本文選題：肺痹湯 + 肺纖維化��； 參考：《北京中醫(yī)藥大學(xué)》2016年博士論文

【摘要】：肺間質(zhì)纖維化是一種以進(jìn)行性呼吸困難、干咳、氣短、喘憋為臨床特征的慢性進(jìn)行性肺間質(zhì)疾病。該疾病可由多種肺系疾病、多種系統(tǒng)性疾病發(fā)展而來(lái),包括無(wú)原發(fā)疾病的特發(fā)性肺間質(zhì)纖維化。其主要病理特征是成纖維細(xì)胞、肌成纖維細(xì)胞的增殖,細(xì)胞外基質(zhì)的過(guò)度沉積。隨著高分辨率CT的普及,肺間質(zhì)纖維化檢出率逐年升高。其發(fā)病率隨年齡增長(zhǎng)而增高,確診后生存期一般為3-8年,中位生存期為3年。該病預(yù)后差,除肺移植外尚無(wú)有效的治療方法,被世界衛(wèi)生組織(WHO)列為難治性疾病。而近幾十年來(lái),中醫(yī)憑借其成熟的辨證論治體系,在治療肺纖維化一病的認(rèn)識(shí)和治療上積累了豐富的臨床經(jīng)驗(yàn),取得了一定的較好療效,值得肯定,但需要進(jìn)一步循證醫(yī)學(xué)的積累和實(shí)驗(yàn)研究數(shù)據(jù)支撐。因此,探索中醫(yī)藥治療本病的有效性具有十分重大的意義。研究目的觀察肺間質(zhì)纖維化一病的臨床中醫(yī)證候特征,為深化中醫(yī)對(duì)該病的認(rèn)識(shí)提供一定的循證醫(yī)學(xué)依據(jù)；通過(guò)動(dòng)物模型實(shí)驗(yàn)和細(xì)胞學(xué)實(shí)驗(yàn),觀察導(dǎo)師經(jīng)驗(yàn)方肺痹湯干預(yù)肺纖維化的療效及其干預(yù)的可能機(jī)制。研究方法1肺纖維化中醫(yī)臨床證候特征研究的方法按照特發(fā)性肺間質(zhì)纖維化與繼發(fā)性肺間質(zhì)纖維的診斷標(biāo)準(zhǔn),制定臨床信息采集表,觀察2006年～2015年北京中醫(yī)藥大學(xué)第二臨床醫(yī)學(xué)院東方醫(yī)院門診收集的116例肺纖維化病人資料,對(duì)其癥狀進(jìn)行整理分析,利用SPSS軟件進(jìn)行統(tǒng)計(jì)學(xué)上的聚類分析法,研究肺纖維化病人的中醫(yī)證候?qū)W特征。2肺痹湯干預(yù)肺纖維化療效機(jī)制研究的方法2.1實(shí)驗(yàn)一：觀察肺痹湯在博萊霉素誘導(dǎo)的肺纖維化小鼠模型造模過(guò)程中的影響,設(shè)置假手術(shù)對(duì)照組、正常模型組、激素干預(yù)組和肺痹湯干預(yù)組,從小鼠一般情況、死亡情況、支氣管肺泡灌洗液中白細(xì)胞計(jì)數(shù)、肺組織內(nèi)膠原總含量等幾個(gè)方面,探討肺痹湯治療肺纖維化的可能機(jī)制和療效。2.2實(shí)驗(yàn)二：觀察人甲殼酶蛋白(YKL-40)和干擾素-γ(INF-γ)對(duì)人肺胚成纖維細(xì)胞(MRC5)在小鼠脫細(xì)胞肺組織片(1nouse lung scaffold)上的生長(zhǎng)情況及蛋白表達(dá),從細(xì)胞水平探討研究熱點(diǎn)的細(xì)胞因子YKL-40對(duì)成纖維細(xì)胞增殖和蛋白表達(dá)的影響及其在肺纖維化過(guò)程中的可能作用。2.3實(shí)驗(yàn)三：觀察不同濃度的中藥單體黃芪甲苷、丹參酮Ⅱ A粉,中藥注射液黃芪注射液、丹參酮ⅡA注射液,中藥肺痹湯對(duì)MRC5的生長(zhǎng)影響,從細(xì)胞水平探討中藥肺痹湯及其主要成份干預(yù)成纖維細(xì)胞增殖的影響。研究結(jié)果1肺間質(zhì)纖維化的中醫(yī)證候?qū)W研究1.1癥狀：肺間質(zhì)纖維化患者常見(jiàn)的癥狀共計(jì)60項(xiàng),出現(xiàn)頻率超過(guò)25%的癥狀共有22項(xiàng),依次為：咳嗽,氣短,喘息,咳痰,乏力,口干,汗出,咽干,咳嗽無(wú)力,畏寒,失眠,心慌,易感冒,痰粘,惡風(fēng),痰難咯,大便干結(jié),耳聾耳鳴,唇甲紫暗,頭暈,腰膝酸軟,盜汗。1.2證候要素：在中醫(yī)證候要素方面,主要提示了“痰”、“氣虛”、“熱”、“陰虛”、“血瘀”是肺間質(zhì)纖維化患者的主要證素特點(diǎn)。1.3證候分類：1.3.1氣虛血瘀型�？人�,咳嗽無(wú)力,咳痰,白痰,乏力,淡暗舌。本組中“咳嗽”、“咳痰”為肺間質(zhì)纖維化患者常見(jiàn)癥狀,“咳嗽無(wú)力”、“乏力”提示氣虛的表現(xiàn),“淡暗舌”提示氣虛血瘀。此組癥狀提示氣虛血瘀證的表現(xiàn)。1.3.2痰熱阻肺型。痰粘,痰難咯,大便干結(jié),脈滑。本組中痰粘、痰難咯提示痰熱的表現(xiàn),肺與大腸相表里,肺熱移于大腸故可見(jiàn)“大便干結(jié)”,脈清提示痰證。本組癥狀為痰熱阻肺證的表現(xiàn)。1.3.3氣陰兩虛型。喘息,氣短,畏寒,汗出,心慌,易感冒,失眠,惡風(fēng),口干,咽干。此組中癥狀較多,提示為肺氣陰兩虛證的表現(xiàn)。1.3.4腎陰虧虛型。盜汗,頭暈,耳聾耳鳴,腰膝酸軟,脈沉,脈細(xì)。此組癥狀提示為腎陰虛證的表現(xiàn)。1.3.5痰瘀阻肺型。唇甲紫暗,暗紅舌�！按郊鬃习怠迸c“暗紅舌”主要為血瘀的表現(xiàn)。結(jié)合臨床經(jīng)驗(yàn),提示此組為痰瘀阻肺證的表現(xiàn)。2肺痹湯干預(yù)肺纖維化機(jī)制的實(shí)驗(yàn)研究2.1肺痹湯對(duì)博萊霉素誘導(dǎo)的小鼠肺纖維化模型有緩解作用,可改善小鼠一般情況,降低小鼠肺內(nèi)膠原蛋白總含量,減少肺泡支氣管灌洗液內(nèi)炎癥細(xì)胞數(shù)量。2.2研究熱點(diǎn)細(xì)胞因子YKL-40可以促進(jìn)MRC5增殖,并能促使其向肌成纖維細(xì)胞轉(zhuǎn)化；其免疫熒光染色結(jié)果顯示YKL-40刺激的MRC5內(nèi),蛋白Ki67、I型膠原和a-肌動(dòng)蛋白合成較對(duì)照組顯著增多,使其更易在小鼠脫細(xì)胞肺組織片(mouse lung scaffold)上粘附生長(zhǎng)增殖,從而促進(jìn)肺纖維化的進(jìn)程。2.3肺痹湯及其主要成份對(duì)MRC5增殖的抑制作用中藥單體黃芪甲苷對(duì)MRC5的抑制作用隨濃度的增加而增強(qiáng),其中從0.078ug/ml開(kāi)始出現(xiàn)抑制,其抑制率為3.06±6.52%,直至200ug/ml時(shí)抑制率為12.55±15.22%。中藥單體丹參酮ⅡA對(duì)MRC5的抑制作用隨濃度的增加而增強(qiáng),其中從10ug/ml開(kāi)始出現(xiàn)抑制,其抑制率為2.17±5.39%,直至160ug/ml時(shí)抑制率為72.62±12.29%.黃芪注射液對(duì)MRC5的抑制作用隨濃度的增加而增強(qiáng),其中從6.25×103ug/ml開(kāi)始出現(xiàn)抑制,其抑制率為8.89±5.88%,直至10Sug/ml濃度時(shí)抑制率為20.58±9.5%。丹參酮Ⅱ A注射液對(duì)MRC5的抑制作用隨濃度的增加而增強(qiáng),其中從0.625ug/ml時(shí)開(kāi)始出現(xiàn)抑制,其抑制率為11.32±10.35%,直至320ug/ml時(shí)抑制率為45.06±37.72%。