本文選題：右美托咪定 + COPD��； 參考：《南方醫(yī)科大學》2017年博士論文

【摘要】：研究背景及目的慢性阻塞性肺疾病(Chronic obstructive pulmonary disease,COPD)是一種以氣道、肺組織為損傷部位,以持續(xù)性氣流受限為特征的慢性支氣管炎和(或)肺氣腫,可進展為肺源性心臟病和呼吸衰竭的常見慢性肺部疾病,與氣道和肺組織對有毒氣體或有害顆粒產(chǎn)生異常炎性反應有關,具有較高發(fā)病率、致殘率和致死率,造成嚴重社會經(jīng)濟負擔。右美托咪定(Dexmedetomidine,Dex)是一種新型高選擇性α2腎上腺素能受體激動劑,是臨床常用麻醉輔助藥物。越來越多臨床研究表明,右美托咪定可通過抑制細胞凋亡、減輕炎癥反應和細胞氧化應激反應等機制對大腦、心臟、腎臟、肝臟及肺臟等多種器官起保護作用,其中,尤以肺臟保護作用最為明顯。miRNA-146a是近年來研究熱點,其可靶定TLR4/依賴MyD88途徑重要組成部分TNF受體相關因子6(TRAF6)和白細胞介素1受體相關激酶1(IRAK1),激活TLR4下游信號分子NF-κB,誘導大量炎癥因子,如IL-6、IL-1β、TNF-α等表達釋放,促進炎癥反應級聯(lián)放大,參與COPD炎癥相關發(fā)病過程,可能是COPD治療新靶點。由此,我們提出假設,右美托咪定可調(diào)控miRNA-146a對COPD肺損傷起到保護作用,其明確機制尚不清楚,是本課題研究重點,也是創(chuàng)新之處。本研究擬建立COPD大鼠模型,明確COPD大鼠肺損傷的病理基礎;闡明右美托咪定調(diào)控miRNA-146a對COPD肺損傷的保護作用及機制。第一部分COPD大鼠動物模型的建立及肺功能檢測與組織學檢查目的建立COPD肺損傷大鼠動物模型,通過觀察大鼠一般狀況、肺功能檢測、動脈血氣分析、支氣管肺泡灌洗液檢測以及肺組織病理學檢查,明確COPD肺損傷的病理基礎。方法選取16只SD大鼠并隨機分為2組,空白對照組(8只)和COPD組(8只),利用煙霧熏吸法建立大鼠COPD肺損傷模型,檢測肺功能指標如潮氣量(Tidal volume,TV)、最大呼氣流量(Peak expiratory flow,PEF)、50%肺活量最大呼氣流量(EF 50)、0.3秒用力呼氣容積(FEV0.3)和FEV0.3與用力肺活量(FVC)比值(FEV0.3/FVC);分析大鼠動脈血氧分壓(Pa02)和二氧化碳分壓(PaC02);收取大鼠支氣管肺泡灌洗液,并進行細胞計數(shù)、分類及蛋白質(zhì)含量檢測;取大鼠肺組織,行濕/干重比檢測和組織病理學檢查。結果1.一般狀況:空白對照組大鼠實驗過程中飲食、飲水正常,體重增長正常,毛發(fā)光滑,無明顯呼吸道癥狀;COPD組大鼠逐漸出現(xiàn)厭食、體重減輕、毛發(fā)暗黃脫落、活動減少,并出現(xiàn)噴嚏、喘息以及呼吸頻率增快等呼吸道癥狀。2.肺功能檢測:空白對照組大鼠TV為2.65±0.21 mL,PEF為38.55±0.24 mL/s,EF50 為 1.81±0.06 mL/s,FEV0.3 為 4.44±0.26 mL,而 FEV0.3/FVC 為 88.45±0.34%;COPD 組大鼠 TV 為 1.26±0.17 mL,PEF 為 17.61±0.35 mL/s,EF50 為 1.20±0.14 mL/s,FEV0.3 為 2.52±0.28 mL,FEV0.3/FVC 為 63.39±0.22%。COPD 組大鼠TV、PEF、EF 50、FEV0.3和FEV0.3/FVC均顯著低于空白對照組大鼠(0.05)。3.動脈血氣分析:空白對照組大鼠動脈血Pa02為89.35±4.30 mmHg,而COPD組動脈血Pa02為73.12±5.11 mmHg,COPD組大鼠動脈血Pa02顯著低于空白對照組大鼠動脈血Pa02(p0.05)。空白對照組大鼠動脈血PaCO2為43.22±5.19 mmHg,而 COPD 組動脈血 PaCO2 為 56.36±6.71 mmHg,COPD 組大鼠動脈血PaC02顯著高于空白對照組大鼠動脈血PaC02(p0.05)。4.支氣管肺泡灌洗液(BALF)細胞計數(shù)及蛋白濃度檢測:相比于空白對照組,COPD組大鼠BALF白細胞總數(shù)顯著增加(2.33±1.19×1 08/L vs.1.45±0.41 × 108/L,p0.05),且中性粒細胞比例顯著增高(17.4±7.2%vs.8.6±3.4%,p0.05),單核巨噬細胞比例顯著減低(73.3±2.6%vs.83.4±1.1%,p0.05),淋巴細胞比例無顯著性差異(8.1±2.0%vs.7.8±2.7%,p0.05)�？瞻讓φ战M大鼠BALF蛋白含量為193.19±33.21 mg/L,COPD組大鼠BALF蛋白含量為363.93±41.38 mg/L,COPD組大鼠BALF蛋白含量顯著高于空白對照組大鼠BALF 蛋白含量(p0.05)。5.大鼠肺臟濕/干重比(W/D):空白對照組大鼠肺臟整體觀呈粉紅色,W/D為4.02±0.39,而COPD組大鼠肺臟整體觀色澤蒼白,肺表面可見大小不等肺大皰,W/D為5.41±1.03,COPD組大鼠肺臟W/D顯著高于空白對照組大鼠肺臟W/D(p0.05)。6.肺組織病理學變化:空白對照組肺組織切片鏡下可見支氣管上皮纖毛豐富、排列整齊、未見脫落,支氣管管壁規(guī)整、未見增厚及炎性細胞浸潤,管腔內(nèi)未見炎性滲出物,肺泡腔結構完整、未見明顯病理性擴大。COPD組肺組織切片鏡下可見支氣管纖毛柱狀上皮呈鋸齒樣增生增厚,纖毛脫落倒伏,粘膜下腺體增生肥大,炎性細胞廣泛浸潤,杯狀細胞增生,支氣管管腔內(nèi)粘液蓄積,管壁結締組織增生,平滑肌增厚,可見單核細胞和淋巴細胞浸潤,肺泡大小不等、結構紊亂,肺泡壁變薄、斷裂,肺泡腔擴大,部分融合成較大的囊腔。結論煙霧熏吸法可有效建立COPD肺損傷大鼠模型,可明確典型COPD肺損傷的病理基礎。第二部分右美托咪定降低miRNA-146a表達抑制COPD大鼠肺泡上皮細胞凋亡目的研究右美托咪定對具有介導COPD大鼠肺泡上皮細胞凋亡作用的miRNA-146a表達的影響,利用流式細胞儀、實時定量PCR檢測miRNA-146a以及凋亡相關因子p53和Bcl-2表達水平改變,以期明確右美托咪定對COPD肺損傷的保護機制。方法選取24只SD大鼠并隨機分為3組:空白對照組(8只)、COPD未給藥組(8只)和COPD右美托咪定給藥組(8只)。分離、純化、培養(yǎng)各組大鼠肺泡上皮細胞�？