慢性阻塞性肺疾病患者肺组织中基质金属蛋白酶抑制剂-1及基质金属蛋白酶-9与细胞黏附因子表达的关系

目的 研究COPD患者肺组织中基质金属蛋白酶抑制剂-1(TIMP-1)、基质金属蛋白酶-9(MMP-9)、细胞黏附因子-1(ICAM-1)蛋白和mRNA的分布和表达,探讨其与气流阻塞的关系及吸烟对其影响.方法 取39例因肺癌行肺叶切除的癌旁肺组织标本,其中不吸烟不伴COPD组(A组)9例、吸烟不伴COPD组(B组)11例、吸烟伴COPD组(C组)19例.用免疫组化和逆转录聚合酶链反应方法检测TIMP-1、MMP-9、ICAM-1的蛋白和mRNA表达,并进行相关性分析.结果 MMP-9表达于肺泡上皮细胞、支气管上皮细胞、血管平滑肌细胞、肺泡巨噬细胞、间质细胞,C组MMP-9免疫组化阳性细胞数(54.0±15.0)明显高于A组和B组(1.2±0.7和1.4±0.8);TIMP-1蛋白表达的主要部位为肺泡巨噬细胞、肺泡上皮细胞、毛细血管内皮细胞、血管平滑肌细胞,C组弱表达,A组和B组无表达;ICAM-1主要表达于肺泡上皮细胞,C组ICAM-1免疫组化阳性细胞数(52.1±13.4)明显高于A组和B组(2.1±1.1和4.5±2.4).C组MMP-9、TIMP-1、ICAM-1的mRNA平均吸光度值(0.71±0.16、0.47±0.10、0.62±0.15)明显高于A组(0.17±0.05、0.20±0.06、0.37±0.11)和B组(0.20±0.08、0.26±0.08、0.44±0.12).C组肺组织TIMP-1、MMP-9与ICAM-1的mRNA表达水平呈直线正相关,MMP-9与ICAM-1蛋白表达水平呈显著正相关.MMP-9和ICAM-1的mRNA及蛋白表达水平、TIMP-1的mRNA表达水平与FEV1占预计值%、FEV1/FVC占预计值%均呈显著负相关.结论 TIMP-1、MMP-9和ICAM-1在促进炎性细胞迁移进入细胞外基底膜及气道上皮细胞,导致肺组织破坏和重塑,引起及加重COPD患者的气流阻塞中起着重要作用.     

Matrix metalloproteinases -8, -9 and -12 in smokers and patients with Stage 0 COPD

COPD is underdiagnosed and its early assessment is problematic. It has been suggested that symptomatic smokers with normal FEV₁/FVC (Stage 0 COPD, GOLD criteria) can develop COPD in the future. Potential early biomarkers in COPD include the matrix metallo-proteinases (MMPs). It is not yet known, whether alterations in MMP expression are associated with smoking alone or with the risk of developing COPD. In this cross-sectional study MMP-8, MMP-9 and MMP-12 were determined from induced sputum and plasma by ELISA, immunocytochemistry, zymography, and/or Western blot in non-smokers (n = 32), smokers with symptoms (Stage 0, GOLD criteria) (n = 23) or without symptoms (n = 23). Only MMP-8 differentiated Stage 0 COPD from non-symptomatic smokers (p = 0.02). MMP-9 levels were significantly elevated in the induced sputum of non-symptomatic smokers and Stage 0 COPD (p = 0.01, p < 0.001) compared to non-smokers, but did not differ between the two subgroups of smokers. MMP-12 was higher only at Stage 0 compared to non-smokers (p = 0.04). MMP-8, MMP-9 and MMP-12 immunoreactivity was localized in macrophages and neutrophils, especially in smokers. MMP-8 levels correlated significantly with the small airway flow parameters (MEF50, MEF25) (p = 0.005 and p = 0.0004) and markers of neutrophil activation (myeloperoxidase, lactoferrin). In conclusion MMP-8 may differentiate Stage 0 from healthy smokers.     

