血管内皮生长因子在慢性阻塞性肺疾病中的作用

慢性阻塞性肺疾病（chronic obstructive pulmonary disease,COPD）由于日益增长的发病率和痫死率成为全世界主要的健康问题。但是,疾病的确切发病机制还没有被阐明。血管内皮生长因子（Vasculare ndothelial growth factor,VEGF）足血管形成的有效介质．对肺的发育和生理有多重作用。VEGF广泛存在于肺组织,对COPD的两种主要病理生理学表现型（肺气肿和慢性支气管炎）起了很重要的作用,观诵对临床的角度研究VEGF在COPD中的作用。     

血管内皮生长因子与慢性阻塞性肺疾病的肺血管重构

血管内皮生长因子（VEGF）具有促进血管内皮细胞增殖和血管生成的作用。研究表明，VEGF在慢性阻塞性肺疾病（COPD）的肺血管重构中起着重要作用，进而加重其气道阻力和气道炎症，影响COPD的预后。如何使VEGF保持一个合适的水平有待于我们进一步的研究。     

Studies of vascular endothelial growth factor in asthma and chronic obstructive pulmonary disease

Vascular endothelial growth factor (VEGF) is a potent stimulator of vascular angiogenesis, permeability, and remodeling that also plays important roles in wound healing and tissue cytoprotection. To begin to define the roles of VEGF in diseases like asthma and COPD, we characterized the effects of lung-targeted transgenic VEGF(165) and defined the innate immune pathways that regulate VEGF tissue responses. The former studies demonstrated that VEGF plays an important role in Th2 inflammation because, in addition to stimulating angiogenesis and edema, VEGF induced eosinophilic inflammation, mucus metaplasia, subepithelial fibrosis, myocyte hyperplasia, dendritic cell activation, and airways hyperresponsiveness via IL-13-dependent and -independent mechanisms. VEGF was also produced at sites of aeroallergen-induced Th2 inflammation, and VEGF receptor blockade ameliorated adaptive Th2 inflammation and Th2 cytokine elaboration. The latter studies demonstrated that activation of the RIG-like helicase (RLH) innate immune pathway using viral pathogen-associated molecular patterns such as Poly(I:C) or viruses ameliorated VEGF-induced tissue responses. In accord with these findings, Poly(I:C)-induced RLH activation also abrogated aeroallergen-induced Th2 inflammation. When viewed in combination, these studies suggest that VEGF excess can contribute to the pathogenesis of Th2 inflammatory disorders such as asthma and that abrogation of VEGF signaling via RLH activation can contribute to the pathogenesis of viral disorders such as virus-induced COPD exacerbations. They also suggest that RLH activation may be a useful therapeutic strategy in asthma and related disorders.     

血管内皮生长因子与慢性阻塞性肺疾病

慢性阻塞性肺疾病是一个发病率和死亡率都很高的慢性疾病，其发病机制涉及肺内细胞的凋亡，肺实质细胞的减少，炎性细胞的浸润和气道、血管的重构。血管内皮生长因子作为一个可特异作用于内皮细胞，调节血管内皮细胞生长、分化、修复及发挥功能的重要因子，与慢性阻塞性肺疾病的发生有着密切的联系。     

血管内皮生长因子与慢性阻塞性肺疾病继发肺动脉高压的关系

血管内皮生长因子(vascular endothelial growth factor,VEGF)是一种重要的血管内皮细胞丝裂原和通透因子.肺血管的重塑与慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)继发肺动脉高压密切相关.VEGF贯穿于COPD发展的全过程,在COPD的不同时期呈现不同的表达水平,发挥不同的生物学作用.气道炎症、低氧等因素可以在COPD早期促进VEGF及其受体的表达上调从而导致肺血管重塑的发生发展,VEGF也可以对COPD后期继发肺动脉高压时的重度肺血管重塑起到一定的修复作用.通过阐述VEGF、COPD肺血管重塑及继发肺动脉高压之间的相互关系,可以对COPD继发肺动脉高压的诊断和治疗提供新的思路.     