瞻讓φ战M肺泡上皮細胞取自正常大鼠肺組織,COPD未給藥組和COPD右美托咪定給藥組肺泡上皮細胞取自COPD大鼠模型肺組織,COPD右美托咪定給藥組加入5 μM右美托咪定培養(yǎng)3天,空白對照組和COPD未給藥組將給予等量生理鹽水培養(yǎng)3天,進行細胞凋亡檢測和實時定量PCR檢測,明確細胞凋亡情況和miRNA-146a以及凋亡相關因子p53和Bcl-2的表達水平。結果1.肺泡上皮細胞凋亡流式細胞儀檢測結果顯示:COPD未給藥組和COPD右美托咪定給藥組損傷細胞比例、壞死細胞比例和凋亡細胞比例均較正常對照組顯著升高(p0.05),而正常存活細胞比例顯著降低(p0.05);COPD右美托咪定給藥組損傷細胞比例和凋亡細胞比例較COPD未給藥組顯著降低(p0.05),正常存活細胞比例則顯著增高(p0.05)。COPD右美托咪定給藥組肺泡上皮細胞凋亡率較COPD未給藥組顯著降低(11.15±0.51vs30.19±1.61%,p0.05)。2.右美托咪定抑制miRNA-146a基因表達情況實時定量PCR檢測結果顯示:COPD未給藥組和COPD右美托咪定給藥組miRNA-146a表達明顯高于空白對照組(p0.05),但COPD右美托咪定給藥組miRNA-146a表達明顯低于COPD未給藥組(p0.05)。3.右美托咪定抑制p53基因表達情況實時定量PCR檢測結果顯示:COPD未給藥組和COPD右美托咪定給藥組p53表達明顯高于空白對照組(p0.05),但COPD右美托咪定給藥組p53表達明顯低于COPD未給藥組(p0.05)。4.右美托咪定抑制Bcl-2基因表達情況實時定量PCR檢測結果顯示:COPD未給藥組和COPD右美托咪定給藥組Bcl-2表達明顯高于空白對照組(p0.05),但COPD右美托咪定給藥組Bcl-2表達明顯低于COPD未給藥組(p0.05)。結論miRNA-146a通過p53和Bcl-2介導肺泡上皮細胞凋亡,右美托咪定可降低miRNA-146a表達抑制COPD大鼠肺泡上皮細胞凋亡從而有效保護肺組織。
[Abstract]:Background and objective Chronic obstructive pulmonary disease (COPD) is a chronic bronchitis and / or emphysema characterized by airway and lung tissue injury, characterized by persistent airflow limitation, and can be developed as a common chronic pulmonary disease of pulmonary heart disease and respiratory failure, with airway and lung tissue. Dexmedetomidine (Dex) is a new type of high selective alpha 2 adrenergic receptor agonist, which is a kind of high selective alpha 2 adrenergic receptor agonist. More and more clinical studies have shown that Dexmedetomidine can protect the brain, heart, kidney, liver, lung and other organs by inhibiting apoptosis, alleviating inflammatory reaction and cell oxidative stress. Especially, the most obvious.MiRNA-146a of lung protection is the research heat point in recent years, and the target TLR4/ depends on the important component of the MyD88 pathway, T NF receptor related factor 6 (TRAF6) and interleukin 1 receptor related kinase 1 (IRAK1) activate NF- kappa B of the downstream signal molecules of TLR4, inducing a large number of inflammatory factors, such as IL-6, IL-1 beta, and TNF- alpha, to release the expression of IL-6, IL-1 beta, and TNF- alpha, to promote the cascade of inflammatory reactions and to participate in the pathogenesis related pathogenesis of COPD, which may be a new target for COPD treatment. Amidazine can regulate the protective effect of miRNA-146a on COPD lung injury. Its clear mechanism is not clear, it is the focus of this study, and it is also an innovation. This study is to establish a COPD rat model to clarify the pathological basis of lung injury in COPD rats, and to clarify the protective effect and mechanism of right metoimidin on COPD lung injury by miRNA-146a. The establishment of COPD rat model and lung function detection and histological examination were established to establish the rat model of COPD lung injury. The