新疆寒燥型慢性阻塞性肺疾病的系统研究

发布时间：2018-06-15 16:01

  本文选题：慢性阻塞性肺疾病 + 中医　； 参考：《新疆医科大学》2013年博士论文

【摘要】：目的： 选择中医药治疗COPD的常用治法,在运用系统评价和Meta分析确定中医药治疗COPD有效和安全的基础上,开展基于流行病学调查的新疆COPD和基于文献研究的内地COPD中医发病特点的对比研究,揭示新疆COPD的中医证型分布特点,找到特殊证型。在此基础上建立新疆寒燥型COPD动物模型,并从实验层面揭示寒燥型COPD的生物学基础,为COPD的方域化防治提供借鉴和参考。 方法： 利用系统评价和Meta分析的方法评价小青龙汤治疗COPD发作期和中医贴敷治疗COPD稳定期的疗效性和安全性；利用中医证候流行病学调查的方法揭示新疆COPD的发病特点,并将其和基于文献的内地COPD的发病特点进行对比研究,揭示新疆COPD的特殊证型。基于病因模拟-慢性应激-生物表征-药物反证的思路,利用气管滴注弹性蛋白酶结合熏烟90天建立COPD模型,在此基础上复合寒燥应激建立寒燥型COPD模型,通过肺功能、肺部病理观察和生物表征判断模型的成功建立,利用ELISA、Real-time PCR、Western-blot等方法检测模型内在病理生理状态,揭示寒燥型COPD的生物学基础。 结果： 1.小青龙汤联合西药内服可提高单纯西药治疗的有效率[MD=3.91,95%CI (2.50,6.12), P0.00001],小青龙汤内服联合有创通气有效率优于单纯有创通气组[MD=3.48,95%CI (1.45,8.32), P=0.005];对于Pa02的改善小青龙汤联合西药内服优于单纯西药组[MD=7.55,95%CI (1.41,13.68), P=0.02];对于PaCO2的改善小青龙汤联合西药内服优于单纯西药组[MD=-7.11,95%CI (-9.89,-4.33),P0.00001],小青龙汤内服联合有创通气优于单纯有创通气组[MD=-6.66,95%CI (-8.79,-4.54), P0.00001];对于FEV1的改善小青龙汤联合西药内服优于单纯西药组[MD=6.97,95%CI (3.60,10.34), P0.0001]。 2.所有加用中医贴敷组的有效率均优于未用中医贴敷组[MD=3.63,95%CI(2.84,4.65),P0.00001]；对于FEV1,贴敷加西药组优于西药组[MD=0.29,95%CI(0.06,0.52),P=0.01]；对于FEV1/FVC,贴敷加中药优于中药组[MD=5.29,95%CI(2.52,8.07),P=0.0002]。 3.1)内地COPD总体症状中出现频次较多的是咳嗽(313,22.88%)、咳痰(204,14.91%)、气喘(124,9.06%)、喘息(120,8.77%)、气短(91,6.65%)、哮鸣音(54,3.95%)、胸闷(45,3.29%)、乏力(40,2.93%)、纳差(38,2.78%)、气促(36,2.63%)、自汗(28,2.05%)、易感冒(27,1.97%)；而新疆COPD出现频次较多的症状是气短(317次,4.43%),咳嗽(310例,4.33%),气喘(288,4.02%),咽干口干(259,3.62%),神疲乏力(244,3.41%),咳痰(235,3.28%),胸闷(227,3.17%),健忘(226,3.16%),汗出(211,2.95%),咽痒(207,2.89%),畏寒(206,2.88%),乏力(206,2.88%)；其中“燥”的表现(咽干、口干、鼻燥)为259例,占到全部调查病例的63%；“寒”的表现(恶风、畏寒、形寒怕冷、腰背冷痛、肢冷)为164例,占到全部调查病例的40%。“寒”兼“燥”的表现同时出现的为110例,占到全部调查病例的27%。内地COPD病位证素以肺(237,59.55%)、脾(81,20.35%)、肾(74,18.59%)为主,病性证素以痰(163,35.21%)、气虚(92,19.87%)、热(89,19.22%)、瘀(65,14.04%)、湿(14,3.02%)为主。