Possible effects of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease

PURPOSE: Expression of vascular endothelial growth factor (VEGF) is reduced in the lungs of patients with emphysema. We examined whether VEGF levels in sputum differed in patients with emphysema, bronchitis, or asthma, as compared with controls. METHODS: Fifty-nine patients with chronic obstructive pulmonary disease (COPD) (25 with emphysema, 19 with chronic bronchitis, and 15 with a mixed type), 20 patients with bronchial asthma, and 11 normal controls were included in the study. The concentration of VEGF in induced sputum and the correlations between VEGF levels and pulmonary function were examined. RESULTS: The mean (+/- SD) concentration of VEGF in induced sputum was significantly higher in patients with asthma (6440 +/- 1820 pg/mL, P <0.0001) or bronchitis (4120 +/- 1100 pg/mL, P <0.0001) than in normal controls (1860 +/- 1220 pg/mL), but significantly lower in patients with emphysema (500 +/- 300 pg/mL, P =0.03). The concentration of VEGF in sputum from patients with bronchitis correlated inversely with forced expiratory volume in 1 second (r = -0.87; P =0.0002); in contrast, there was a positive correlation between these two measurements in patients with emphysema (r = 0.82; P <0.0001). In addition, sputum VEGF concentrations correlated with the diffusing capacity of carbon monoxide in patients with emphysema (r = 0.87; P <0.0001), but not in those with bronchitis (r = -0.22; P =0.36). CONCLUSION: In patients with bronchitis, increased levels of VEGF in induced sputum were associated with airflow limitation. In contrast, decreased levels of VEGF were associated with airflow limitation and alveolar destruction in patients with emphysema. Thus, our findings suggest that VEGF may affect the pathogenesis of these two common types of COPD.     

结缔组织生长因子在吸烟者及慢性阻塞性肺疾病患者肺血管中的表达及其与肺血管重塑的关系

目的探讨吸烟者及慢性阻塞性肺疾病（COPD）患者的肺血管重塑中结缔组织生长因子（CTGF）的表达及意义。方法取24份（非吸烟对照组、吸烟组、吸烟伴COPD组,每组8例）手术切除的肺组织,HE染色观察肺血管重塑,天狼猩红染色检测胶原增殖,免疫组化观察CTGF在肺动脉的表达,RT-PCR检测肺动脉CTGF mRNA表达。结果（1）肺动脉管壁面积／管总面积（WA％）,非吸烟对照组为（28．4±4．7）％,吸烟组为（46．3±3．5）％,吸烟伴COPD组为（55．5±3．9）％（P〈0．01）。HE染色可见,吸烟组、吸烟伴COPD组肺动脉管壁B月显增厚。（2）肺动脉壁胶原厚度,非吸烟对照组为（6．4±1．6）μm,吸烟组为（15．9±2．4）μm,吸烟伴COPD组为（16．4±2．3）μm（P〈0．01）。天狼猩红染色可见,吸烟组、吸烟伴COPD组肺动脉管壁胶原明显增多。（3）CTGF mRNA表达量,非吸烟对照组为0．095±0．015,吸烟组为0．396±0．167,吸烟伴COPD组为0．501±0．177（P〈0．01）。（4）CTGF蛋白表达量,非吸烟对照组为0．085±0．011,吸烟组为0．245±0．095,吸烟伴COPD组为0．303±0．191（P〈0．01）。（5）相关分析：CTGF mRNA及蛋白表达量与WA％呈正相关（r分别为0．915、0．919,P〈0．01）。结论单纯吸烟者即有肺血管重塑,吸烟伴COPD者的肺血管重塑程度更重,CTGF可能在此过程中起重要作用。     

吸烟患或未患慢性阻塞性肺疾病患者肺组织中巨噬细胞移动抑制因子表达

 目的 通过检测吸烟患或未患慢性阻塞性肺疾病（COPD）患者肺组织中巨噬细胞移动抑制因子（MIF）表达水平,为进一步了解COPD易患机制提供基础研究资料。方法 肺组织来源于因肺癌行肺叶切除术的41例患者,分吸烟患COPD组（16例）、吸烟未患COPD组（13例）、无吸烟对照组（12例）3组。所有受试者均于术前1周做肺功能检查［第1秒用力呼气容积（FEV₁）,用力肺活量（FVC）］,采用实时定量PCR和免疫组化检测肺组织中MIF mRNA和蛋白表达水平,并行相关分析。结果 (1）实时定量PCR检测肺组织内MIF mRNA表达水平,吸烟患COPD组（4.87±1.79）高于吸烟未患COPD组（2.16±0.72）,而吸烟未患COPD组又高于无吸烟对照组（1.09±0.48;P<0.01）。（2）免疫组化显示,肺组织内MIF蛋白表达吸光度值吸烟患COPD组（0.277±0.025）高于吸烟未患COPD组（0.199±0.034）,而吸烟未患COPD组高于无吸烟对照组（0.130±0.021;P<0.01）。（3）相关性分析：肺组织内MIF mRNA表达与FEV₁占预计值百分比、FEV₁／FVC呈负相关(r分别为-0.578、-0.607,P值均<0.01)。结论 吸烟患COPD者肺组织中MIF表达明显增加,且与气流受限程度呈正相关,提示MIF可能在吸烟致COPD发病机制中起重要作用。     

