本文選題：哮喘 + 三拗湯�。� 參考：《南京中醫(yī)藥大學(xué)》2017年博士論文

【摘要】：目的:1.本研究在梳理中醫(yī)對(duì)支氣管哮喘的認(rèn)識(shí)和三拗湯(出《太平惠民和劑局方·卷二》)及加味治療哮喘的基礎(chǔ)上,以三拗湯及其加味方中的五拗湯(出《醫(yī)學(xué)集要·卷二》,藥用麻黃、杏仁、甘草、石膏、細(xì)茶)為研究對(duì)象,構(gòu)建其配伍藥物的功效成分多靶點(diǎn)網(wǎng)絡(luò)藥理學(xué)模型,并與哮喘的靶點(diǎn)通路進(jìn)行比較研究,預(yù)測(cè)三拗湯及加味方防治哮喘的潛在靶標(biāo)。2.結(jié)合臨床哮喘發(fā)病特點(diǎn),以空氣污染物PM2.5作為刺激因素,建立OVA復(fù)合PM2.5誘導(dǎo)加重哮喘模型,探討三拗湯及加味方干預(yù)PM2.5誘導(dǎo)加重哮喘的效應(yīng)及效應(yīng)機(jī)制。方法:1.整理歷代醫(yī)家對(duì)哮喘病因病機(jī)、辨證分型以及治法方藥的認(rèn)識(shí),系統(tǒng)回顧三拗湯方證及其加味配伍,分析其證治特點(diǎn),并對(duì)現(xiàn)代文獻(xiàn)中哮喘方高頻藥物進(jìn)行統(tǒng)計(jì),對(duì)三拗湯臨床療效、功效物質(zhì)、效應(yīng)及效應(yīng)機(jī)制的研究進(jìn)行梳理。2.以三拗湯及其加味方為研究對(duì)象,采用網(wǎng)絡(luò)藥理學(xué)方法,構(gòu)建其配伍藥物的功效成分靶點(diǎn)通路網(wǎng)絡(luò),并與哮喘的靶點(diǎn)通路分析比較,預(yù)測(cè)三拗湯及加味方防治哮喘的潛在靶標(biāo)。3.分別建立OVA復(fù)合空氣污染物PM2.5誘導(dǎo)加重的28天和42天哮喘小鼠模型,比較兩者在炎癥反應(yīng)、氣道高反應(yīng)、肺組織病變以及TRP通道表達(dá)方面的區(qū)別,獲得效應(yīng)確切且穩(wěn)定的OVA復(fù)合空氣污染物PM2.5誘導(dǎo)加重型哮喘小鼠模型。4.在潛在靶標(biāo)篩選和PM2.5誘導(dǎo)加重哮喘模型研究的基礎(chǔ)上,觀察三拗湯及其加味方對(duì)PM2.5誘導(dǎo)加重哮喘在改善氣道炎癥、氣道高反應(yīng)和肺組織病變方面的作用,采用ELISA法觀察小鼠BALF中IL-13、SP、PGD2、NGF含量的差異,q-PCR法測(cè)定肺組織TRPA1、TRPV1、TRPV4、TRPM8基因水平的表達(dá),篩選對(duì)三拗湯及加味方效應(yīng)敏感基因,以Western blot法進(jìn)行相關(guān)蛋白水平測(cè)定,闡述兩方干預(yù)PM2.5誘導(dǎo)加重哮喘的效應(yīng)機(jī)制。結(jié)果:1.歷代醫(yī)家認(rèn)為哮喘是病機(jī)復(fù)雜的疾病,根據(jù)其病證特點(diǎn)提出了宣降肺氣、散寒祛痰法、散寒清肺法、清肺化痰法、引吐導(dǎo)痰法、降氣豁痰法等治法。現(xiàn)代醫(yī)家進(jìn)一步提出了哮喘發(fā)作期標(biāo)本兼治、從瘀論治、從風(fēng)論治等治法。統(tǒng)計(jì)發(fā)現(xiàn)現(xiàn)代哮喘方中寒哮方和熱哮方支持度較高的藥物為麻黃、杏仁、甘草等。2.歷代文獻(xiàn)分析,三拗湯以咳嗽、哮喘為主證,其主要配伍為:加味解表藥、化痰止咳平喘藥、清熱藥、溫里藥、收澀藥、理氣藥等�，F(xiàn)代研究顯示,三拗湯及加味方主要從抑制炎癥、調(diào)節(jié)免疫、調(diào)控神經(jīng)-受體和氣道反應(yīng)等方面干預(yù)哮喘。3.網(wǎng)絡(luò)藥理模型顯示,三拗湯藥物配伍后11個(gè)功效成分作用于74個(gè)靶點(diǎn)以及代謝-信號(hào)傳導(dǎo)-免疫-細(xì)胞過(guò)程等47條通路,其中絲裂原活化蛋白激酶(MAPK)是其核心靶點(diǎn)群,與三拗湯宣肺平喘功效相關(guān)。三拗湯加味后功效成分和靶點(diǎn)通路均有增加。如五拗湯16個(gè)功效成分作用于98個(gè)靶點(diǎn)以及代謝-疾病-信號(hào)傳導(dǎo)-免疫等71條通路,三磷酸鳥(niǎo)苷(GTP)蛋白酶和MAPK構(gòu)成了五拗湯的核心靶點(diǎn)群,主要增加了代謝、疾病相關(guān)通路,這些改變與五拗湯宣肺清熱的功效有關(guān)。哮喘82個(gè)靶點(diǎn)涉及疾病-免疫-信號(hào)傳導(dǎo)-細(xì)胞過(guò)程等52條通路,腫瘤壞死因子(TNF)、核因子-1κB(NF-κB)家族是其核心靶點(diǎn)群,神經(jīng)配體-受體相互作用通路靶點(diǎn)群是哮喘的潛在靶標(biāo)。與哮喘靶點(diǎn)通路比較,三拗湯及其加味方的特點(diǎn)表現(xiàn)為主要通過(guò)酶調(diào)控多種活性物質(zhì)的合成代謝以及免疫蛋白、炎癥細(xì)胞因子等介質(zhì)的參與,對(duì)哮喘氣道炎癥、信號(hào)傳導(dǎo)等環(huán)節(jié)發(fā)揮作用。4.OVA復(fù)合PM2.5誘導(dǎo)加重小鼠哮喘反應(yīng)主要表現(xiàn)在:增加血液和BALF中炎癥細(xì)胞(尤其EOS)數(shù)量和比率,肺氣道反應(yīng)性增高,肺組織損傷嚴(yán)重,出現(xiàn)炎癥滲出增加、支支氣管黏膜層損壞以及氣管平滑肌增厚。此外,哮喘小鼠出現(xiàn)了TRPA1、TRPV1蛋白及相關(guān)因子如IL-13、SP、PDG2和NGF的高表達(dá)。這些加重哮喘的效應(yīng)以42天模型中施予PM2.5暴露的小鼠表現(xiàn)最為顯著。5.三拗湯及其加味方五拗湯能改善PM2.5誘導(dǎo)加重哮喘小鼠(造模42天)的癥狀,尤其以?xún)烧吒邉┝啃?yīng)更為顯著,如減少血液和BALF中炎癥細(xì)胞(尤其EOS)數(shù)量和比率,降低肺氣道高反應(yīng)性,改善肺組織損傷,其炎癥滲出、支氣管黏膜損害和支氣管平滑肌增厚等病變程度均有所減輕。此外,三拗湯、五拗湯能夠降低哮喘小鼠肺組織TRPA1、TRPV1基因和蛋白水平以及IL-13、SP、PDG2和NGF的高表達(dá)。與OVA+PM2.5組比較,三拗湯高劑量組顯著降低TRPA1蛋白、IL-13、PDG2和NGF的高表達(dá)(P0.01),五拗湯高劑量組顯著降低TRPV1蛋白、IL-13、SP、NGF(P0.01)和TRPA1蛋白、PDG2(P0.05)的高表達(dá)。結(jié)論:1.