慢性阻塞性肺疾病不同表型患者CAT评分与肺功能及预后的相关性分析

摘要 目的：探讨慢性阻塞性肺疾病（chronic obstructive pulmonary disease,COPD）不同表型评估测试问卷（COPD assessment test,CAT）评分与肺功能及预后的关系。方法：收集361例COPD患者临床资料、CAT评分、肺功能检查结果及肺外合并症、肺内并发症等情况,按临床表型分为肺气肿组（n=200）和支气管炎组（n=161）,分析肺气肿组200例和支气管炎组161例COPD患者CAT评分与肺功能及预后的关系。结果：肺气肿组CAT评分高于支气管炎组（P<0.05）,一秒用力呼气容积（FEV₁）占预计值百分比（FEV₁%）、FEV₁/用力肺活量（FVC）低于支气管炎组（P<0.05）,吸气分数（IC/TLC）低于支气管炎组,残总比（RV/TLC）高于支气管炎组（P<0.05）;肺气肿组肺间质性病变、肺动脉高压发生率均高于支气管炎组（P<0.05）;支气管炎、肺气肿组CAT评分均与FEV₁%、FEV₁/FVC、IC/TLC呈负相关（P<0.05）,与RV/TLC呈正相关（P<0.05）,肺气肿各参数相关度更高（P<0.05）;肺气肿组不同CAT评分患者肺间质性病变、肺动脉高压发生率比较差异有统计学意义（P<0.05）,支气管炎组不同CAT评分肺动脉高压发生率比较差异有统计学意义（P<0.05）,随CAT评分的升高,肺气肿组肺间质性病变、肺动脉高压发生率上升,支气管炎组肺动脉高压发生率上升。结论： COPD肺气肿表型CAT评分较支气管炎表型高,肺功能降低更明显,呈现肺过度通气,气流受限特点,更易并发肺间质纤维化、肺动脉高压,且与CAT评分变化密切相关。     

The dendritic cell niche in chronic obstructive pulmonary disease

The pulmonary innate immune system is heavily implicated in the perpetual airway inflammation and impaired host defense characterizing Chronic Obstructive Pulmonary Disease (COPD). The airways of patients suffering from COPD are infiltrated by various immune and inflammatory cells including macrophages, neutrophils, T lymphocytes, and dendritic cells. While the role of macrophages, neutrophils and T lymphocytes is well characterized, the contribution of dendritic cells to COPD pathogenesis is still the subject of emerging research. A paper by Botelho and colleagues in the current issue of Respiratory Research investigates the importance of dendritic cell recruitment in cigarette-smoke induced acute and chronic inflammation in mice. Dendritic cells of the healthy lung parenchyma and airways perform an important sentinel function and regulate immune homeostasis. During inflammatory responses the function and migration pattern of these cells is dramatically altered but the underlying mechanisms are incompletely understood. Botelho and colleagues demonstrate here the importance of IL-1R1/IL-1α related mechanisms including CCL20 production in cigarette-smoke induced recruitment of dendritic cells and T cell activation in the mouse lung.     

Design,synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β2-adrenoceptor agonists

A series of novel β₂-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β₂-adrenoceptor agonistic effects and high β₂/β₁-selectivity with EC₅₀ values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.     

脉冲震荡肺功能在稳定期COPD治疗中的应用价值

目的:探讨脉冲震荡肺功能(Impulse oscillometry,IOS)在稳定期COPD患者中应用价值及其和常规肺功能检测指标的相关性。方法:62例重度稳定期COPD患者,同时选择健康对照组人群40例纳入研究。经噻托溴铵联合沙美特罗替卡松治疗,将重度COPD患者缓解至中度。检测治疗前后常规肺功能指标(FEV1/FVC、FEV1)和IOS指标(ZRS、Fres、R5、X5、R20),分析常规肺功能指标和IOS各指标的相关性。结果:COPD患者FEV1和FEV1/FVC和对照组相比明显降低,差异有统计学意义(P0.05),观察组治疗后FEV1和FEV1/FVC明显改善,差异有统计学意义(P0.05)。观察组ZRS、Fres、R5、R20各项指标明显高于对照组,差异有统计学意义(P0.05);治疗后ZRS、Fres、R5明显改善,差异有统计学意义(P0.05)。FEV1、FEV1/FVC和ZRS、Fres、R5呈负相关性(P0.05),和X5呈正相关性(P0.05)。结论:脉冲震荡肺功能多项指标和传统肺功能指标有良好的相关性,是一种简便、低配合度、准确的的肺功能新的检测技术手段。     

