發(fā)布時間：2018-05-31 01:00

  本文選題：支氣管肺發(fā)育不良 + 轉(zhuǎn)錄因子CASZ1��； 參考：《南方醫(yī)科大學(xué)》2016年碩士論文

【摘要】：研究背景支氣管肺發(fā)育不良(Bronchopulmonary dysplasia, BPD)是早產(chǎn)兒疾病中的一種常見并發(fā)癥,近年來在新生兒重癥監(jiān)護病房中此種疾病的發(fā)病率和死亡率大大增加。在過去的幾十年里,盡管新生兒醫(yī)療水平在不斷進步,如先進的機械通氣模式、產(chǎn)后使用肺表面活性物質(zhì)和產(chǎn)前使用激素等,然后新生兒支氣管肺發(fā)育不良的發(fā)生率卻沒有下降。在國,每年有10,000—15,000例患兒出現(xiàn)此病,這些患兒大多是出生體重1250 g的早產(chǎn)兒。此種疾病的呼吸和神經(jīng)系統(tǒng)后遺癥會一直持續(xù)到成年。1967年,William (Bill) Northway和他的同事首次報道并命名這一疾病。支氣管肺發(fā)育不良主要出現(xiàn)在伴有急性呼吸衰竭并接受機械通氣和氧療的早產(chǎn)兒,正壓機械通氣引起的氣壓傷和容量傷加劇了早產(chǎn)兒的肺損傷。此外,氧毒性和肺部炎癥阻礙了新生兒出生后肺的發(fā)育。支氣管肺發(fā)育不良的主要病理特征為肺泡和肺微血管發(fā)育受阻,表現(xiàn)為肺泡結(jié)構(gòu)簡單化,肺毛細血管生成減少等。支氣管肺發(fā)育不良是嬰幼兒最常見的慢性呼吸系統(tǒng)疾病,胎肺發(fā)育過程有五個不同的階段分別是：胚胎期、假腺管期、微管期、囊泡期和肺泡期,胚胎肺發(fā)育在微管期和囊泡早期出生的早產(chǎn)兒容易發(fā)生BPD。原始肺泡、肺泡毛細血管和Ⅰ型、Ⅱ型肺泡壁細胞主要在微管后期形成和發(fā)育,囊泡早期主要發(fā)育特點是肺表面活性物質(zhì)的產(chǎn)生,肺血管的形成分化和終末氣道擴張等。早產(chǎn)嬰兒胎肺的正常發(fā)育中斷,在加上可能由感染、機械通氣或高氧引起的炎癥,使胎兒肺泡化受阻從而導(dǎo)致BPD的發(fā)生。支氣管肺發(fā)育不良確切的病因和發(fā)病機制仍不十分明確,目前認為主要是在遺傳易感性的基礎(chǔ)上,氣壓傷、容量傷、氧化應(yīng)激、宮內(nèi)感染、炎癥反應(yīng)等因素共同作用于發(fā)育未成熟的肺組織而導(dǎo)致的肺泡和肺微血管發(fā)育障礙和肺組織損傷后異常修復(fù)的結(jié)果。有研究發(fā)現(xiàn)肺微血管發(fā)育障礙與BPD的發(fā)生發(fā)展密切相關(guān),調(diào)控肺微血管發(fā)育的基因表達失衡會干擾肺微血管的正常發(fā)育以及減慢肺泡化進程,其在BPD的發(fā)病機制中起了關(guān)鍵作用。在肺發(fā)育過程中,肺血管的生成可以促進肺泡的發(fā)育,并維持肺泡的正常結(jié)構(gòu)；另外肺泡分化的同時肺血管網(wǎng)隨之?dāng)U張,從而形成有效的氣血屏障,早產(chǎn)兒由于肺尚未發(fā)育完善,輔助通氣等治療可能使肺血管床減少肺泡發(fā)育受阻,導(dǎo)致氣血交換不足引起一系列臨床癥狀,調(diào)控肺微血管發(fā)育的基因和蛋白也成為近年來國內(nèi)外研究的熱點。亦有研究發(fā)現(xiàn),早產(chǎn)兒吸入高濃度氧或長期機械通氣時,肺組織大量的氧自由基及炎癥介質(zhì)的產(chǎn)生,引起炎癥細胞在肺內(nèi)聚集,最終導(dǎo)致的BPD的發(fā)生�？梢�,氧化應(yīng)激及其誘發(fā)的炎癥反應(yīng)在BPD的發(fā)生發(fā)展中起了至關(guān)重要的作用。轉(zhuǎn)錄因子CASZ1又稱ZNF693,是新近發(fā)現(xiàn)的一種轉(zhuǎn)錄因子,屬于鋅指基因家族的成員之一,其蛋白產(chǎn)物只要通過與DNA結(jié)合或聚合而起轉(zhuǎn)錄因子的重要作用,參與正常細胞的增值、凋亡和分化過程。Charpentier等研究表明CASZ1主要在血管內(nèi)皮細胞中表達,CASZ1通過EGFL7/RhoA通路調(diào)控內(nèi)皮細胞的行為促進血管網(wǎng)的形成和分支,另外CASZ1還可通過RhoA調(diào)節(jié)內(nèi)皮細胞的黏附從而促進血管生芽,這些研究顯示CASZ1在微血管的出芽和重建中起著重要作用,為血管的生成和形態(tài)發(fā)生所必須。前B細胞集落增強因子(pre-B cell colony enhancing factor, PBEF)又稱為內(nèi)脂素或煙酰胺磷酸核糖轉(zhuǎn)移酶,是近年來發(fā)現(xiàn)的主要由成熟脂肪細胞和激活的炎癥細胞分泌,全身多器官均可表達的炎癥因子,與炎癥、代謝綜合征、腫瘤、自身免疫性疾病等密切相關(guān)具有調(diào)控炎癥、細胞生長、血管生成和凋亡等多種作用的蛋白。目前有體外細胞實驗研究發(fā)現(xiàn)炎癥刺激可以使肺泡上皮細胞、肺微動脈內(nèi)皮細胞等大量表PBEF,而減少PBEF的表達則可減輕上述細胞由炎癥刺激引起的相關(guān)損害,這表明PBEF可能涉及包括肺微血管損傷、肺泡上皮細胞損傷、通透性增加等在內(nèi)有關(guān)呼吸系統(tǒng)疾病的多個病理生理過程。本研究采用80%的高體積分數(shù)氧制作新生鼠BPD模型,觀察各組新生鼠肺組織的病理學(xué)變化,微血管密度測定,轉(zhuǎn)錄因子CASZ1和炎癥因子PBEF的基因的蛋白表達,探討轉(zhuǎn)錄因子CASZ1在高氧致支氣管肺發(fā)育不良新生大鼠肺組織中的表達及其對肺微血管發(fā)育的關(guān)系和前B細胞集落增強因子(PBEF)在高氧致新生大鼠支氣管肺發(fā)育不良中的表達及意義。研究目的1、用80%的高體積分數(shù)氧制作新生鼠BPD模型,觀察各組新生鼠肺組織的病理學(xué)變化,微血管密度測定,以及CASZ1和PBEF的基因和蛋白表達情況。2、分析高氧組新生大鼠肺組織中CASZ1的蛋白表達水平與肺微血管密度之間的關(guān)系,探討CASZ1在BPD發(fā)生發(fā)展過程的可能機制。3、觀察肺組織中PBEF的表達在BPD發(fā)生發(fā)展中的動態(tài)變化規(guī)律,分析其在BPD發(fā)病過程中的可能作用。研究方法1、實驗動物模型的建立：以足月新生鼠為研究對象,將48只新生鼠在出生24小時內(nèi)隨機分為實驗組和對照組,每組均為24只。實驗組持續(xù)暴露于80%左右的氧氣中,制作新生鼠BPD模型。對照組置于同一室內(nèi)的空氣中,其他實驗控制因素和實驗組相同。2、分別于實驗開始后3天、7天、14天觀察高氧對新生鼠一般狀況的影響,并取肺組織用HE染色方法光鏡下觀察各實驗組肺組織病理學(xué)變化并進行放射狀肺泡計數(shù)(RAC),采用IPP6圖像分析系統(tǒng)測量肺泡呼吸膜厚度(ST)。