肺痹湯對(duì)MRC5的抑制作用隨濃度的增加而增強(qiáng),其中從0.156ul/ml開(kāi)始出現(xiàn)抑制,其抑制率為2.89±14.7%,直至2.5ul/ml及更高的濃度,抑制作用尤其明顯,均在60%以上,其中2.5u1/ml的抑制率為66.2±34.75%。結(jié)論從116例肺纖維化病人資料臨床觀察分析結(jié)果,認(rèn)為肺纖維化一病常見(jiàn)證候可能包括：氣虛血瘀、痰熱阻肺、氣陰兩虛、腎陰虧虛、痰瘀阻肺；其中醫(yī)證候特征以氣虛血瘀較為常見(jiàn),氣虛為其發(fā)病之本,血瘀為久病之實(shí)。肺痹湯能夠緩解博萊霉素誘導(dǎo)的小鼠肺纖維化模型的肺內(nèi)情況,該療效機(jī)制可能是從抑制炎癥反應(yīng)和抗膠原合成兩個(gè)方面實(shí)現(xiàn)的。細(xì)胞因子YKL-40能夠促進(jìn)MRC5增殖,合成分泌膠原,并向肌成纖維細(xì)胞轉(zhuǎn)化,是一種促肺纖維化的因子；而肺痹湯及其主要成份能夠抑制MRC5的增殖,其中肺痹湯抑制效果最佳且多次重復(fù)實(shí)驗(yàn)的結(jié)果穩(wěn)定,其主要成分丹參抑制效果亦可,且較黃芪的抑制效果好。在以肺纖維化常見(jiàn)證候氣虛血瘀證基礎(chǔ)上擬定的經(jīng)驗(yàn)方肺痹湯,對(duì)肺纖維化有一定緩解作用,其作用機(jī)制可能是通過(guò)抑制成纖維細(xì)胞增殖,抑制肺內(nèi)炎癥反應(yīng)程度和抑制膠原合成等幾個(gè)方面。
[Abstract]:Pulmonary fibrosis is a chronic progressive interstitial lung disease characterized by progressive dyspnea, dry cough, shortness of breath, and asthma. This disease can be developed by a variety of lung diseases and multiple systemic diseases, including idiopathic pulmonary fibrosis without primary disease. Its main pathological feature is fibroblasts and myofibroblasts. Proliferation, excessive deposition of extracellular matrix. With the popularization of high resolution CT, the detection rate of pulmonary fibrosis is increasing year by year. The incidence of the pulmonary fibrosis increases with age. The survival period is generally 3-8 years and the median survival period is 3 years. The prognosis is poor, except for lung transplantation, there is no effective treatment, and the WHO (WHO) is a difficult one. In recent decades, with its mature syndrome differentiation and treatment system, Chinese medicine has accumulated rich clinical experience in the treatment of the disease of pulmonary fibrosis, and has achieved good curative effect. It is worth affirming, but it needs further evidence-based medicine to accumulate and verify the data support. Therefore, to explore the treatment of this disease by traditional Chinese medicine. The purpose of this study is to observe the characteristics of TCM Syndromes of pulmonary fibrosis (PF), and to provide a evidence-based medical basis for deepening the understanding of the disease. Through animal model experiments and cytological experiments, the effect and intervention of tutor experience Fang Fei Bi Decoction in the intervention of pulmonary fibrosis are observed. The method of study method 1 the clinical syndrome characteristics of TCM syndrome of pulmonary fibrosis, according to the diagnostic criteria of idiopathic pulmonary fibrosis and secondary pulmonary interstitial fiber, set up a clinical information collection table, and observe 116 cases of pulmonary fibrosis patients in the outpatient department of the second clinical medicine hospital of Beijing University of Chinese Medicine from 2006 to 2015. In order to investigate the effect of lung Bi Decoction on pulmonary fibrosis, the effect of lung Bi Decoction (.2) on the effect mechanism of pulmonary fibrosis was studied by SPSS software. The effect of lung Bi Decoction on the model of pulmonary fibrosis induced by bleomycin was observed. The possible mechanism and efficacy of lung Bi Decoction in the treatment of pulmonary fibrosis in the control group, the normal model group, the hormone intervention group and the lung