和弱脈多于新疆(P0.05)；澀脈、緊脈新疆多于內(nèi)地(P0.05),浮脈和細(xì)脈新疆多于內(nèi)地(P0.01)；另外內(nèi)地患者出現(xiàn)的無力、濡、結(jié)代、大脈本次調(diào)查新疆患者未見,遲脈則僅在新疆患者中出現(xiàn),且占到7.93%。 4.1) COPD組及寒燥型COPD組肺部均有肺泡斷裂融合、炎癥細(xì)胞浸潤和小支氣管下平滑肌增厚現(xiàn)象,肺功能寒燥型COPD組的PEF、Ti、Te、EF50均高于對照組和COPD組,COPD組的Te和EF50高于空白對照組；2)COPD組及寒燥型COPD組體質(zhì)量、體質(zhì)量指數(shù)和Lee's指數(shù)均小于對照組(P0.01),且寒燥型COPD組此三項指標(biāo)均小于COPD組(P0.01,P0.05,P0.01)。寒燥型COPD組每10g體質(zhì)量每天進食量大于對照組和COPD組；3)寒燥型COPD組血清IL-1β含量高于空白對照組(P0.05), IL-6、IL-8、TNF-α含量寒燥型COPD組均高于空白對照組(P0.055、P0.01、P0.01), COPD組此三項指標(biāo)也均高于空白對照組(P0.01、P0.05、P0.05)；IL-10三組相比無統(tǒng)計學(xué)意義。寒燥型COPD組肺泡灌洗液IL-1p含量高于空白對照組(P0.01), IL-6、IL-8、TNF-α含量寒燥型COPD組均高于空白對照組(P0.01、P0.01、 P0.01), COPD組此三項指標(biāo)也均高于空白對照組(P0.05、P0.05、P0.05)；而且對于IL-6、IL-8寒燥型COPD組高于COPD組(P0.05、P0.05)；IL-10三組相比無統(tǒng)計學(xué)意義；4) MMP-2mRNA的表達量寒燥型COPD組和COPD組均高于空白對照組(P0.01),且寒燥型COPD組高于COPD組(P0.01)；對于MMP-9mRNA的表達量寒燥型COPD組和COPD組均高于空白對照組(P0.01),且寒燥型COPD組高于COPD組(P0.05)：而對于TIMP-1mRNA的表達量寒燥型COPD組和COPD組均高于空白對照組(P0.01)；對于MMP-9mRNA/TIMP-lmRNA的比值寒燥型COPD組COPD組空白對照組；5)外周血中CD4+含量寒燥型COPD組低于空白對照組和COPD組(P0.01)；CD8+含量寒燥型COPD組和COPD組均高于空白對照組(P0.01),同時寒燥型COPD組高于COPD組(P0.01)；CD4+/CD8比值寒燥型COPD組和COPD組均低于空白對照組(P0.01),同時寒燥型COPD組低于COPD組(P0.05)；6)對于AQP-5mRNA的表達量寒燥型COPD組和COPD組均低于空白對照組(P0.01),且寒燥型COPD組低于COPD組(P0.05)：對于MUC5ACmRNA的表達量寒燥型COPD組和COPD組均高于空白對照組(P0.01),且寒燥型COPD組高于COPD組(P0.01)；對于MUC5BmRNA的表達量寒燥型COPD組和COPD組均高于空白對照組(P0.01),且寒燥型COPD組高于COPD組(P0.05)；對于MUC5ACmRNA/MUC5BmRNA的比值COPD組寒燥型COPD組空白對照組；7)對于AQP-4、AQP-5蛋白的表達量寒燥型COPD組低于COPD組,COPD組低于空白對照組；對于MUC5AC、MUC5B的表達量寒燥型COPD組高于COPD組,COPD組高于空白對照組；8)大鼠模型肺部IL-8與TIMP-1、MMP-2、MUC5B相關(guān),IL-8與MMP-9、MUC5AC密切相關(guān),IL-8與AQP5負(fù)相關(guān)；IL-10與MMP-2、MMP-9負(fù)相關(guān),IL-10與AQP5相關(guān)；TNF-a與MUC5AC密切相關(guān)；IL-6與TIMP-1相關(guān),IL-6與AQP5負(fù)相關(guān),IL-6與MMP-2、MMP-9、MUC5AC、MUC5B密切相關(guān)；TIMP-1與MMP-2、MMP-9相關(guān)；MMP-2與MMP-9、MUC5AC、MUC5B密切相關(guān),MMP-2與AQP-5負(fù)相關(guān)；MMP-9與MUC5AC、MUC5B密切相關(guān),MMP-9與AQP-5負(fù)相關(guān)；AQP5與MUC5AC、MUC5B負(fù)相關(guān)；MUC5AC與MUC5B密切相關(guān)。 結(jié)論： 1.發(fā)現(xiàn)中醫(yī)內(nèi)、外療法治療COPD均可顯示出一定的療效,但針對性不同,可與西醫(yī)治療實現(xiàn)優(yōu)勢互補。小青龍湯內(nèi)服聯(lián)合西醫(yī)治療COPD,可一定程度提高臨床療效,具體表現(xiàn)在增加有效率,提升Pa02、降低PaCO2上,同時可以某種程度提高患者FEVI。中醫(yī)貼敷作為外治法如果聯(lián)合內(nèi)服藥,則應(yīng)根據(jù)患者表現(xiàn)選擇相應(yīng)的西藥或中藥聯(lián)合。中醫(yī)貼敷可以提高西藥對FVC和FEV1改善的療效,而中醫(yī)貼敷不能提高中藥對FEV1的改善程度。中醫(yī)貼敷可提高中藥對FEV1/FVC的改善,但對西藥反而沒有協(xié)同作用。 2.指出寒燥誘導(dǎo)和加劇了COPD的發(fā)病,是新疆COPD異于內(nèi)地COPD發(fā)病、方域化發(fā)病的重要病因病機特點之一。體現(xiàn)在證型上則寒燥型是新疆COPD發(fā)病的特殊證型和多發(fā)證型之一,體現(xiàn)在病機上則該證型“局部燥,全身寒”、“內(nèi)燥外寒”,體現(xiàn)在程度上則寒燥型屬COPD的一個早期證型。內(nèi)地COPD發(fā)病主要是痰、熱、瘀為標(biāo),肺、脾、腎虛為本,痰、瘀、虛貫穿COPD發(fā)作期和緩解期的各個環(huán)節(jié),是病機的主要環(huán)節(jié)所在,癥狀表現(xiàn)以咳嗽、咳痰、氣喘、氣短為主,臨床治療中應(yīng)該注意祛痰、活血、補氣藥物的應(yīng)用。而新疆COPD的發(fā)病則以氣虛、寒、陽虛為主,肺、腎、脾虛為本,癥狀表現(xiàn)以氣短、咳嗽、氣喘、咽干口干、神疲乏力為主。臨床治療中應(yīng)該注意祛痰止咳、溫肺潤燥、補氣藥的應(yīng)用。 3.證實熏煙結(jié)合氣道滴注彈性蛋白酶90天可以成功復(fù)制COPD模型,而在此基礎(chǔ)上施加寒燥環(huán)境刺激建立新疆寒燥型COPD模型是可行的。寒燥型COPD模型表現(xiàn)為體型消瘦、體重下降、毛色黃無澤,氣道內(nèi)可聞及痰鳴音,體質(zhì)量指數(shù)和Lee's指數(shù)減小,飲水、進食量增加且食物利用率低；PEF和EF50值降低、Ti、Te值增高。具有溫肺潤燥功效的中藥止嗽散加減方對改善該病證的癥狀及肺功能有明顯效果。但鑒于本證病機,法當(dāng)辛開溫潤,不可過用溫?zé)岫飩颉?4.揭示寒燥通過COPD肺部AQP5mRNA和MUC5ACmRNA、MUC5BmRNA表達及其相應(yīng)蛋白分泌的調(diào)節(jié),降低了水通道蛋白的分泌,增加了黏蛋白的分泌,打破了水通道蛋白和黏蛋白的平衡,進而影響了氣道黏液的功能狀態(tài),增加氣道阻塞程度,促進以肺部炎癥反應(yīng)為主的肺部及全身炎癥反應(yīng),擾亂了機體的免疫功能,導(dǎo)致機體肺氣虛、衛(wèi)外功能減弱,加重COPD的蛋白酶-抗蛋白酶失衡,進而促進和加重了COPD發(fā)病,可能是寒燥型COPD的重要生物學(xué)基礎(chǔ)。
[Abstract]:Purpose :