COPD大动脉弹性与血管内皮功能关系的研究

目的研究脉博波速度(PWV)与COPD心血管危险因素的相关性。方法应用自动PWV测定仪测定颈-股动脉脉搏波速度(C-FPWV)和颈-桡动脉脉搏波速度(C-RPWV)分别作为评估大动脉缓冲能力和外周中等肌性动脉弹性的指标。对86例COPD患者和64例健康人进行了PWV检测,并测定血清一氧化氮(Nox)、内皮素(ET)。结果 COPD患者C-FPWV、C-RPWV明显高于正常对照组,P<0.001;COPD患者NOX、NOX/ET明显低于正常对照组;COPD患者ET高于正常对照组,P均小于0.001。吸烟指数、年龄、FEV1%Pre是影响C-FPWV的独立因素;NOX、ET、FEV1/FVC%是影响C-RPWV的独立因素。结论 COPD为一种系统性疾病,大动脉弹性的降低为COPD发生心血管疾病的危险因素。     

Treatment of patients with transposition of great arteries and pulmonary vascular obstructive disease

Twenty-two patients with transposition of the great arteries with or without ventricular septal defect and one with double outlet right ventricle, d-malposition, and severe pulmonary vascular obstructive disease were treated surgically. All were cyanosed and had very limited exercise tolerance. Preoperatively, systemic arterial oxygen saturation (SaO2) varied from 45 to 79% (mean 65), haemoglobin was 13 to 23 g/dl (mean 19). Pulmonary arteriolar resistance was 6.4 to 35 units m2 (mean 17). In the patients with a ventricular septal defect the Mustard operation was done without closure of the ventricular septal defect, and in the 3 patients with intact ventricular septum the Mustard operation was combined with creation of a ventricular septal defect. All patients survived the operation and improved. Postoperative SaO2 ranged from 75 to 96% (mean 89) and haemoglobin from 10.6 to 17.8 g/dl (mean 14.0). This improvement was significant (P less than 0.05). Five patients have had a postoperative cardiac catheterisation. The pulmonary arteriolar resistance remains high in all. Postoperative follow-up varies from 4 to 40 months (mean 14 months). So far there have been no late deaths and all patients remain improved.     

血管内皮生长因子与慢性支气管炎合并肺气肿大鼠早期肺动脉重构关系的研究

目的研究血管内皮生长因子（VEGF）在慢性支气管炎合并肺气肿早期（非低氧血症期）肺动脉重构中的作用及N-乙酰半胱氨酸（NAC）的抗氧化作用对其的影响。方法24只健康雄性Wistar大鼠随机分为4组,每组6只：假吸烟组（A组）、慢性支气管炎合并肺气肿组（B组）、NAC预防组（C组）、NAC治疗组（D组）,B、C及D组采用两次气管内注入脂多糖（LPS）及烟熏4周法制备慢性支气管炎合并肺气肿大鼠模型,C组在烟熏及气管内注入LPS前每天给予NAC（50mg／只）灌胃,D组在第15～28天烟熏前每天给子NAC（50mg／只）灌胃。各组作血气分析、对肺组织进行苏木精-伊红染色、维多利亚蓝＋VG（Van—Gieson）染色观察气道炎症、肺泡面积改变、肺血管改变及采用免疫组化法观察VEGF的表达情况。结果与A组比较,B组各大鼠小气道出现组织细胞损伤、管壁炎症细胞浸润及平均肺泡面积增大（P〈0.05）,符合慢性支气管炎合并肺气肿的病理改变;B组动脉氧分压、氧饱和度及二氧化碳均在正常范围。与A组比较,B组肺血管管壁增厚、管腔缩小（P〈0．01）,且肌化动脉、部分肌化动脉比率增加（P〈0．01）,VEGF在肺动脉周围表达增多（P〈0.01）。而C组及D组经NAC抗氧化干预后肺血管管壁增厚及管腔缩小减轻（P〈0．05）,并且肌化动脉、部分肌化动脉比率减少（P〈0．01）,肺动脉周围VEGF表达比B组减少（P〈0．01）。结论由吸烟及LPS诱导的大鼠慢性支气管炎合并肺气肿早期（非低氧皿症期）VEGF表达增多参与了肺动脉重构,NAC可抑制肺动脉重构与其通过抗氧化作用降低VEGF表达有关。     