Bi Decoction intervention group, from the mice general condition, the death situation, the white blood cell count in the bronchoalveolar lavage fluid and the total collagen content in the lung tissue, the possible mechanism and efficacy of lung Bi Decoction in the treatment of pulmonary fibrosis were discussed in.2.2 two: YKL-4 0) the growth and protein expression of human lung fibroblast cells (MRC5) on mouse 1nouse lung scaffold (1nouse lung scaffold), and the effect of cytokine YKL-40 on the proliferation and protein expression of fibroblasts and the possible role of.2.3 in the process of pulmonary fibrosis in the process of pulmonary fibrosis. Test three: To observe the effects of different concentrations of Radix Astragali, tanshinone II A, Radix Astragali, tanshinone II A, tanshinone II A, and lung Bi Decoction of traditional Chinese medicine on the growth of MRC5, and the effect of the traditional Chinese medicine lung Bi Decoction and its main components on the proliferation of fibroblast from the cell level. Results 1 TCM syndrome of pulmonary fibrosis Symptomatic study 1.1 symptoms: the common symptoms of pulmonary fibrosis were 60, and there were 22 symptoms of more than 25% of the symptoms. The symptoms were: cough, short breath, wheezing, expectoration, fatigue, dry mouth, sweat, dry throat, cough weakness, fear of cold, insomnia, palpitation, phlegm, phlegm, phlegm, deafness and tinnitus, labia dark, dizziness, .1.2 syndrome factors: "phlegm", "Qi Deficiency", "heat", "Yin Deficiency" and "blood stasis" are the main syndromes and characteristics of.1.3 syndrome in the patients with pulmonary interstitial fibrosis: 1.3.1 Qi deficiency and blood stasis type. Cough, cough weakness, expectoration, white phlegm, fatigue and dim tongue. "Cough" in this group. "Expectoration" is a common symptom of pulmonary fibrosis in the patients. "Cough is weak" and "fatigue" suggests Qi deficiency. "Light dark tongue" suggests Qi deficiency and blood stasis. The symptoms suggest that qi deficiency and blood stasis syndrome shows.1.3.2 phlegm heat resistance lung type. Phlegm sticky, phlegm difficult, stool dry and vein slippery. In intestinal form, the lung heat shifted to the large intestine. The symptoms of phlegm and heat resistance syndrome were.1.3.3 Qi and yin deficiency syndrome. The symptoms of this group were asthmatic, short, cold, perspiration, panic, cold, insomnia, evil wind, dry mouth, and dry pharynx. The symptoms of this group were more, suggesting the manifestation of the deficiency of.1.3.4 kidney yin deficiency, the two deficiency of Lung Qi Yin, night sweats, Dizziness, deafness and tinnitus, waist and knee soft, pulse sinks, pulse fine. The symptoms of this group are.1.3.5 phlegm and blood stasis syndrome. Lip a dark red tongue, dark red tongue. "Lip a dark" and "dark red tongue" are the main manifestations of blood stasis. Combined with clinical experience, it is suggested that this group is the performance of phlegm stasis syndrome in.2 lung Bi Decoction in the mechanism of pulmonary fibrosis. The study of 2.1 lung Bi decoction can relieve the pulmonary fibrosis model induced by bleomycin in mice. It can improve the general situation of mice, reduce the total content of