本研究系統(tǒng)梳理了歷代文獻(xiàn)對(duì)哮喘病因病機(jī)、辨證分型以及治法方藥的認(rèn)識(shí),并對(duì)現(xiàn)代文獻(xiàn)中哮喘方高頻藥物進(jìn)行統(tǒng)計(jì),其中寒哮方和熱哮方支持度較高的藥物為麻黃、杏仁、甘草等。系統(tǒng)回顧了三拗湯方證及加味應(yīng)用,其主要配伍為:加味解表藥、化痰止咳平喘藥、清熱藥、溫里藥、收澀藥、理氣藥等�，F(xiàn)代研究顯示,三拗湯及加味方主要從抑制炎癥、調(diào)節(jié)免疫、調(diào)控神經(jīng)-受體和氣道反應(yīng)等方面干預(yù)哮喘。2.構(gòu)建了三拗湯、加味方五拗湯以及哮喘的網(wǎng)絡(luò)藥理學(xué)模型。三拗湯配伍藥物11個(gè)功效成分作用于74個(gè)靶點(diǎn)以及代謝-信號(hào)傳導(dǎo)-免疫-細(xì)胞過(guò)程等47條代謝通路,其中MAPK是其核心靶點(diǎn)群,與三拗湯宣肺平喘功效相關(guān)。三拗湯加味后功效成分和靶點(diǎn)通路均有增加。如五拗湯16個(gè)功效成分作用于98個(gè)靶點(diǎn)以及代謝-疾病-信號(hào)傳導(dǎo)-免疫等71條通路,GTP蛋白酶和MAPK構(gòu)成五拗湯的核心靶點(diǎn)群,主要增加了代謝、疾病相關(guān)通路,這些改變與五拗湯宣肺清熱的功效有關(guān)。哮喘82個(gè)靶點(diǎn)涉及疾病-免疫-信號(hào)傳導(dǎo)-細(xì)胞過(guò)程等52條通路,腫瘤壞死因子(TNF)、核因子-κB(NF-1κB)家族是其核心靶點(diǎn)群,神經(jīng)配體-受體相互作用通路靶點(diǎn)群是哮喘的潛在靶標(biāo)。與哮喘靶點(diǎn)通路比較,三拗湯及其加味方的特點(diǎn)表現(xiàn)為主要通過(guò)酶調(diào)控多種活性物質(zhì)的合成代謝以及免疫蛋白、炎癥細(xì)胞因子等多種介質(zhì)的參與,在哮喘氣道炎癥、信號(hào)傳導(dǎo)等環(huán)節(jié)發(fā)揮作用。3.成功建立OVA復(fù)合PM2.5誘導(dǎo)加重哮喘模型,結(jié)合三拗湯及其加味方網(wǎng)絡(luò)靶標(biāo)篩選結(jié)果,考察并比較三拗湯及加味方五拗湯的效應(yīng),揭示其潛在的神經(jīng)-免疫學(xué)機(jī)制。研究證實(shí)三拗湯、五拗湯可改善哮喘癥狀,表現(xiàn)為減少炎癥細(xì)胞浸潤(rùn)、降低氣道反應(yīng)性,減輕肺組織病理?yè)p傷,以?xún)烧吒邉┝扛纳菩?yīng)最為顯著。三拗湯、五拗湯可以通過(guò)神經(jīng)調(diào)控干預(yù)TRP通道及神經(jīng)遞質(zhì)釋放對(duì)哮喘產(chǎn)生治療作用,三拗湯調(diào)控TRPA1通道較為明顯,五拗湯可顯著調(diào)控TRPA1和TRPV1通道。
[Abstract]:Objective: 1. on the basis of combing the understanding of bronchial asthma in traditional Chinese medicine and on the basis of the three depression Decoction (Taiping Huimin and agent Bureau square.) and the treatment of asthma, the study object is to establish the work of the combination of three depression Decoction and the five depression soup of the Jiawei recipe (medicine jisayao, medicinal ephedra, almond, Gump, plaster and fine tea). A multi target network pharmacology model was used and compared with the target pathway of asthma. The potential target.2. of three depression soup and Jiawei Fang was predicted to combine the characteristics of asthma. The air pollutant PM2.5 was used as a stimulating factor to establish a OVA compound PM2.5 induced heavy asthma model, and the intervention of PM2.5 and the decoction of adding flavour to PM2.5 were discussed. The effect and effect mechanism of inducing exacerbation of asthma. Methods: 1. collation of the understanding of asthma pathogenesis, syndrome differentiation and treatment of prescription medicine by the past generation of doctors, the systematic review of the prescription and combination of three depression decoction, and the analysis of the characteristics of the syndrome, and the statistics of the high frequency medicine of the asthma prescription in the modern literature, the clinical effect, the effect substance and the effect of the three depression decoction. The research on the effect mechanism of.2. and the three depression soup and its flavour prescription as the research object, the network pharmacology method was used to construct the function component target network of its compatibility drugs, and