Decreased level of vascular endothelial growth factor in bronchoalveolar lavage fluid of normal smokers and patients with pulmonary fibrosis

Vascular endothelial growth factor (VEGF) plays multifunctional roles in both the development of vasculature and the maintenance of vascular function. A decrease in VEGF reduces angiogenesis and induces apoptosis of vascular endothelial cells. Inhibition of the VEGF receptor causes endothelial cell apoptosis and emphysema. We postulated that VEGF concentrations might be reduced in patients with chronic lung diseases. The level of VEGF was evaluated by enzyme-liked immunosorbent assay in bronchoalveolar lavage fluid (BALF) from normal smokers, nonsmoking volunteers, idiopathic pulmonary fibrosis, pulmonary fibrosis associated with a connective tissue disease, and sarcoidosis. The isoforms of VEGF in BALF were determined by high-performance liquid chromatography. VEGF in nonsmoking volunteers was detectable at a high concentration. In contrast, VEGF in most of the normal smokers was below the detectable limit. The VEGF found in nonsmoking volunteers BALF was VEGF165. VEGF was significantly decreased in idiopathic pulmonary fibrosis, pulmonary fibrosis associated with a connective tissue disease, and sarcoidosis compared with nonsmoking volunteers. The smoking patients showed a further decrease in VEGF. These data suggest that the decrease in VEGF in smokers and patients with chronic lung diseases may reduce angiogenesis and induce apoptosis of vascular endothelial cells.     

Gender and chronic obstructive pulmonary disease in high-risk smokers

BACKGROUND: Data suggest that women are more susceptible to develop airway obstruction compared to men for the same number of cigarettes smoked. OBJECTIVES: To compare the prevalence of chronic obstructive lung disease (COPD) and the effect of smoking on the risk of developing COPD according to gender, in a population of high-risk smokers. METHODS: In 795 smokers, spirometry was performed using the criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to determine airflow obstruction. COPD prevalence was determined in smokers grouped according to the number of cigarettes smoked per year [<20 (I), 20-40 (II), 40-60 (III) and >60 pack-years (IV)] and age. RESULTS: Men were older, smoked more and for a longer period. Age at smoking initiation and the number of packs smoked per day did not differ. COPD was diagnosed in 26% of the subjects (30.5% men and 22.3% women, p < 0.001) with similar degree of obstruction (forced expiratory volume in 1 s: 78% of predicted in men vs. 75% in women). COPD prevalence was lower in women in all categories irrespective of the pack-year history (I: 9 vs. 19%; II: 16 vs. 28%; III: 28 vs. 39%, and IV: 25 vs. 42%, respectively, p < 0.001). In those older than 50 years, 34% men and 17% women (p < .001) had COPD. CONCLUSIONS: Using the GOLD criteria, the prevalence of COPD in smokers was higher than previous reports. In this self-selected sample of high-risk smokers having the same smoking history, prevalence was lower in women than in men, suggesting a lower susceptibility for the development of airway obstruction.     

血管内皮生长因子及其受体在肺气肿患者肺组织中的表达

目的探讨血管内皮生长因子(VEGF)及其受体2(VEGF受体2/KDR)在肺气肿患者肺组织中的表达及其与肺气肿的相关性。方法取35例行肺叶切除术患者[A组(吸烟伴肺气肿组)16例,B组(不吸烟肺功能正常组)14例,C组(吸烟但肺功能正常组)5例]的外周肺组织标本,ELISA法检测肺组织匀浆中VEGF的含量,免疫组化法检测KDR蛋白表达,RT PCR检测VEGF和KDRmRNA水平,TUNEL法检测肺泡隔细胞的凋亡。结果A组患者肺组织VEGF、KDR表达均低于B组(P<0.01),肺泡隔细胞凋亡率高于B组(P<0.01)。C组与B组相比,VEGF及KDR表达差异无统计学意义(P>0.05)。结论VEGF及KDR水平减少与肺泡隔细胞凋亡的增加可能与肺气肿的发生相关。     

Treatment of patients with transposition of great arteries and pulmonary vascular obstructive disease.