collagen in the lung of mice and reduce the number of inflammatory cells in the alveolar lavage fluid.2.2 research hot spot factor YKL-40 can promote the proliferation of MRC5 and promote its conversion to myofibroblast. The results of immunofluorescence staining showed that the synthesis of protein Ki67, type I collagen and a- actin increased significantly in the MRC5 stimulated by YKL-40, making it easier to adhere and proliferate on the mouse cell lung tissue slices (mouse lung scaffold), and thus promote the progression of pulmonary fibrosis in the process of.2.3 lung Bi Decoction and its main components on the proliferation of MRC5. The inhibitory effect of Astragaloside on MRC5 was enhanced with the increase of concentration, in which the inhibitory rate was 3.06 + 6.52% from 0.078ug/ml, and the inhibition rate was 12.55 + 15.22%., and the inhibitory effect of tanshinone II A on MRC5 was enhanced with the increase of concentration, which began to appear from 10ug/ml. The inhibition rate was 2.17 + 5.39%, and the inhibition rate was 72.62 + 12.29%. at 160ug/ml. The inhibitory effect of Astragalus Membranaceus Injection on MRC5 increased with the increase of concentration, in which the inhibition rate was 8.89 + 5.88% from 6.25 x 103ug/ml, and the inhibition rate was 20.58 + 9.5%. tanshinone II A injection to MRC5 under 10Sug/ml concentration. With the increase of concentration, the inhibitory rate was 11.32 + 10.35%, the inhibition rate was 11.32 + 10.35%, and the inhibition rate was 45.06 + 37.72%., and the inhibitory effect of lung Bi Decoction on MRC5 increased with the increase of concentration, and the inhibitory rate was 2.89 + 14.7% from 0.156ul/ml, until 2.5ul/ml and higher concentration. The inhibitory effect was more than 60%, and the inhibitory rate of 2.5u1/ml was 66.2 + 34.75%.. Conclusion from 116 cases of pulmonary fibrosis, the common syndromes of pulmonary fibrosis may include Qi deficiency and blood stasis, phlegm heat resistance, deficiency of Qi and Yin, deficiency of kidney yin, phlegm and stasis of lung, and Qi deficiency syndrome characteristics of TCM syndrome. Blood stasis is more common, Qi deficiency is the origin of the disease, and blood stasis is a long-term disease. Lung Bi decoction can relieve the pulmonary fibrosis induced by bleomycin in the pulmonary fibrosis model of mice. This mechanism may be realized from two aspects: inhibition of inflammatory reaction and synthesis of anti collagen. Cytokine YKL-40 can promote the proliferation of MRC5, synthesize and secrete collagen. The transformation of myofibroblast is a factor for promoting pulmonary fibrosis, and the lung Bi Decoction and its main components can inhibit the proliferation of MRC5, in which the inhibitory effect of the lung Bi decoction is the best and the results of repeated repeated experiments are stable. The main ingredient of the main ingredient of Salvia miltiorrhiza is also better than the Astragalus. On the basis of stasis syndrome, empirical Fang Fei Bi decoction has some relieving effect on pulmonary fibrosis. Its mechanism may be by inhibiting the proliferation of fibroblasts, inhibiting the degree of inflammatory reaction in the lung and inhibiting the synthesis of collagen.