pathological basis of COPD lung injury was confirmed by observing the general condition of the rat, the lung function test, the arterial blood gas analysis, the bronchoalveolar lavage fluid and the pathological examination of the lung tissue. Methods 16 SD were selected. Rats were randomly divided into 2 groups, blank control group (8 rats) and COPD group (8 rats). COPD lung injury model was established by smoke fumigation. The lung function indexes such as tidal volume (Tidal volume, TV), maximum expiratory flow (Peak expiratory flow, PEF), 50% vital expiratory flow (EF 50), 0.3 second forced expiratory volume (FEV0.3) and FEV0.3 and exertion were measured. Lung activity (FVC) ratio (FEV0.3/FVC); analysis of rat arterial oxygen pressure (Pa02) and carbon dioxide partial pressure (PaC02); collection of rat bronchoalveolar lavage fluid, cell count, classification and protein content detection; rat lung tissue, wet / dry weight ratio test and histopathology examination. Results 1. general condition: blank control group rats Diet, normal drinking water, normal weight growth, smooth hair and no obvious respiratory symptoms; group COPD rats gradually appeared anorexia, weight loss, dark yellow and shedding of hair, reduced activity, and respiratory symptoms of respiratory symptoms, such as sneezing, wheezing and increasing respiratory rate, and.2. lung function test: the TV in the blank control group was 2.65 + 0.21 mL, PEF was 38.5. 5 + 0.24 mL/s, EF50 is 1.81 + 0.06 mL/s, FEV0.3 is 4.44 + 0.26 mL, and FEV0.3/FVC is 88.45 + 0.34%, TV in COPD group is 1.26 + 0.17 mL, PEF is 17.61 + 0.35 mL/s, EF50 is 1.20. The arterial blood gas analysis in the white control group (0.05).3. artery blood gas analysis: the arterial blood of the blank control group was 89.35 + 4.30 mmHg, and the arterial blood of the COPD group was 73.12 + 5.11 mmHg, and the arterial blood Pa02 of the COPD group was significantly lower than that of the blank control group (P0.05). The arterial blood of the blank control group was 43.22 + 5.19 mmHg, while the arterial blood of the control group was 43.22 + 5.19. PaCO2 was 56.36 + 6.71 mmHg, and the arterial blood PaC02 of group COPD rats was significantly higher than that of PaC02 (P0.05).4. bronchoalveolar lavage (BALF) cell count and protein concentration in the arterial blood of the blank control group. Compared with the blank control group, the total number of BALF leucocytes in the COPD group rats increased significantly (2.33 + 1.19 * 1 08/L vs.1.45 0.41 * 0.41), and The proportion of neutrophils increased significantly (17.4 + 7.2%vs.8.6 + 3.4%, P0.05), the proportion of mononuclear macrophages decreased significantly (73.3 + 2.6%vs.83.4 + 1.1%, P0.05), and there was no significant difference in the proportion of lymphocytes (8.1 + 