【摘要】：實(shí)驗(yàn)研究目的探索清金化痰湯在慢阻肺模型大鼠中性粒細(xì)胞彈性蛋白酶(Neutrophil elastase,NE)-表皮生長因子受體(epidermal growth factor receptor, EGFR)-有絲分裂原激活蛋白激酶(Mitogen-activated protein kinase, MAPK)-粘蛋白MUC5AC分泌”信號通路中的作用靶點(diǎn)。方法氣道滴注脂多糖聯(lián)合煙熏的方法建立慢性阻塞性肺疾病模型。50只清潔級Wistar大鼠隨機(jī)分為空白對照組、模型組、清金化痰湯組、克拉霉素組與解毒清肺組。模型組、清金化痰湯組、克拉霉素組、解毒清肺組分別給予0.9%氯化鈉溶液、清金化痰湯、克拉霉素片、解毒清肺合劑灌胃,空白對照組正常喂養(yǎng),連續(xù)30天。實(shí)驗(yàn)第31日取材,每組隨機(jī)選取6只,HE染色觀察肺組織病理形態(tài)及黏液腺體增生,阿爾新藍(lán)-過碘酸雪夫染色觀察杯狀細(xì)胞增生,實(shí)時(shí)熒光定量PCR檢測各組大鼠肺組織NE.EGFR. MUC5AC基因表達(dá),免疫組化檢測肺組織及氣道上皮NE、P-EGFR、磷酸化細(xì)胞外信號調(diào)節(jié)激酶(phosphorylated extracellular signal-regulated kinase, P-ERK)、磷酸化c-Jun氨基末端激酶(phosphorylated c-Jun N-terminal kinase, P-JNK).磷酸化p38絲裂原活化蛋白激酶(P-p38MAPK)、MUC5AC蛋白表達(dá)。結(jié)果與空白對照組比較,模型組粘液腺體增生、杯狀細(xì)胞數(shù)目、NEmRNA、 MUC5ACmRNA表達(dá)、氣道上皮NE、P-EGFR、P-ERK、P-JNK、P-p38、MUC5AC蛋白表達(dá)均顯著升高。與模型組比較,清金化痰湯組粘液腺體增生、杯狀細(xì)胞數(shù)目、NEmRNA、EGFRmRNA、MUC5ACmRNA、氣道上皮NE、P-ERK、P-p38、MUC5AC蛋白表達(dá)均顯著降低,且抑制NEmRNA、EGFRmRNA、MUC5ACmRNA、NE蛋白表達(dá)作用優(yōu)于克拉霉素組。與模型組比較,清金化痰湯組大鼠氣道上皮P-JNK表達(dá)顯著升高,而克拉霉素組P-JNK表達(dá)顯著降低,差異具有統(tǒng)計(jì)學(xué)意義。與模型組比較,清金化痰湯及克拉霉素對慢阻肺模型大鼠氣道上皮P-EGFR蛋白表達(dá)均無影響。結(jié)論 清金化痰湯可能通過抑制NE及EGFR下游信號通路中ERK、p38信號通路,干預(yù)慢阻肺氣道粘液高分泌。臨床研究目的探索清金化痰湯通過NE調(diào)節(jié)慢阻肺急性加重期(acute exacerbation of chronic obstructive pulmonary disease, AECOPD,簡稱慢阻肺急性加重)(痰熱壅肺證)氣道粘液高分泌的作用。方法將符合納入標(biāo)準(zhǔn)的慢阻肺急性加重期(痰熱壅肺證)患者應(yīng)用隨機(jī)數(shù)字表法隨機(jī)分為治療組和對照組,共納入病例156例,脫落21例,資料完整、具有統(tǒng)計(jì)學(xué)意義病例135例,治療組71例,對照組64例。對照組在慢阻肺急性加重期常規(guī)西醫(yī)治療方案基礎(chǔ)上,予以痰熱清注射液30ml靜脈滴注,每日1次,治療組在常規(guī)西醫(yī)治療方案基礎(chǔ)上,予以清金化痰湯顆粒劑口服,每日2次,每次1袋,療程7天。觀察指標(biāo)：(1)治療前檢測患者動(dòng)脈血?dú)釶aO2、PaCO2、SpO2、PH值；(2)分別在治療第1、7天觀察咳嗽頻次、痰粘稠度、痰色、痰量、喘息、胸悶、呼吸困難癥狀積分及血常規(guī)白細(xì)胞總數(shù)、中性粒細(xì)胞百分比、C反應(yīng)蛋白(C-reactionprotein, CRP)等實(shí)驗(yàn)室指標(biāo)；(3)Elisa法檢測患者治療第1、7天血清NE、MUC5AC含量。結(jié)果(1)135例慢阻肺急性加重發(fā)病人群中,男性67人(49.63%),女性68人(50.37%)；(2)135例慢阻肺急性加重發(fā)病人群中,最小年齡46歲,最大年齡97歲,平均年齡(75.81±9.88)歲,其中在81-90歲分布最多(43.7%),其余依次是71-80歲(28.15%)、61-70歲(17.78%)、51-60歲(7.41%)、90歲(2.22%)、40-50歲(0.74%)；(3)135例慢阻肺急性加重發(fā)病人群中,有吸煙史77人(57.04%),無吸煙史58人(42.97%)；(4)135例慢阻肺急性加重發(fā)病人群既往病史中,從高到低依次是高血壓病(52.59%)、冠狀動(dòng)脈粥樣硬化性心臟病(45.93%)、糖尿病(22.96%)、高脂血癥(20.74%)、反流性食管炎(17.78%)、脂肪肝(16.30%)、心律失常(12.59%)、腦梗死(11.11%)、腎功能不全(8.15%)、胃炎(7.41%)、甲狀腺疾病(4.44%)；(5)135例慢阻肺急性加重住院人群中,肺功能Ⅲ級人群最多(45.19%),其余依次是肺功能Ⅱ級人群(34.07%)、肺功能Ⅰ級人群(20.74%)；(6)與治療前相比,兩組治療后咳嗽頻次、痰色、痰質(zhì)、痰量、喘息、胸悶、mMRC評分、口干、小便黃、大便干單項(xiàng)癥狀積分均顯著降低(P0.01),且治療組在改善慢阻肺患者咳嗽頻次、痰色、痰質(zhì)、痰量方面顯著優(yōu)于對照組(P0.01)；(7)與治療前相比,兩組治療后血清NE、MUC5AC含量、N%、CRP均顯著降低(P0.01),且治療組在減少黏蛋白MUC5AC分泌方面,作用顯著優(yōu)于對照組(P0.01)。