Circulating Progenitor Cells and Vascular Dysfunction in Chronic Obstructive Pulmonary Disease

Background

In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown.

Objectives

To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function.

Methods

62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45⁺CD34⁺CD133⁺ labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects.

Results

Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries.

Conclusions

Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit.     

结缔组织生长因子在慢性阻塞性肺疾病血管重建中表达研究

目的:探讨结缔组织生长因子(CTGF)在慢性阻塞性肺疾病(COPD)血管重建中的表达及意义。方法:将30例有吸烟史的男性鳞癌需要手术的患者按其肺功能结果分成二组,对照组:(肺功能正常组);COPD稳定期组:(肺功能异常组),每组15例,标本来自于癌旁的肺组织,肺血管重塑的形态学观察行HE和MASSON三色染色,行免疫组化来观察CTGF蛋白、PCNA蛋白在肺血管平滑肌中的表达。结果:(1)COPD组肺动脉管壁面积/管总面积(WA%)、管壁的胶原厚度、肺动脉平滑肌中CTGF蛋白及PCNA蛋白的表达与对照组相比差异有统计学意义。(2)CTGF与管壁面积/管总面积(WA%)、管壁的胶原厚度及血管平滑肌中PCNA表达呈正相关(,r值分别为0.81、0.68、0.86,P<0.05)。吸烟指数与管壁面积/管总面积及PCNA的表达呈正相关(r=0.73,0.99,P<0.01)。结论:单纯吸烟者即有血管重建,吸烟伴COPD者血管重建更加严重,CTGF在COPD患者肺血管中的表达较对照组高,可能参与了COPD血管重建过程。     

结缔组织生长因子在慢性阻塞性肺疾病血管重建中表达研究

目的：探讨结缔组织生长因子（CTGF）在慢性阻塞性肺疾病（COPD）血管重建中的表达及意义。方法：将30例有吸烟史的男性鳞癌需要手术的患者按其肺功能结果分成二组,对照组：（肺功能正常组）;COPD稳定期组：（肺功能异常组）,每组15例,标本来自于癌旁的肺组织,肺血管重塑的形态学观察行HE和MASSON三色染色,行免疫组化来观察CTGF蛋白、PCNA蛋白在肺血管平滑肌中的表达。结果：（1）COPD组肺动脉管壁面积/管总面积（WA%）、管壁的胶原厚度、肺动脉平滑肌中CTGF蛋白及PCNA蛋白的表达与对照组相比差异有统计学意义。（2）CTGF与管壁面积/管总面积（WA%）、管壁的胶原厚度及血管平滑肌中PCNA表达呈正相关（,r值分别为0.81、0.68、0.86,P〈0.05）。吸烟指数与管壁面积/管总面积及PCNA的表达呈正相关（r=0.73,0.99,P〈0.01）。结论：单纯吸烟者即有血管重建,吸烟伴COPD者血管重建更加严重,CTGF在COPD患者肺血管中的表达较对照组高,可能参与了COPD血管重建过程。     

Cognitive Impairment in Chronic Obstructive Pulmonary Disease

Background/Purpose

Chronic obstructive pulmonary disease (COPD), especially in severe forms, is commonly associated with multiple cognitive problems. Montreal Cognitive Assessment test (MoCA) is used to detect cognitive impairment evaluating several areas: visuospatial, memory, attention and fluency. Our study aim was to evaluate the impact of stable COPD and exacerbation (AECOPD) phases on cognitive status using MoCA questionnaire.

Methods

We enrolled 39 patients (pts), smokers with COPD group D (30 stable and 9 in AECOPD) and 13 healthy subjects (control group), having similar level of education and no significant differences regarding the anthropometric measurements. We analyzed the differences in MoCA score between these three groups and also the correlation between this score and inflammatory markers.

Results

Patients with AECOPD had a significant (p<0.001) decreased MoCA score (14.6±3.4) compared to stable COPD (20.2±2.4) and controls (24.2±5.8). The differences between groups were more accentuated for the language abstraction and attention (p<0.001) and delayed recall and orientation (p<0.001) sub-topics. No significant variance of score was observed between groups regarding visuospatial and naming score (p = 0.095). The MoCA score was significantly correlated with forced expiratory volume (r = 0.28) and reverse correlated with C-reactive protein (CRP) (r = −0.57), fibrinogen (r = −0.58), erythrocyte sedimentation rate (ESR) (r = −0.55) and with the partial pressure of CO₂ (r = −0.47).