compared with the target pathway analysis of asthma, it was predicted that the potential target of the three depression soup and the flavour prescription for the prevention and treatment of asthma was to establish the OVA compound air pollutant P respectively. M2.5 induced exacerbation of 28 and 42 days of asthma mice model, compared both in the inflammatory response, airway hyperresponsiveness, lung tissue lesion and TRP channel expression, to obtain the exact and stable OVA compound air pollutants PM2.5 induced by heavy asthma mice model.4. in the potential target screening and PM2.5 induced exacerbation model of asthma model research On the basis of the study, we observed the effect of three depression soup and its flavour Recipe on PM2.5 induced asthma in improving airway inflammation, airway hyperresponsiveness and lung tissue lesions. ELISA was used to observe the difference of IL-13, SP, PGD2 and NGF in BALF of mice. The expression of TRPA1, TRPV1, TRPV4, TRPM8 gene level in lung tissue was determined by q-PCR method, and the three depression soup was screened by the method of q-PCR. Western blot method was used to determine the level of related protein, and the effect mechanism of two parties to interfere with the exacerbation of asthma was introduced. Results: 1. physicians in the past generations believed that asthma was a complicated disease. According to the characteristics of the disease, the lung qi, dispel cold and expectorant method, scattered cold and clear lung method, clearing lung and phlegm method, and spitting and guiding the phlegm method were put forward. The modern doctors further put forward the specimen and treatment of the asthma attack period, from the stasis treatment and the wind theory. The statistics found that the drugs with high support for the cold wheeze and the hot wheeze in the modern asthma are the.2. literature of ephedra, almond and licorice, and the three depression soup is coughed and asthma is the main syndrome, and its main compatibility is: add The modern study shows that three depression Decoction and Jiawei prescription mainly interfere with the.3. network pharmacological model of asthma, such as inhibiting inflammation, regulating immunity, regulating nerve receptor and airway reaction, and 11 efficacy components of three depression decoction are used to act on 74 targets. 47 pathways, such as metabolic signal transduction and immuno cellular process, in which mitogen activated protein kinase (MAPK) is the core target group, which is related to the efficacy of three depression soup to promote lung antiasthmatic effect. The effect components and target pathways of the three depression soup are increased after adding flavour. For example, the 16 functional components of five depression soup are used in 98 targets and metabolic disease signal transduction. Immune and other 71 pathways, GTP protease and MAPK constitute the core target group of five depression soup, which