3、應(yīng)用免疫組化方法檢測各時間點兩組新生鼠肺組織中CD31、CASZ1、 PBEF蛋白的分布和表達；以肺組織CD31免疫染色陽性的內(nèi)皮細胞所占的面積與肺實質(zhì)細胞總面積的百分比計算肺微血管密度。4、應(yīng)用ELISA方法檢測各時間點新生鼠肺泡灌洗液中PBEF的蛋白濃度。5、Real-Time PCR方法檢測各組各時間點新生鼠肺組織中CASZ1、PBEF的基因表達水平。6、Western blot方法檢測各組各時間點新生鼠肺組織中CASZ1、PBEF的蛋白表達水平。7、實驗數(shù)據(jù)用均數(shù)±標(biāo)準(zhǔn)差(X±SD)表示,應(yīng)用SPSS 17.0軟件對數(shù)據(jù)進行分析, 同一時間點兩組比較采用t檢驗,各組間比較采用單因素方差分析,相關(guān)分析采用Pearson相關(guān)分析, P0.05為差異有統(tǒng)計學(xué)意義。結(jié)果1、隨著日齡的增加對照組新生鼠肺組織逐漸發(fā)育成熟,肺泡大小均勻,結(jié)構(gòu)規(guī)整,放射狀肺泡計數(shù)逐漸增加,呼吸膜較�。欢哐踅M新生鼠肺組織肺泡逐漸出現(xiàn)融合,肺間隔斷裂,肺泡大小不均,放射狀肺泡計數(shù)明顯減少,呼吸膜增厚,肺間質(zhì)中有大量炎性細胞浸潤,肺組織結(jié)構(gòu)發(fā)生類似BPD的病理改變。2、兩組新生鼠肺組織RAC和ST,3天時無明顯差異,7天和14天時高氧組RAC明顯減少、ST顯著增厚與對照組相比差異均有統(tǒng)計學(xué)意義(P0.05)。3、免疫組織化學(xué)染色結(jié)果顯示：1)CD31廣泛表達于肺微血管內(nèi)皮細胞的胞質(zhì)中,隨日齡的增加對照組CD31表達水平逐漸升高,高氧組和對照組相比,各時間點微血管密度均顯著下降(P0.05)；2)肺組織中CASZ1主要表達于支氣管上皮細胞、肺泡上皮細胞和肺血管內(nèi)皮細胞中。高氧組3天、7天、14天CASZ1陽性細胞的積分光密度值均顯著低于相應(yīng)對照組(P0.01)；3)肺組織中PBEF的表達于支氣管上皮細胞、肺泡上皮細胞和炎癥細胞中,高氧組和對照組PBEF的表達都有逐漸升高的趨勢,高氧組3天、7天、14天PBEF陽性細胞的積分光密度值均高于相應(yīng)對照組,差異有統(tǒng)計學(xué)意義(P0.05)。4、3天、7天兩組新生鼠肺組織支氣管肺泡灌洗液中PBEF蛋白濃度無統(tǒng)計學(xué)差異,14天時高氧組顯著高于對照組(P0.01)。5、與對照組相比,各時間點高氧組CASZ1基因和蛋白表達水平降低(P0.01)；而高氧組PBEF基因和蛋白表達平水平較對照組升高(P0.05)。6、高氧組新生鼠肺組織中CASZ1蛋白表達水平與肺微血管密度呈正相關(guān)(r=0.519,P=0.0090.01)。結(jié)論1、新生大鼠持續(xù)吸入80%高氧后,肺泡逐漸出現(xiàn)融合,肺間隔斷裂,肺泡大小不均,放射狀肺泡計數(shù)明顯減少,呼吸膜增厚,肺間質(zhì)中有大量炎性細胞浸潤,肺組織結(jié)構(gòu)發(fā)生類似BPD的病理改變。2、高氧組新生鼠CASZ1 mRNA和蛋白表達隨著高氧暴露時間的延長而逐漸下降,各時間點均顯著低于對照組,提示高濃度氧可以抑制轉(zhuǎn)錄因子CASZ1的表達。3、高氧組新生大鼠肺組織中CASZ1的蛋白表達水平與肺微血管密度呈正相關(guān),推測高氧可能通過抑制CASZ1的表達,從而阻礙肺血管的發(fā)育,導(dǎo)致BPD的發(fā)生。4、研究結(jié)果顯示BPD實驗組PBEF的表達顯著高于正常對照組(P0.05),表明PBEF參與了支氣管肺發(fā)育不良的發(fā)生發(fā)展,但PBEF參與支氣管肺發(fā)育不良發(fā)生的具體機制尚不清楚,有待進一步研究。
[Abstract]:Background Bronchopulmonary dysplasia (BPD) is a common complication of premature infant disease. In recent years, the incidence and mortality of this disease have increased greatly in the neonatal intensive care unit. In the past few decades, although the medical level of newborn infants is progressing, such as advanced mechanical ventilation Patterns, postpartum use of pulmonary surfactant and prenatal hormone, and then the incidence of bronchopulmonary dysplasia in the newborn did not decline. In the country, 10000 to 15000 children have this disease each year, most of which are premature babies born with birth weight of 1250 g. The respiratory and nervous system sequelae of this disease will continue to continue. By the age of.1967, William (Bill) Northway and his colleagues first reported and named the disease. Bronchopulmonary dysplasia mainly appeared in premature infants accompanied by acute respiratory failure and undergoing mechanical ventilation and oxygen therapy. Barometric and volumetric injuries caused by positive mechanical ventilation combined with lung injury in preterm infants. Inflammation hinders the development of the lung after birth. The main pathological features of bronchopulmonary dysplasia are the obstruction of alveolar and pulmonary microvascular development, characterized by the simplification of the alveolar structure and