Conclusions

According to this study, COPD significantly decreases the cognitive status in advanced and acute stages of the disease.     

慢性阻塞性肺疾病合并肺曲菌病一例及文献复习

目的:提高对慢性阻塞性肺疾病合并侵袭性肺曲菌病(COPD合并IPA)临床特点、诊断及治疗的认识.方法:回顾性分析2011年4月收治的一例COPD合并IPA患者的临床资料及诊治经过,并复习相关文献.结果:男患,“咳嗽、咳痰30余年,气短3年,加重1月余”入院,肺部CT示双肺多发结节影、空洞影,经抗炎、抗念珠菌治疗无效,CT下肺结节病灶活检病理示肺曲菌.抗曲菌治疗后症状好转、肺部影像明显吸收.结论:COPD合并IPA正逐渐引起重视,临床特征无明显特异性,肺部影像以结节影、空洞影多见,早期常规治疗无效时应积极抗曲菌治疗,可明显改善症状,降低死亡率,病理活检是确诊的依据.     

细辛脑联合多索茶碱治疗慢性阻塞性肺病疗效观察

目的:观察细辛脑联合多索茶碱治疗慢性阻塞性肺疾病急性加重期（AECOPD）的临床疗效。方法:将164例AECOPD患者随机分为观察组（82例）和对照组（82例）,对照组予低流量吸氧、抗炎、抗感染、纠正水电解质紊乱等综合治疗,观察组在此基础上加用注射用细辛脑、多索茶碱静脉治疗。观察两组治疗前后症状、体征改善情况及血气分析变化。结果:观察组与对照组临床总有效率分别为93.9%、81.7%（P<0.05）,观察组在发热、咳嗽咳痰、喘息症状消失时间,以及肺部罗音减少50%以上时间均显著短于对照组（P<0.01）,在FEV1、FEV1/FVC、PEF、PaO₂、PaCO₂等指标也显著优于对照组（P<0.01）。结论:在常规治疗基础上加用细辛脑、多索茶碱可以有效提高AECOPD患者的临床疗效。     

FeNO在慢性阻塞性肺疾病急性发作期患者中的临床应用

目的：探讨呼出气一氧化氮浓度(FeNO)在慢性阻塞性肺疾病急性期(AECOPD)患者中的变化情况及与一秒用力呼气容积 (FEV1)的关系。方法：选取上海第九人民医院2013 年8 月~2014 年2 月呼吸内科病区治疗的AECOPD 患者30 例,目前仍在吸 烟或患有哮喘、自身免疫性疾病及肿瘤的患者排除在外。对照组选取18 例健康的体检老年人。入组患者在治疗前先测定FeNO、 FEV1 值及完成CAT 评分,并进行病情分组。治疗后再次测定FeNO、FEV1 %值。结果：治疗前实验组FeNO、FEV1 %水平与对照 组相比有统计学差异(P<0.01)。治疗后实验组FeNO与对照组相比,无统计学差异(P>0.05)。而治疗前后两组间FEV1%变化有统计 学差异(P<0.01)。实验组不同亚组治疗前后FeNO、FEV1 %变化有统计学差异(P<0.05),且治疗前FeNO与FEV1 %呈负相关(r=-0. 098,P=0.042),治疗后FeNO与FEV1 %无明显相关(r=-0.248,P=0.784)。结论：FeNO可反映COPD急性期患者气道慢性炎症控制 情况,且对提示预后有一定意义。     

细辛脑联合多索茶碱治疗慢性阻塞性肺病疗效观察

目的：观察细辛脑联合多索茶碱治疗慢性阻塞性肺疾病急性加重期（AECOPD）的临床疗效。方法：将164例AECOPD患者随机分为观察组（82例）和对照组（82例）,对照组予低流量吸氧、抗炎、抗感染、纠正水电解质紊乱等综合治疗,观察组在此基础上加用注射用细辛脑、多索茶碱静脉治疗。观察两组治疗前后症状、体征改善情况及血气分析变化。结果：观察组与对照组临床总有效率分别为93．9％、81．7％（P〈0．05）,观察组在发热、咳嗽咳痰、喘息症状消失时间,以及肺部罗音减少50％以上时间均显著短于对照组（P〈0．01）,在FEV1、FEV1／FVC、PEF、PaO2、PaCO2等指标也显著优于对照组（P〈0．01）。结论：在常规治疗基础上加用细辛脑、多索茶碱可以有效提高AECOPD患者的临床疗效。     