On the basis of applying systematic evaluation and Meta - analysis to determine the effectiveness and safety of COPD , a comparative study of the characteristics of Chinese traditional Chinese medicine syndrome based on epidemiology investigation was carried out to reveal the characteristics of traditional Chinese medicine syndrome distribution in Xinjiang COPD and to find the special syndrome type . On the basis of this , a cold - dryness type COPD animal model was established , and the biological basis of cold - dryness type COPD was revealed from the experimental level , which provided reference and reference for the prevention and treatment of COPD .

Method :

To evaluate the efficacy and safety of Xiaoqinglong decoction in the treatment of COPD with COPD and the treatment of COPD by systematic evaluation and Meta - analysis .
In this paper , the characteristics of COPD in Xinjiang were revealed by the methods of TCM syndrome - based epidemiological investigation , and the characteristics of COPD in Xinjiang were compared and studied .

Results :

1 . Xiaoqinglong decoction combined western medicine oral administration can improve the effective rate of simple western medicine treatment : MD = 3.91 , 95 % CI ( 2.50 , 6.12 ) , P = 0.005 respectively . The combined western medicine oral administration of Xiaoqinglong decoction is superior to that of pure western medicine group ( MD = - 6.66 , 95 % CI ( - 8.79 , - 4.54 ) , P0.01 ) .