the decrease of pulmonary capillary formation. Bronchopulmonary dysplasia is the most common chronic respiratory system disease in infants and five different fetal lung development processes. The stages are: embryonic stage, false glandular tube stage, microtubule stage, vesicle stage and alveolar period. Embryonic lung development is prone to BPD. primordial alveoli, alveolar capillaries and type I, type I alveolar wall cells in the early stage of microtubule and early birth of vesicles. The main development characteristics of the early vesicle are pulmonary surface activity. The formation of substance, the formation and differentiation of the pulmonary vessels, and the dilatation of the terminal airway. The normal development of the fetal lung in premature infants is interrupted by the addition of inflammation that may be caused by infection, mechanical ventilation or hyperoxia, causing fetal pulmonary alveolar obstruction to cause BPD. The exact etiology and pathogenesis of bronchopulmonary dysplasia are still not very clear, currently recognized. The results of abnormal repair of pulmonary alveolar and pulmonary microvascular development and lung tissue damage caused by factors such as air pressure injury, volume injury, oxidative stress, intrauterine infection, inflammatory reaction and other factors, mainly on the basis of genetic susceptibility. It is closely related that the imbalance of gene expression in the regulation of pulmonary microvascular development will interfere with the normal development of pulmonary microvessels and slow the process of alveolar degeneration. It plays a key role in the pathogenesis of BPD. In the process of lung development, the formation of pulmonary vessels can promote the development of the alveoli, and maintain the normal structure of the alveoli; in addition, the alveolar differentiation is simultaneously differentiated. The pulmonary vascular network expands, thus forming an effective air blood barrier, the premature infant has not developed the lung yet, and the auxiliary ventilation may cause the pulmonary vascular bed to reduce the pulmonary alveolar development and cause a series of clinical symptoms. The basic causes and proteins that regulate the development of the pulmonary microvessel have also become a hot spot of research at home and abroad in recent years. It is also found that a large number of oxygen free radicals and inflammatory mediators in the lung tissue are produced in preterm infants when high concentrations of oxygen or long term mechanical ventilation are inhaled, resulting in the accumulation of inflammatory cells in the lungs and the occurrence of BPD. Oxidative stress and its induced inflammatory response have played a vital role in the development of BPD. CASZ1, also known as ZNF693, is a newly discovered transcription factor, one of the members of the zinc finger gene family. Its protein product is an important role of the transcription factor by combining or polymerizing with DNA. It participates in the increment of normal