Twenty-two patients with transposition of the great arteries with or without ventricular septal defect and one with double outlet right ventricle, d-malposition, and severe pulmonary vascular obstructive disease were treated surgically. All were cyanosed and had very limited exercise tolerance. Preoperatively, systemic arterial oxygen saturation (SaO2) varied from 45 to 79% (mean 65), haemoglobin was 13 to 23 g/dl (mean 19). Pulmonary arteriolar resistance was 6.4 to 35 units m2 (mean 17). In the patients with a ventricular septal defect the Mustard operation was done without closure of the ventricular septal defect, and in the 3 patients with intact ventricular septum the Mustard operation was combined with creation of a ventricular septal defect. All patients survived the operation and improved. Postoperative SaO2 ranged from 75 to 96% (mean 89) and haemoglobin from 10.6 to 17.8 g/dl (mean 14.0). This improvement was significant (P less than 0.05). Five patients have had a postoperative cardiac catheterisation. The pulmonary arteriolar resistance remains high in all. Postoperative follow-up varies from 4 to 40 months (mean 14 months). So far there have been no late deaths and all patients remain improved.     

慢性阻塞性肺疾病肺血管内皮细胞和肺泡上皮细胞凋亡的实验研究

目的 研究COPD患者及烟雾暴露COPD大鼠肺血管内皮细胞和肺泡上皮细胞凋亡的相互关系及其与肺功能和肺气肿的相关性.方法 采用烟雾暴露法建立COPD大鼠模型.分别采集COPD患者(13例)和对照患者(12例)及烟雾暴露80 d大鼠(11只)和对照大鼠(12只)的肺组织标本,用HE染色评估肺部病理改变,用平均内衬间隔(MLI)与平均肺泡数(MAN)评估大鼠肺气肿程度;用原位末端标记法对肺血管内皮细胞和肺泡上皮细胞凋亡进行定量检测,分析这两种细胞凋亡的相关性,及其与肺功能和肺气肿指标的相关性.正态分布的计量资料以x±s表示,采用两独立样本的t检验进行分析;非正态分布的计量资料以中位数(四分位间距)表示,采用两个独立样本比较的Wilcoxon秩和检验;采用Spearman秩相关进行相关分析.结果 COPD患者和大鼠均出现明显肺气肿病理改变.COPD患者肺血管内皮细胞和肺泡上皮细胞凋亡指数[(13.2±2.6)%和(28.9±3.1)%]明显高于对照患者[(5.6±1.5)%和(5.8±1.2)%].COPD患者肺泡上皮细胞凋亡指数[(28.9±3.1)%]明显高于肺血管内皮细胞凋亡指数[(13.2±2.6)%],二者间呈正相关(r=0.60,P<0.05);COPD患者肺血管内皮细胞和肺泡上皮细胞的凋亡指数与FEV.占预计值%呈负相关(r值分别为-0.83和-0.69,均P<0.05),与FEV1/FVC呈负相关(r值分别为-0.95和-0.71,均P<0.05),与残气容积/肺总量呈正相关(r值分别为0.93和0.70,均P<0.05).COPD大鼠肺血管内皮细胞和肺泡上皮细胞凋亡指数[(4.1±0.4)%和(10.0±1.0)%]明显高于对照大鼠[(0.2±0.1)%和(2.1±0.4)%],COPD大鼠肺组织MLI与肺泡上皮细胞凋亡指数呈正相关(r=0.59,P<0.05),MAN与肺泡上皮细胞凋亡指数呈负相关(r=-0.81,P<0.05).结论 COPD患者和大鼠肺内存在异常的细胞凋亡现象,其肺泡上皮细胞凋亡较肺血管内皮细胞凋亡更为明显,且二者呈正相关;COPD患者和大鼠肺血管内皮细胞和肺泡上皮细胞的凋亡与其肺功能及肺气肿的改变明显相关,推测肺血管内皮细胞和肺泡上皮细胞凋亡可能参与COPD的发病过程.