证型主要以痰热蕴肺(69,19.77%)、痰瘀阻肺(43,12.32%)、肺脾气虚(33,9.46%)、肺。肾两虚(24,6.88%)、痰浊阻肺(20,5.73%)为主；新疆COPD病位证素以肺(287,61.46%),肾(142,30.41%),脾(38,8.14%)为主；病性为气虚(120,16.37%),寒(117,15.96%),阳虚(109,14.87%),痰(98,13.37%),阴虚(90,12.28%)为主。2)新疆和内地COPD患者相比舌质、舌苔和脉象总体分布不同。内地舌质瘀斑和舌质淡的多于新疆(P0.01,P0.05)；新疆舌质紫的则多于内地(P0.01)；新疆舌质少津的构成比2.84%,内地舌质少津的构成比0.56%,新疆多于内地,但无统计学差异；内地患者舌质出现的胖、齿痕、绛、青则本次调查中新疆患者未见。内地黄苔和腻苔多于新疆(P0.01),白苔和薄苔新疆多于内地(P0.01),本次研究内地患者出现的浊苔、厚苔,本次调查新疆患者则未见。内地滑脉多于新疆(P0.01),沉脉和弱脉多于新疆(P0.05)；涩脉、紧脉新疆多于内地(P0.05),浮脉和细脉新疆多于内地(P0.01)；另外内地患者出现的无力、濡、结代、大脉本次调查新疆患者未见,迟脉则仅在新疆患者中出现,且占到7.93%。 4.1) COPD组及寒燥型COPD组肺部均有肺泡断裂融合、炎症细胞浸润和小支气管下平滑肌增厚现象,肺功能寒燥型COPD组的PEF、Ti、Te、EF50均高于对照组和COPD组,COPD组的Te和EF50高于空白对照组；2)COPD组及寒燥型COPD组体质量、体质量指数和Lee's指数均小于对照组(P0.01),且寒燥型COPD组此三项指标均小于COPD组(P0.01,P0.05,P0.01)。寒燥型COPD组每10g体质量每天进食量大于对照组和COPD组；3)寒燥型COPD组血清IL-1β含量高于空白对照组(P0.05), IL-6、IL-8、TNF-α含量寒燥型COPD组均高于空白对照组(P0.055、P0.01、P0.01), COPD组此三项指标也均高于空白对照组(P0.01、P0.05、P0.05)；IL-10三组相比无统计学意义。寒燥型COPD组肺泡灌洗液IL-1p含量高于空白对照组(P0.01), IL-6、IL-8、TNF-α含量寒燥型COPD组均高于空白对照组(P0.01、P0.01、 P0.01), COPD组此三项指标也均高于空白对照组(P0.05、P0.05、P0.05)；而且对于IL-6、IL-8寒燥型COPD组高于COPD组(P0.05、P0.05)；IL-10三组相比无统计学意义；4) MMP-2mRNA的表达量寒燥型COPD组和COPD组均高于空白对照组(P0.01),且寒燥型COPD组高于COPD组(P0.01)；对于MMP-9mRNA的表达量寒燥型COPD组和COPD组均高于空白对照组(P0.01),且寒燥型COPD组高于COPD组(P0.05)：而对于TIMP-1mRNA的表达量寒燥型COPD组和COPD组均高于空白对照组(P0.01)；对于MMP-9mRNA/TIMP-lmRNA的比值寒燥型COPD组COPD组空白对照组；5)外周血中CD4+含量寒燥型COPD组低于空白对照组和COPD组(P0.01)；CD8+含量寒燥型COPD组和COPD组均高于空白对照组(P0.01),同时寒燥型COPD组高于COPD组(P0.01)；CD4+/CD8比值寒燥型COPD组和COPD组均低于空白对照组(P0.01),同时寒燥型COPD组低于COPD组(P0.05)；6)对于AQP-5mRNA的表达量寒燥型COPD组和COPD组均低于空白对照组(P0.01),且寒燥型COPD组低于COPD组(P0.05)：对于MUC5ACmRNA的表达量寒燥型COPD组和COPD组均高于空白对照组(P0.01),且寒燥型COPD组高于COPD组(P0.01)；对于MUC5BmRNA的表达量寒燥型COPD组和COPD组均