聚焦慢性阻塞性肺病治疗药物

慢性阻塞性肺病(COPD) 是肺部进行性疾病,需长期治疗。预计到2020 年,每年COPD 将会导致全球600 多万人死亡。尽管对新型药物开发投资不断增加,但该领域的治疗仍以缓解症状的支气管扩张吸入剂为主,而不是治愈性疗法,故应对COPD 的创新药的研发仍困难重重。与乳腺癌等疾病领域相比,呼吸系统药物的研发成功率不到50%,但每种获批药物的研发成本却翻倍。因此,制药公司致力于药品生命周期的管理,在当前治疗的基础上进一步改进。其策略包括不同种类药物联用、开发新配方和各种剂量剂型,改善疗效,方便给药。其中以长效β 受体激动剂 (LABA)/ 长效毒蕈碱拮抗剂(LAMA) 的定量复方药的需求增长最多。领导市场的GSK 公司的LABA 沙美特罗和吸入型皮质类固醇 (ICS) 氟替卡松的复方药Advair,就是应用以上方法的典型。虽已出现潜在新型靶标,但这些药物还处于早期开发阶段。吸入型LABA/ICS 定量复方药短期内仍是 COPD 治疗领域的主力军。     

Prevalence and Global Initiative for Chronic Obstructive Lung Disease Group Distribution of Chronic Obstructive Pulmonary Disease Detected by Preoperative Pulmonary Function Test

Background

Despite being a major public health problem, chronic obstructive pulmonary disease (COPD) remains underdiagnosed, and only 2.4% COPD patients are aware of their disease in Korea. The objective of this study was to estimate the prevalence of COPD detected by spirometry performed as a preoperative screening test and to determine the Global Initiative for Chronic Obstructive Lung Disease (GOLD) group distribution and self-awareness of COPD.

Methods

We reviewed the medical records of adults (age, ≥40 years) who had undergone spirometry during preoperative screening between April and August 2013 at a tertiary hospital in Korea. COPD was defined as a postbronchodilator forced expiratory volume in 1 s/forced vital capacity ratio of <0.7. We analyzed self-administered COPD questionnaires for the assessment of the frequency of acute exacerbation over the previous year and dyspnea severity using the modified Medical Research Council dyspnea scale and COPD assessment test.

Results

Among 3029 patients aged >40 years who had undergone spirometry as a preoperative screening test, 474 (15.6%; 404 men; median age, 70 years; range, 44–93 years) were diagnosed with COPD. Only 26 (5.5%) patients reported previous diagnosis of COPD (2.1%), emphysema (0.8%), or chronic bronchitis (2.5%). The GOLD group distribution was as follows: 63.3% in group A, 31.2% in group B, 1.7% in group C, and 3.8% in group D.

Conclusions

The prevalence of COPD diagnosed by preoperative spirometry was 15.6%, and only 5.5% patients were aware of their disease. Approximately one-third of the COPD patients belonged to GOLD groups B, C, and D, which require regular treatment.     

Epicardial Adipose Tissue in Patients with Chronic Obstructive Pulmonary Disease

Rationale

Epicardial Adipose Tissue (EAT) volume as determined by chest computed tomography (CT) is an independent marker of cardiovascular events in the general population. COPD patients have an increased risk of cardiovascular disease, however nothing is known about the EAT volume in this population.

Objectives

To assess EAT volume in COPD and explore its association with clinical and physiological variables of disease severity.

Methods

We measured EAT using low-dose CT in 171 stable COPD patients and 70 controls matched by age, smoking history and BMI. We determined blood pressure, cholesterol, glucose and HbA1c levels, microalbuminuria, lung function, BODE index, co-morbidity index and coronary artery calcium score (CAC). EAT volume were compared between groups. Uni and multivariate analyses explored the relationship between EAT volume and the COPD related variables.

Results

COPD patients had a higher EAT volume [143.7 (P_25–75, 108.3–196.6) vs 129.1 (P_25–75, 91.3–170.8) cm³, p = 0.02)] and the EAT volume was significantly associated with CAC (r = 0.38, p<0.001) and CRP (r = 0.32, p<0.001) but not with microalbuminuria (r = 0.12, p = 0.13). In COPD patients, EAT volume was associated with: age, pack-years, BMI, gender, FEV₁%, 6 MWD, MMRC and HTN. Multivariate analysis showed that only pack-years (B = 0.6, 95% CI: 0.5–1.3), BMI (B = 7.8, 95% CI: 5.7–9.9) and 6 MWD (B = −0.2, 95% CI: −0.3–−0.1), predicted EAT volume.