2 . The effective rate of all the applied traditional Chinese medicine dressing group was better than that of unapplied traditional Chinese medicine plaster group ( MD = 3.63 , 95 % CI ( 2.84 , 4.65 ) , P0.01 ) .
Compared with western medicine group , FEV1 , patch and western medicine group were better than Western medicine group , MD = 0.29 , 95 % CI ( 0.06 , 0.52 ) , P = 0.01 ;
For FEV1 / FVC , the applied traditional Chinese medicine was better than that of traditional Chinese medicine group ( MD = 5.29 , 95 % CI ( 2.52 , 8.07 ) , P = 0 . 0002 ) .

3.1 ) Cough ( 313 , 22.88 % ) , cough ( 204 , 14.91 % ) , asthma ( 124 , 9.06 % ) , asthma ( 124 , 9.06 % ) , asthma ( 124 , 9.06 % ) , asthma ( 124 , 9.06 % ) , asthma ( 91 , 6.65 % ) , asthma ( 54 , 3.95 % ) , chest distress ( 45 , 3.29 % ) , asthma ( 36 , 2.63 % ) , spontaneous sweating ( 28 , 2 . 05 % ) , common cold ( 27 , 1.97 % ) .
The symptoms of COPD in Xinjiang were short ( 317 , 4.43 % ) , cough ( 310 cases , 4.33 % ) , asthma ( 288 , 4.02 % ) , dry mouth dry ( 259 , 3.62 % ) , mental fatigue ( 244 , 3.41 % ) , chest distress ( 227 , 3.17 % ) , amnesia ( 226 , 3.16 % ) , sweating ( 211 , 2.95 % ) , throat itching ( 207 , 2.89 % ) , chills ( 206 , 2.88 % ) , asthenia ( 206 , 2.88 % ) ;
Among them , " dryness " ( dry throat , dry mouth , nasal dryness ) was 259 cases , accounting for 63 % of all cases .
The manifestations of " cold " ( aversion to wind , aversion to cold , cold aversion to cold , cold pain in the waist and cold and cold pain in the waist ) were 164 cases , accounting for 40 % of the total cases . The symptoms of " cold " and " dryness " occurred in 110 cases , accounting for 27 % of all cases . The symptoms mainly mainly phlegm - heat accumulation lung ( 69 , 19.77 % ) , phlegm - stasis - resistant lung ( 43 , 12.32 % ) , lung - qi deficiency ( 33 , 9.46 % ) , lung - kidney deficiency ( 24 , 6.88 % ) , phlegm - turbid phlegm - resistant lung ( 20 , 5.73 % ) .
In Xinjiang COPD , lung ( 287 , 61.46 % ) , kidney ( 142 , 30.41 % ) and spleen ( 38 , 8.14 % ) were predominant .
The symptoms were Qi deficiency ( 120 , 16.37 % ) , cold ( 117 , 15.96 % ) , Yang deficiency ( 109 , 14.87 % ) , sputum ( 98 , 13.37 % ) , Yin deficiency ( 90 , 12.28 % ) .
In Xinjiang , the purple color of tongue is more than that of the mainland ( P0.01 ) .
In Xinjiang , the composition ratio was 2.84 % , the composition ratio of the tongue was less than 0.56 % in the mainland , and there was no statistical difference in Xinjiang than in the Mainland .
In the mainland of Xinjiang , there were not only those in Xinjiang ( P0.01 ) , the white coating and the thin moss in Xinjiang ( P0.01 ) , and there were more cloudy and thick moss in the mainland of China than in Xinjiang ( P0.01 ) . The data of the mainland were more than that in Xinjiang ( P0.01 ) .
There were more than the inland ( P0.05 ) , the floating pulse and the fine vein in Xinjiang were more than that in the Mainland ( P0.01 ) .
In addition , the patients in the mainland of Xinjiang were unable to meet the symptoms of weakness , tenderness , junction and large vein . In Xinjiang patients , the delayed pulse appeared only in Xinjiang patients , and accounted for 7.93 % .

4.1 ) In COPD group and COPD group , the pulmonary alveolar rupture fusion , inflammatory cell infiltration and small bronchial smooth muscle thickening phenomenon , PEF , Ti , Te and EF50 in COPD group were higher than those in control group and COPD group , and Te and EF50 in COPD group were higher than those in control group .
2)COPD緇勫強瀵掔嚗鍨婥OPD緇勪綋璐ㄩ噺,浣撹川閲忔寚鏁板拰Lee's鎸囨暟鍧囧皬浜庡鐓х粍(P0.01),涓斿瘨鐕ュ瀷COPD緇勬涓夐」鎸囨爣鍧囧皬浜嶤OPD緇，

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