【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R259

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2 張紓難;孫瑞華;;建立肺纖維化生存質(zhì)量評(píng)價(jià)體系方法初探[A];第五次全國(guó)中西醫(yī)結(jié)合呼吸病學(xué)術(shù)交流大會(huì)論文匯編[C];2000年

3 黃山英;宋良文;張勇;孫麗;尹紀(jì)業(yè);;Ⅳ型膠原和基質(zhì)金屬蛋白酶在大鼠早期肺纖維化啟動(dòng)中的作用機(jī)制[A];第六屆全國(guó)生物醫(yī)學(xué)體視學(xué)學(xué)術(shù)會(huì)議暨第九屆全軍軍事病理學(xué)學(xué)術(shù)會(huì)議、第五屆全軍定量病理學(xué)學(xué)術(shù)會(huì)議論文匯編[C];2005年

4 畢黎琦;孫文鑄;郭嘉隆;杜娟;周鳳嬌;;胰島素樣生長(zhǎng)因子-Ⅰ和轉(zhuǎn)化生長(zhǎng)因子-β1在肺纖維化形成中的作用研究[A];第十二屆全國(guó)風(fēng)濕病學(xué)學(xué)術(shù)會(huì)議論文集[C];2007年

5 王星;李世彬;王詠梅;吳琦;;酒精與大鼠肺纖維化關(guān)系的研究[A];中華醫(yī)學(xué)會(huì)呼吸病學(xué)年會(huì)——2011（第十二次全國(guó)呼吸病學(xué)學(xué)術(shù)會(huì)議）論文匯編[C];2011年

6 楊乃女;嚴(yán)賴莎;陳少賢;;氟伐他汀對(duì)大鼠肺纖維化干預(yù)作用的研究[A];中華醫(yī)學(xué)會(huì)呼吸病學(xué)年會(huì)——2011（第十二次全國(guó)呼吸病學(xué)學(xué)術(shù)會(huì)議）論文匯編[C];2011年

7 劉建秋;黃利華;李竹英;;化纖湯防治肺纖維化的實(shí)驗(yàn)研究[A];第七次全國(guó)中西醫(yī)結(jié)合呼吸病學(xué)術(shù)交流大會(huì)論文匯編（一）[C];2004年

8 楊s，

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