cells, the process of apoptosis and the process of differentiation,.Charpentier and so on, which indicate that CASZ1 is mainly expressed in vascular endothelial cells, CASZ 1 the regulation of endothelial cells through the EGFL7/RhoA pathway promotes the formation and branching of vascular networks, and CASZ1 also regulates the adhesion of endothelial cells by RhoA to promote vascular buds. These studies show that CASZ1 plays an important role in the buds and reconstructions of microvessels, which is necessary for the formation and morphogenesis of blood vessels. The colony of the former B cells Pre-B cell colony enhancing factor (PBEF), also known as endogenous lipoprotein or nicotinamide phosphonotinase, is found in recent years mainly secreted by mature adipocytes and activated inflammatory cells, and can be expressed in multiple organs. It is closely related to inflammation, metabolic syndrome, tumor, autoimmune disease and so on. There is a variety of proteins that regulate inflammation, cell growth, angiogenesis, and apoptosis. In vitro cell experiments have found that inflammatory stimulation can make the alveolar epithelial cells, pulmonary microarterial endothelial cells and so on a large number of PBEF, and the reduction of PBEF expression can reduce the related damage caused by the inflammatory stimulation, which indicates that PBEF can be used. It can involve multiple pathophysiological processes related to respiratory diseases, including pulmonary microvascular injury, alveolar epithelial cell damage, and increased permeability. This study used 80% high body integral oxygen to make the BPD model of neonatal rats, to observe the pathological changes of lung tissue, microvessel density, transcription factor CASZ1 and inflammatory causes in the newborn rats. Protein expression of the subPBEF gene and the expression of transcription factor CASZ1 in the lung tissue of neonatal rats with hyperoxic bronchopulmonary dysplasia and its relationship to pulmonary microvascular development and the expression and significance of B cell colony enhancement factor (PBEF) in hyperoxic neonatal rats with bronchopulmonary dysplasia. Objective 1, with a high volume of 80% The BPD model of neonatal rats was made by fractional oxygen. The pathological changes of lung tissue, microvessel density, and gene and protein expression of CASZ1 and PBEF were observed in each group. The relationship between the protein expression level of CASZ1 in the lung tissue of the hyperoxic group and the relationship between the microvascular density of the lung was analyzed, and the development of CASZ1 in BPD was discussed. Energy mechanism.3, observe the dynamic change rule of PBEF expression in the development of BPD in the lung tissue and analyze its possible role in the pathogenesis of BPD. Method 1, the establishment of experimental animal model: a term newborn rat was used as the study object, and the 48 newborn rats were randomly divided into the experimental group and the control group within 24 hours of birth, each