與治療前相比,治療組WBC治療后顯著降低(P0.01),而對照組治療后WBC與治療前相比無差異(P0.05)；(8)與治療前相比,兩組治療后癥狀總積分均顯著降低(P0.01),且治療組作用優(yōu)于對照組(P0.01)。結(jié)論清熱化痰類中藥(清金化痰湯、痰熱清)聯(lián)合西藥可以顯著改善慢阻肺急性加重患者臨床癥狀及實(shí)驗(yàn)室指標(biāo)。清金化痰湯聯(lián)合西藥可以改善慢阻肺急性加重患者臨床癥狀,尤其在咳嗽頻次、痰粘稠度、痰色、痰量方面療效顯著,優(yōu)于痰熱清聯(lián)合西藥治療組。清金化痰湯聯(lián)合西藥可以顯著降低慢阻肺急性加重患者血清NE、MUC5AC. WBC、N%、CRP水平,且降低MUC5AC作用顯著優(yōu)于痰熱清聯(lián)合西藥治療組。
[Abstract]:Objective To explore the role of Qingjin Huatan Decoction in the rat neutrophil elastase (NE)-epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (EGFR)-mitogen-activated protein kinase (EGFR)-mitogen-activated protein kinase (EGFR)-mitogen-activated protein kinase (EGFR) in slow-resistance lung model rats. Methods A model of chronic obstructive pulmonary disease was established by the method of combined smoking with lipopolysaccharides in the airway. Fifty-one clean-grade Wistar rats were randomly divided into the blank control group, the model group, the Qingjin Huatan Decoction group, The Clarithromycin group and the Jiedu Qingfei Group. The model group, the Qingjin Huatan Decoction group, the Clarithromycin group, the Jiedu Qingfei group were given 0.9% sodium chloride solution, the Qingjin Huatan Decoction, the Clarithromycin Tablets, the Jiedu Qingfei Mixture, and the blank control group was normally fed for 30 days. The experiment was made on the 31st of the experiment. The expression of NE, EGFR and MUC5AC in the lung tissues of each group was detected by real-time fluorescence quantitative PCR. The expression of NE, EGFR and MUC5AC in the lung of each group was detected by real-time fluorescence quantitative PCR. P-EGFR, phosphorylated extracellular signal-regulated kinase (P-ERK), phosphorylated c-Jun amino terminal kinase (P-JNK), phosphorylated p38 mitogen-activated protein kinase (P-p38 MAPK), MUC5AC protein expression. The number of goblet cells, the expression of NEmRNA, MUC5ACmRNA, airway epithelium NE, P-EGFR, P-ERK, P-JNK, P-p38 and MUC5AC were all significantly increased. Compared with the model group, the expression of mucus glands, goblet cells, NEmRNA, EGFRmRNA, MUC5ACmRNA, airway epithelium NE, P-ERK, P-p38, The expression of MUC5AC was significantly lower, and the expression of NEmRNA, EGFRmRNA, MUC5ACmRNA and NE protein was better than that of clarithromycin. Conclusion Qingjin Huatan Decoction can inhibit the signal pathway of ERK and p38 in the downstream signal pathway of NE and EGFR, compared