mainly increases metabolism and disease related pathways. These changes are related to the efficacy of five depression soup lung clearing heat. 82 targets of asthma involve 52 pathways, such as disease immuno signal conduction cell process, tumor necrosis factor (TNF), and nuclear factor -1 Kappa B (NF- kappa B) family is the core target group, and the target group of the nerve ligand receptor interaction pathway is a potential target for asthma. Compared with the target pathway of asthma, the characteristics of the three depression soup and its flavour formula are mainly through the enzyme regulating the synthesis and metabolism of various active substances and the involvement of immunoglobulin, inflammatory cytokines and other mediators. Airway inflammation, signal transduction and other links play a role in.4.OVA compound PM2.5 induced exacerbation of asthma response in mice: increasing the number and ratio of inflammatory cells (especially EOS) in blood and BALF, increased pulmonary airway reactivity, severe lung tissue damage, increased inflammatory exudation, bronchoalveolar mucosa damage and thickening of tracheal smooth muscle. In addition, asthma mice showed high expression of TRPA1, TRPV1 protein and related factors such as IL-13, SP, PDG2 and NGF. These effects of exacerbating asthma in mice exposed to PM2.5 in the 42 day model were the most significant of.5. three depression soup and flavored prescription five depression soup to improve the symptoms of PM2.5 induced exacerbation of asthma mice (42 days of modeling), especially both high and high. The dose effect is more significant, such as reducing the number and ratio of inflammatory cells (especially EOS) in blood and BALF, reducing pulmonary airway hyperresponsiveness, improving lung tissue damage, inflammatory exudation, bronchial mucosa damage and bronchial smooth muscle thickening. In addition, three depression soup, five depression soup can reduce lung tissue TRPA1 in asthmatic mice. TRPV1 gene and protein levels as well as the high expression of IL-13, SP, PDG2 and NGF. Compared with the OVA+PM2.5 group, the high dose group of the three depression soup significantly reduced the high expression of TRPA1 protein, IL-13, PDG2 and NGF (P0.01). The high dose group of the five depression soup significantly reduced the expression of TRPV1 protein. The history of the literature on asthma pathogenesis, syndrome differentiation and treatment of prescription medicine, and the modern literature of asthma prescription high frequency medicine statistics, of which cold wheech and hot wheeze prescription high support medicine for ephedra, almond, licorice and so on. Systematic review of the three depression soup prescription and flavored application, the main compatibility of the combination of flavored solution medicine, chemical Phlegm antitussive antiasthmatic medicine, antipyretic medicine, warm medicine, astringent medicine, physical Qi medicine and so on. Modern studies show that the three depression soup and Jiawei prescription mainly from the inhibition of inflammation, regulating immunity, regulating nerve receptor and airway reaction and other aspects of the intervention of asthma.2. construction of three depression soup, Jiafang five depression soup and Asthma Network pharmacological model. Three depression decoction combined with 11 drugs. 