2.0%vs.7.8 2.7%, P0.05). The content of BALF protein in the blank control group was 193.19 + 33.21 mg/L, and the BALF protein content of COPD group was 363.93 + 41. The content of BALF protein in.38 mg/L, group COPD rats was significantly higher than that of BALF protein content (P0.05) in the blank control group (P0.05), the lung wet / dry weight ratio (W/D) in.5. rats: the whole view of lung in the blank control group was pink, W/D was 4.02 + 0.39, while the lungs of the COPD group were pale with the whole lung, and the lung surface showed the size of different lung bullus, W/D 5.41 + 1.03. COPD The lung W/D in the rats of the group was significantly higher than that in the lungs of the blank control group. The lung tissue of W/D (P0.05).6. lung tissue was found in the blank control group. The lung tissue section of the blank control group showed that the bronchoepithelial cilium was rich and orderly. The bronchial tube wall was not shedding, the bronchial tube wall was regular, no thickening and inflammatory cell infiltration, no inflammatory exudation was found in the lumen, and the alveolar cavity was intact. There was no obvious pathological enlargement of.COPD group in the lung tissue section, which showed that the bronchial ciliated columnar epithelium was thickened with serrated hyperplasia, ciliated and lodged, the submucous gland hyperplasia and hypertrophy, extensive infiltration of inflammatory cells, goblet cell proliferation, mucus accumulation in the bronchus cavity, hyperplasia of connective tissue in the tube wall, thickening of smooth muscle, and monocyte and monocyte. Lymphocyte infiltration, alveolar size, structure disorder, alveolar wall thinning, fracture, alveolar cavity enlargement, partial fusion into larger capsule cavity. Conclusion smoke fumigation can effectively establish a rat model of COPD lung injury, and can clarify the pathological basis of typical COPD lung injury. Second right metoimidin reduces miRNA-146a expression and inhibits the alveoli of COPD rats Objective to investigate the effect of dexmedetomidin on the expression of miRNA-146a expression in the apoptosis of alveolar epithelial cells in COPD rats, using flow cytometry, real-time quantitative PCR detection of miRNA-146a and the changes of p53 and Bcl-2 expression levels of apoptosis related factors, in order to clarify the protective mechanism of right metoimidin on COPD lung injury. 