with the model group. The purpose of the clinical study was to explore the acute exacerbation of chronic obstructive pulmonary disease (AECOPD) through NE. The method is to randomly divide into treatment group and control group according to the application of random digital table method in the patients with acute exacerbation of chronic obstructive pulmonary disease (phlegm-heat and lung syndrome), which are included in the standard. The data was complete,135 cases with statistical significance,71 in the treatment group and 64 in the control group. The control group, on the basis of the conventional western medicine treatment plan of the acute exacerbation of the chronic obstructive pulmonary disease, was given a 30-ml intravenous drip of the phlegm-heat-clearing injection, once a day, and the treatment group was on the basis of the conventional western medicine treatment plan. The preparation method comprises the following steps: (1) detecting the PaO2, PaCO2, SpO2 and PH value of the arterial blood gas of the patient before treatment; (2) observing the cough frequency, the phlegm viscosity, the phlegm color, the sputum volume and the wheezing after the treatment on the first and the seventh day respectively; Results (1) The serum NE and MUC5AC content in the first and 7th day of the treatment were detected by the Elisa method. Results (1)135 patients with acute exacerbation of chronic obstructive pulmonary disease, 67 (49.63%) males and 68 (50.37%) females; (2)135 patients with acute exacerbation of chronic obstructive pulmonary disease, with a minimum age of 46, a maximum age of 97, an average age (75.81 to 9.88), with a maximum distribution of (43.7%) at the age of 81 to 90; The rest were 71-80 years (28.15%),61-70 years (17.78%),51-60 years (7.41%),90-year-old (2.22%),40-50 years (0.74%), (3)135 patients with chronic obstructive pulmonary disease with a history of 77 (57.04%), no smoking history of 58 (42.97%), (4)135 patients with chronic obstructive pulmonary disease with prior medical history, From high to low, hypertension (52.59%), coronary atherosclerotic heart disease (45.93%), diabetes (22.96%), hyperlipidemia (20.74%), reflux esophagitis (17.78%), fatty liver (16.30%), arrhythmia (12.59%), and cerebral infarction (11.11%). Renal insufficiency (8.15%), gastritis (7.41%), thyroid disease (4.44%), (5)135 patients with chronic obstructive pulmonary acute exacerbation, the lung function class 鈪，

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