74 targets and 47 metabolic pathways, such as 74 targets and metabolic signal transduction and immuno cellular process, are the core target groups, which are related to the efficacy of three depression soup to promote lung antiasthmatic effect. Three depression soup has increased effect components and target pathways after adding flavour. For example, 16 components of five depression soup act on 98 targets and metabolic disease signal 71 pathways of conduction and immunization, GTP protease and MAPK constitute the core target group of the five depression soup, which mainly increases metabolism and disease related pathways. These changes are related to the efficacy of the five depression soup lung clearing heat. 82 targets of asthma involve 52 routes of disease immuno signal conduction cell process, tumor necrosis factor (TNF), nuclear factor kappa B (NF-1 kappa B). The family is the core target group, and the target group of the nerve ligand receptor interaction pathway is the potential target of asthma. Compared with the target pathway of asthma, the characteristics of the three depression soup and its flavour formula are mainly through the enzyme regulating the synthesis and metabolism of a variety of active substances and the involvement of various media, such as immunoglobulin, inflammatory cytokines, and asthma. Inflammation, signal transduction and other links play a role.3. successfully establish OVA compound PM2.5 induced aggravated asthma model, combined with the three depression soup and its Jiawei prescription network target screening results, investigate and compare the effect of three depression soup and Jiawei Fang five depression soup, reveal its potential neuroimmunological mechanism. The study confirmed that three depression soup, five depression soup can improve asthma. The expression is to reduce the infiltration of inflammatory cells, reduce airway responsiveness and reduce the pathological damage of lung tissue. The effect of high dose improvement is the most significant. Three depression soup, five depression soup can interfere with the TRP channel and the release of neurotransmitter in the treatment of asthma through neural regulation. The three depression soup is more obvious in the regulation of the TRPA1 channel, and the five depression soup can be significantly adjusted. Control TRPA1 and TRPV1 channels.
【學(xué)位授予單位】：南京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R289.5

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3 楊，

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