group was 24. The experimental group was exposed to about 80% oxygen to make the BPD model of newborn rats. The control group was placed in the same indoor air. The other experimental control factors were the same as the experimental group.2. The effects of hyperoxia on the general condition of the newborn rats were observed on the 3 day, the 7 day and the 14 day after the experiment, and the lung tissues were observed under the HE staining method under the light microscope. The pathological changes of lung tissue and radiate alveolar count (RAC) were carried out. The pulmonary alveolar membrane thickness (ST).3 was measured by IPP6 image analysis system. The distribution and expression of CD31, CASZ1, PBEF protein in the lung tissues of two new groups of newborn rats were detected by immunohistochemical method, and the surface of the endothelial cells positive for CD31 immunoreactivity in lung tissue was detected. The percentage of lung microvascular density.4 was calculated with the percentage of the total area of lung parenchyma. The protein concentration of PBEF in the alveolar lavage fluid of newborn rats at every time point was detected by ELISA method. The Real-Time PCR method was used to detect the CASZ1, PBEF gene expression level.6 in the lung tissue of each time point of each group, and the Western blot method was used to detect the new generation of each time point. The protein expression level of CASZ1 and PBEF in rat lung tissue was.7, and the experimental data were expressed with mean standard deviation (X + SD). The data were analyzed with SPSS 17 software and t test was used in two groups at the same time point. The single factor analysis of variance was used in each group. The correlation analysis was analyzed with Pearson correlation. P0.05 was statistically significant. Fruit 1, with the increase of day age, the lung tissues of the control group gradually developed and mature, the size of the alveoli was uniform, the structure was regular, the number of radiate alveoli increased gradually, and the respiratory membrane was thinner, while the pulmonary alveolus of the newborn rats were gradually fused, the pulmonary septum was broken, the size of alveoli was uneven, the number of radiate alveoli decreased obviously, the respiratory membrane thickened and lung was thickened. There were a large number of inflammatory cells infiltrating in the interstitial tissue and the pathological changes of lung tissue similar to BPD,.2. There was no significant difference between the two groups of newborn rats' lung tissue RAC and ST. The RAC in the hyperoxia group was significantly reduced at the 7 and 14 days, and the significant thickening of ST was statistically significant compared with the control group (P0.05).3, and the immunohistochemical staining results showed 1) CD31 wide. In the cytoplasm of the pulmonary microvascular endothelial cells, the expression level of CD31 in the control group increased gradually with the increase of day age. Compared with the control group, the microvascular density decreased significantly at every time point (P0.05). 