Conclusions

EAT volume is increased in COPD patients and is independently associated with smoking history, BMI and exercise capacity, all modifiable risk factors of future cardiovascular events. EAT volume could be a non-invasive marker of COPD patients at high risk for future cardiovascular events.     

The Lung Microbiome in Moderate and Severe Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder characterized by incompletely reversible airflow obstruction. Bacterial infection of the lower respiratory tract contributes to approximately 50% of COPD exacerbations. Even during periods of stable lung function, the lung harbors a community of bacteria, termed the microbiome. The role of the lung microbiome in the pathogenesis of COPD remains unknown. The COPD lung microbiome, like the healthy lung microbiome, appears to reflect microaspiration of oral microflora. Here we describe the COPD lung microbiome of 22 patients with Moderate or Severe COPD compared to 10 healthy control patients. The composition of the lung microbiomes was determined using 454 pyrosequencing of 16S rDNA found in bronchoalveolar lavage fluid. Sequences were analyzed using mothur, Ribosomal Database Project, Fast UniFrac, and Metastats. Our results showed a significant increase in microbial diversity with the development of COPD. The main phyla in all samples were Actinobacteria, Firmicutes, and Proteobacteria. Principal coordinate analyses demonstrated separation of control and COPD samples, but samples did not cluster based on disease severity. However, samples did cluster based on the use of inhaled corticosteroids and inhaled bronchodilators. Metastats analyses demonstrated an increased abundance of several oral bacteria in COPD samples.     

Effects of N-Acetylcysteine in Ozone-Induced Chronic Obstructive Pulmonary Disease Model

Introduction

Chronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice. We determined the recovery from ozone-induced injury and whether an antioxidant, N-acetylcysteine (NAC), could prevent or reverse the lung damage.

Methods

Mice were exposed to ozone (2.5 ppm, 3 hours/12 exposures, over 6 weeks) and studied 24 hours (24h) or 6 weeks (6W) later. Nac (100 mg/kg, intraperitoneally) was administered either before each exposure (preventive) or after completion of exposure (therapeutic) for 6 weeks.

Results

After ozone exposure, there was an increase in functional residual capacity, total lung volume, and lung compliance, and a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV₂₅/FVC, FEV₅₀/FVC). Mean linear intercept (L_m) and airway hyperresponsiveness (AHR) to acetylcholine increased, and remained unchanged at 6W after cessation of exposure. Preventive NAC reduced the number of BAL macrophages and airway smooth muscle (ASM) mass. Therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells.

Conclusion

Emphysema and lung function changes were irreversible up to 6W after cessation of ozone exposure, and were not reversed by NAC. The beneficial effects of therapeutic NAC may be restricted to the ASM.     

Multidrug-Resistant Tuberculosis in Patients with Chronic Obstructive Pulmonary Disease in China

Background

Relatively little is known about the specific relationship and impact from chronic obstructive pulmonary disease (COPD) on multidrug-resistant tuberculsosis (MDR-TB).

Methods

We conducted a retrospective study included patients aged ≥40 years with a confirmed pulmonary TB at three tertiary hospitals (Shandong, China) between January 2011 and October 2014. Univariable and multivariable analyses were performed to identify the relationship of MDR-TB and COPD.

Results

A total of 2164 patients aged ≥ 40 years with available results of drug susceptibility test (DST) and medical records were screened for this study: 268 patients with discharge diagnosis of COPD and 1896 patients without COPD. Overall, 14.2% of patients with COPD and 8.5% patients without COPD were MDR-TB. The rate of MDR-TB were significantly higher in patients with COPD (P<0.05). Migrant (odds ratios (OR) 1.32, 95% confidence interval (CI) 1.02–1.72), previous anti-TB treatment (OR 4.58, 95% CI 1.69–12.42), cavity (OR 2.33, 95% CI 1.14–4.75), and GOLD stage (OR 1.86, 95% CI 1.01–2.93) were the independent predictors for MDR-TB among patients with COPD.

Conclusions

MDR-TB occurs more frequently in patients with underlying COPD, especially those with being migrant, previous anti-TB therapy, cavity and severe airway obstruction.     

Cluster Analysis in Patients with GOLD 1 Chronic Obstructive Pulmonary Disease

Background

We hypothesized that heterogeneity exists within the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 spirometric category and that different subgroups could be identified within this GOLD category.