Smoking and COPD increase sputum levels of extracellular superoxide dismutase

Extracellular superoxide dismutase (ECSOD) is the major superoxide-scavenging enzyme in the lung. Certain ECSOD polymorphisms are protective against COPD. We postulated that smokers and COPD subjects would have altered levels of ECSOD in the lung, airway secretions, and/or plasma. Lung tissue ECSOD was evaluated from nonsmokers, smokers, and subjects with mild to very severe COPD by Western blot, immunohistochemistry, and ELISA. ECSOD levels in plasma, bronchoalveolar lavage fluid (BALF), and induced-sputum supernatants were analyzed by ELISA and correlated with smoking history and disease status. Immunohistochemistry identified ECSOD in extracellular matrix around bronchioles, arteries, and alveolar walls, with decreases seen in the interstitium and vessels of severe COPD subjects using digital image analysis. Plasma ECSOD did not differ between COPD subjects and controls nor based on smoking status. ECSOD levels in induced sputum supernatants were elevated in current smokers and especially in COPD subjects compared to nonsmokers, whereas corresponding changes could not be seen in the BALF. ECSOD expression was reduced around vessels and bronchioles in COPD lungs. Substantial increases in sputum ECSOD in smokers and COPD is interpreted as an adaptive response to increased oxidative stress and may be a useful biomarker of disease activity in COPD.     

Discovery of substituted phenyl urea derivatives as novel long-acting β2-adrenoreceptor agonists

The synthesis of diverse functionalized ureas in a semi-parallel fashion is described, as well as their β₁/β₂-adrenergic activities and the corresponding structure-activity relationship (SAR). We have focused on lipophilicity and duration of action, and we have discovered a strong correlation in this series of molecules. A quantitative structure-activity relationship (QSAR) analysis will be presented that quantifies this relationship.     

Design,synthesis and evaluation of dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors

A novel series of formoterol–phthalazinone hybrids were synthesised and evaluated as dual pharmacology β₂-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β₂-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC₅₀ = 1.05 nM, pEC₅₀ = 9.0) and potent PDE4B2 inhibitory activities (IC₅₀ = 0.092 μM).     

COPD association and repeatability of blood biomarkers in the ECLIPSE cohort

Background

There is a need for biomarkers to better characterise individuals with COPD and to aid with the development of therapeutic interventions. A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE) cohort.

Methods

Thirty-four blood biomarkers were assessed in 201 subjects with COPD, 37 ex-smoker controls with normal lung function and 37 healthy non-smokers selected from the ECLIPSE cohort. Biomarker repeatability was assessed using baseline and 3-month samples. Intergroup comparisons were made using analysis of variance, repeatability was assessed through Bland-Altman plots, and correlations between biomarkers and clinical characteristics were assessed using Spearman correlation coefficients.

Results

Fifteen biomarkers were significantly different in individuals with COPD when compared to former or non-smoker controls. Some biomarkers, including tumor necrosis factor-α and interferon-γ, were measurable in only a minority of subjects whilst others such as C-reactive protein showed wide variability over the 3-month replication period. Fibrinogen was the most repeatable biomarker and exhibited a weak correlation with 6-minute walk distance, exacerbation rate, BODE index and MRC dyspnoea score in COPD subjects. 33% (66/201) of the COPD subjects reported at least 1 exacerbation over the 3 month study with 18% (36/201) reporting the exacerbation within 30 days of the 3-month visit. CRP, fibrinogen interleukin-6 and surfactant protein-D were significantly elevated in those COPD subjects with exacerbations within 30 days of the 3-month visit compared with those individuals that did not exacerbate or whose exacerbations had resolved.

Conclusions

Only a few of the biomarkers assessed may be useful in diagnosis or management of COPD where the diagnosis is based on airflow obstruction (GOLD). Further analysis of more promising biomarkers may reveal utility in subsets of patients. Fibrinogen in particular has emerged as a potentially useful biomarker from this cohort and requires further investigation.

Trial Registration

SCO104960, clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00292552","term_id":"NCT00292552"}}NCT00292552