2) CASZ1 in the lung tissue was mainly expressed in the bronchial epithelial cells, alveolar epithelial cells and pulmonary vascular endothelial cells. The hyperoxia group was 3. The integral light density values of CASZ1 positive cells in days, 7 days and 14 days were significantly lower than that in the corresponding control group (P0.01), and 3) the expression of PBEF in the lung tissue was gradually increased in the bronchial epithelial cells, alveolar epithelial cells and inflammatory cells, and the expression of PBEF in the hyperoxia group and the control group was gradually increased, and the integral light density of the PBEF positive cells of the hyperoxia group for 3 days, 7 days and 14 days of PBEF positive cells. The difference was statistically significant (P0.05).4,3 days, and there was no statistical difference in the concentration of PBEF protein in the bronchoalveolar lavage fluid of the two groups of neonatal rats on the 7 day, and at 14 days, the hyperoxia group was significantly higher than the control group (P0.01).5. Compared with the control group, the CASZ1 gene and protein expression level in the hyperoxia group were decreased (P0.01). The level of PBEF gene and protein expression in the hyperoxic group was higher than that of the control group (P0.05).6, and the expression level of CASZ1 protein in the lung tissue of the hyperoxic group was positively correlated with the pulmonary microvascular density (r=0.519, P=0.0090.01). Conclusion 1, after the newborn rats inhaled 80% hyperoxia, the alveoli gradually appeared to fuse, the pulmonary septum fracture, the alveolar size uneven, and the radiate alveoli. The count decreased obviously, the respiratory membrane was thickened, a large number of inflammatory cells were infiltrated in the pulmonary interstitium and the pathological changes of the lung tissue were similar to that of BPD. The expression of CASZ1 mRNA and protein in the hyperoxic group decreased gradually with the prolongation of the exposure time of hyperoxia, and the time points were significantly lower than those in the group, suggesting that the high concentration of oxygen could inhibit the transcription factor CASZ1. Expression of.3, the protein expression level of CASZ1 in the lung tissue of the hyperoxic group was positively correlated with the lung microvascular density. It is suggested that hyperoxia may inhibit the expression of CASZ1, thus hindering the development of pulmonary vessels and causing the occurrence of.4 in BPD. The results of the study showed that the expression of PBEF in the BPD experimental group was significantly higher than that of the normal control group (P0.05), indicating that PBEF was involved in the study. The pathogenesis of bronchopulmonary dysplasia is unclear, but the specific mechanism of PBEF involvement in bronchopulmonary dysplasia is unclear.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R722.1

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