24 SD rats were randomly divided into 3 groups: blank control group (8), COPD non administration group (8) and COPD right metomomidine administration group (8). Isolated, purified and cultured rat alveolar epithelial cells. Alveolar epithelial cells in blank control group were derived from normal rats' lung tissue, COPD non administration group and COPD right metomomidin group's alveolar epithelium fine The cells were taken from the COPD rat model lung tissue, and the COPD right metomomomidine administration group was added to 5 u M dexmeimidin for 3 days. The blank control group and the COPD non administration group were given the same amount of normal saline for 3 days. The apoptosis detection and real-time quantitative PCR detection were carried out to determine the cell apoptosis and the table of miRNA-146a and apoptosis related factors p53 and Bcl-2. Results 1. the results of the 1. alveolar epithelial cell apoptosis flow cytometry showed that the proportion of damaged cells, the proportion of necrotic cells and the proportion of apoptotic cells in the group of COPD and right metomomidin increased significantly (P0.05), while the proportion of normal living cells decreased significantly (P0.05); COPD right metoimidin administration group The ratio of damaged cells and apoptotic cells was significantly lower than that of COPD (P0.05), and the proportion of normal living cells increased significantly (P0.05), the apoptosis rate of alveolar epithelial cells in.COPD dexmeimidine group was significantly lower than that in COPD group (11.15 + 0.51vs30.19 + 1.61%, P0.05).2. right metomomidin inhibition of miRNA-146a gene expression The results of quantitative PCR detection showed that the expression of miRNA-146a in the COPD group and COPD dexmedetomidine administration group was significantly higher than that in the blank control group (P0.05), but the miRNA-146a expression in the COPD right metoimidin group was significantly lower than that of the COPD non administration group (P0.05) (P0.05).3. right metomomidin The expression of p53 in the administration group and the COPD dexmedetomidine administration group was significantly higher than that in the blank control group (P0.05), but the expression of p53 in the COPD dexmedetomidin group was significantly lower than that in the COPD group (P0.05). The real-time quantitative PCR detection results of the inhibition of the Bcl-2 gene expression in the right metomomidin group (P0.05) showed that COPD was not given to the drug group and the right metoimidine administration group was expressed. It was significantly higher than that in the blank control group (P0.05), but the expression of Bcl-2 in the COPD dexmedetomidine administration group was significantly lower than that in the COPD group (P0.05). Conclusion miRNA-146a mediated the apoptosis of alveolar epithelial cells through p53 and Bcl-2, and dexmedetomidine could reduce the miRNA-146a expression to inhibit the apoptosis of pulmonary alveolar cells in COPD rats and effectively protect the lung tissue.
【學位授予單位】：南方醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R614

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