高于空白对照组(P0.01),且寒燥型COPD组高于COPD组(P0.05)；对于MUC5ACmRNA/MUC5BmRNA的比值COPD组寒燥型COPD组空白对照组；7)对于AQP-4、AQP-5蛋白的表达量寒燥型COPD组低于COPD组,COPD组低于空白对照组；对于MUC5AC、MUC5B的表达量寒燥型COPD组高于COPD组,COPD组高于空白对照组；8)大鼠模型肺部IL-8与TIMP-1、MMP-2、MUC5B相关,IL-8与MMP-9、MUC5AC密切相关,IL-8与AQP5负相关；IL-10与MMP-2、MMP-9负相关,IL-10与AQP5相关；TNF-a与MUC5AC密切相关；IL-6与TIMP-1相关,IL-6与AQP5负相关,IL-6与MMP-2、MMP-9、MUC5AC、MUC5B密切相关；TIMP-1与MMP-2、MMP-9相关；MMP-2与MMP-9、MUC5AC、MUC5B密切相关,MMP-2与AQP-5负相关；MMP-9与MUC5AC、MUC5B密切相关,MMP-9与AQP-5负相关；AQP5与MUC5AC、MUC5B负相关；MUC5AC与MUC5B密切相关。 结论： 1.发现中医内、外疗法治疗COPD均可显示出一定的疗效,但针对性不同,可与西医治疗实现优势互补。小青龙汤内服联合西医治疗COPD,可一定程度提高临床疗效,具体表现在增加有效率,提升Pa02、降低PaCO2上,同时可以某种程度提高患者FEVI。中医贴敷作为外治法如果联合内服药,则应根据患者表现选择相应的西药或中药联合。中医贴敷可以提高西药对FVC和FEV1改善的疗效,而中医贴敷不能提高中药对FEV1的改善程度。中医贴敷可提高中药对FEV1/FVC的改善,但对西药反而没有协同作用。 2.指出寒燥诱导和加剧了COPD的发病,是新疆COPD异于内地COPD发病、方域化发病的重要病因病机特点之一。体现在证型上则寒燥型是新疆COPD发病的特殊证型和多发证型之一,体现在病机上则该证型“局部燥,全身寒”、“内燥外寒”,体现在程度上则寒燥型属COPD的一个早期证型。内地COPD发病主要是痰、热、瘀为标,肺、脾、肾虚为本,痰、瘀、虚贯穿COPD发作期和缓解期的各个环节,是病机的主要环节所在,症状表现以咳嗽、咳痰、气喘、气短为主,临床治疗中应该注意祛痰、活血、补气药物的应用。而新疆COPD的发病则以气虚、寒、阳虚为主,肺、肾、脾虚为本,症状表现以气短、咳嗽、气喘、咽干口干、神疲乏力为主。临床治疗中应该注意祛痰止咳、温肺润燥、补气药的应用。 3.证实熏烟结合气道滴注弹性蛋白酶90天可以成功复制COPD模型,而在此基础上施加寒燥环境刺激建立新疆寒燥型COPD模型是可行的。寒燥型COPD模型表现为体型消瘦、体重下降、毛色黄无泽,气道内可闻及痰鸣音,体质量指数和Lee's指数减小,饮水、进食量增加且食物利用率低；PEF和EF50值降低、Ti、Te值增高。具有温肺润燥功效的中药止嗽散加减方对改善该病证的症状及肺功能有明显效果。但鉴于本证病机,法当辛开温润,不可过用温热而助燥伤津。 4.揭示寒燥通过COPD肺部AQP5mRNA和MUC5ACmRNA、MUC5BmRNA表达及其相应蛋白分泌的调节,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,进而影响了气道黏液的功能状态,增加气道阻塞程度,促进以肺部炎症反应为主的肺部及全身炎症反应,扰乱了机体的免疫功能,导致机体肺气虚、卫外功能减弱,加重COPD的蛋白酶-抗蛋白酶失衡,进而促进和加重了COPD发病,可能是寒燥型COPD的重要生物学基础。
[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缁勫強瀵掔嚗鍨婥OPD缁勪綋璐ㄩ噺,浣撹川閲忔寚鏁板拰Lee's鎸囨暟鍧囧皬浜庡�圭収缁�(P0.01),涓斿瘨鐕ュ瀷COPD缁勬�や笁椤规寚鏍囧潎灏忎簬COPD缁，

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