Methods

Pre-randomization study participants from two clinical trials were symptomatic/asymptomatic GOLD 1 chronic obstructive pulmonary disease (COPD) patients and healthy controls. A hierarchical cluster analysis used pre-randomization demographics, symptom scores, lung function, peak exercise response and daily physical activity levels to derive population subgroups.

Results

Considerable heterogeneity existed for clinical variables among patients with GOLD 1 COPD. All parameters, except forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC), had considerable overlap between GOLD 1 COPD and controls. Three-clusters were identified: cluster I (18 [15%] COPD patients; 105 [85%] controls); cluster II (45 [80%] COPD patients; 11 [20%] controls); and cluster III (22 [92%] COPD patients; 2 [8%] controls). Apart from reduced diffusion capacity and lower baseline dyspnea index versus controls, cluster I COPD patients had otherwise preserved lung volumes, exercise capacity and physical activity levels. Cluster II COPD patients had a higher smoking history and greater hyperinflation versus cluster I COPD patients. Cluster III COPD patients had reduced physical activity versus controls and clusters I and II COPD patients, and lower FEV₁/FVC versus clusters I and II COPD patients.

Conclusions

The results emphasize heterogeneity within GOLD 1 COPD, supporting an individualized therapeutic approach to patients.

Trial registration

www.clinicaltrials.gov. NCT01360788 and NCT01072396.     

Unequal Twice-Daily,Sustained-Release Theophylline Dosing in Chronic Obstructive Pulmonary Disease

Three regimens of sustained-release theophylline (SRT), Theostat® were administered to 12 male patients with chronic obstructive pulmonary disease in a randomized cross-over trial. Each 7-day treatment consisted of

treatment A—8 mg/kg at 0700 hr and 4 mg/kg at 1900 hr

treatment B—6 mg/kg at 0700 hr and 6 mg/kg at 1900 hr

treatment C—4 mg/kg at 0700 hr and 8 mg/kg at 1900 hr.

Peak expiratory flow (PEF) was recorded each day at 0700, 1100, 1500, 1900 and 2300 hr and theophylline plasma levels were determined on the 7th day of each treatment sequence. Cosinor analysis of the data revealed significant circadian rhythms in PEF for each treatment: the mesor (24-hr average) was significantly higher with C and acrophases (Φ, peak time of PEF rhythm) were located at 1426 hr for A and 1425 hr for C; a shift of the acrophase to an earlier timing was detected for B (Φ = 0958 hr. These findings suggest that an unequal, twice-daily SRT dosing with the greater amount of drug at night may be beneficial in the treatment of COPD.     

Predicting Daily Physical Activity in Patients with Chronic Obstructive Pulmonary Disease

Background

Objectively measuring daily physical activity (PA) using an accelerometer is a relatively expensive and time-consuming undertaking. In routine clinical practice it would be useful to estimate PA in patients with chronic obstructive pulmonary disease (COPD) with more simple methods.

Objectives

To evaluate whether PA can be estimated by simple tests commonly used in clinical practice in patients with COPD.

Methods

The average number of steps per day was measured for 7 days with a SenseWear Pro™ accelerometer and used as gold standard for PA. A physical activity level (PAL) of <1.4 was considered very inactive. Univariate and multivariate analyses were used to examine the relationship between the 6-minute walking distance (6MWD), the number of stands in the Sit-to-Stand Test (STST), hand-grip strength and the total energy expenditure as assessed by the Zutphen Physical Activity Questionnaire (TEE_ZPAQ). ROC curve analysis was used to identify patients with an extremely inactive lifestyle (PAL<1.4).

Results

In 70 patients with COPD (21 females) with a mean [SD] FEV₁ of 43.0 [22.0] %predicted, PA was found to be significantly and independently associated with the 6MWD (r = 0.69, 95% CI 0.54 to 0.80, p<0.001), STST (r = 0.51, 95% CI 0.31 to 0.66, p = 0.001) and TEEZPAQ (r = 0.50, 95% CI 0.30 to 0.66, p<0.001) but not with hand-grip strength. However, ROC curve analysis demonstrated that these tests cannot be used to reliably identify patients with an extremely inactive lifestyle.

Conclusions

In patients with COPD simple tests such as the 6-Minute Walk Test, the Sit-to-Stand Test and the Zutphen Physical Activity Questionnaire cannot be used to reliably predict physical inactivity.