COPD is associated with reduced pulmonary interstitial expression of pentraxin-3

Pentraxin (PTX)3 is involved in antimicrobial defence, apoptotic cell clearance and extracellular matrix stability. As these processes are altered in chronic obstructive pulmonary disease (COPD), we aimed to investigate PTX3 expression in patients with this disease. PTX3 expression was quantified by immunohistochemical staining of lung tissue from never-smokers, smokers without COPD, and in patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I, II and III-IV. mRNA expression was examined in total lung tissue by quantitative RT-PCR. PTX3 concentration was measured in induced sputum and plasma by ELISA. PTX3 is mainly localised in the interstitium of the small airways and alveolar walls. There were no significant differences in pulmonary, sputum and plasma PTX3 expression between study groups. However, PTX3 expression in small airways correlated significantly with forced expiratory volume in 1 s (r = 0.35, p = 0.004). In the alveolar walls, PTX3 expression correlated significantly with carbon monoxide transfer coefficient (r = 0.28, p = 0.04). In sputum, PTX3 levels were highly correlated with the number of neutrophils. Finally, systemic levels of PTX3 tended to be lower in severe COPD compared with mild COPD. In COPD, airflow limitation and reduced transfer coefficient for carbon monoxide are associated with lower pulmonary interstitial expression of PTX3.     

Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema.

This review covers protease-antiprotease imbalance in the development of emphysema in smokers. This imbalance is likely to play a major pathogenic role in the development of emphysema in subjects with severe alpha1-antitrypsin deficiency who smoke because of a deficient antiprotease protection against neutrophil elastase release in the lung. Neutrophil elastase is a potent elastolytic enzyme, and its instillation in the lungs of animals results in emphysema. Smoking attracts neutrophils to the lungs and there is an additional accumulation of neutrophils, because the abnormal antitrypsin polymerizes in the lungs and acts as a chemo-attractant to neutrophils. In subjects who do not have antitrypsin deficiency, the case for elastolytic injury by neutrophils causing emphysema is less definite, because of the lack of a severe deficiency of active alpha1-ntitrypsin leading to unopposed elastolysis by neutrophil elastase. It is likely that alveolar macrophages play a pathogenic role in emphysema; they express potent elastolytic enzymes, cathepsins and matrix metalloproteases (MMPs), which are induced by smoking. The numbers of macrophages are increased in the region of the respiratory bronchiole, where centrilobular emphysema develops in smokers. Macrophage cathepsins are inhibited by an antiprotease cystatin C, while the MMPs are inhibited by the tissue inhibitors of metalloproteases (TIMPs). Some pro-inflammatory mediators induce release of MMPs from macrophages without inducing increase in TIMPs, leading to possible protease-antiprotease imbalance. Studies of proteases in alveolar macrophages obtained by bronchoalveolar lavage and studies on lung tissue indicate increased protease expression in subjects with chronic obstructive pulmonary disease (COPD) compared to subjects without COPD.     

Emphysema detected by lung cancer screening with low-dose spiral CT: prevalence, and correlation with smoking habits and pulmonary function in Japanese male subjects

OBJECTIVE: Screening with low-dose spiral CT is a promising new tool for early lung cancer detection. A study was undertaken to assess the prevalence of emphysema detected by CT screening, and to assess the correlation between the extent of emphysema and the severity defined according to the recently published Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. METHODS: After informed consent, CT screening and pulmonary function tests were performed on 615 men between the ages of 40 and 69. Severity of emphysema was assessed visually. Only the pulmonary function data for male subjects were analysed because there were too few female subjects with emphysema. RESULTS: Emphysema was detected in 30.5% of current smokers, 14.1% of former smokers and 3.0% of non-smokers. In male current smokers, airflow obstruction (FEV(1)/FVC < 0.7) was seen in 18.1% of subjects with mild emphysema, and in 33.3% of subjects with moderate emphysema. FEV(1) values were less than 80% of the predicted normal in 8.5% of subjects with mild emphysema, and 28.6% of subjects with moderate emphysema. The percentage of male subjects with emphysema equivalent to GOLD stage 0 was 90.0% for subjects in their 40s, 82.5% for those in their 50s, and 68.2% for those in their 60s. CONCLUSION: A considerable percentage of the subjects with emphysema as detected by CT screening had GOLD stage 0. CT screening assists in detecting early-stage emphysema.     

Dynamic Contrast Enhanced Magnetic Resonance Perfusion Imaging in High-Risk Smokers and Smoking-Related COPD: Correlations with Pulmonary Function Tests and Quantitative Computed Tomography

The study aimed to prospectively evaluate correlations between dynamic contrast-enhanced (DCE) MR perfusion imaging, pulmonary function tests (PFT) and volume quantitative CT in smokers with or without chronic obstructive pulmonary disease (COPD) and to determine the value of DCE-MR perfusion imaging and CT volumetric imaging on the assessment of smokers. According to the ATS/ERS guidelines, 51 male smokers were categorized into five groups: At risk for COPD (n = 8), mild COPD (n = 9), moderate COPD (n = 12), severe COPD (n = 10), and very severe COPD (n = 12). Maximum slope of increase (MSI), positive enhancement integral (PEI), etc. were obtained from MR perfusion data. The signal intensity ratio (R_SI) of the PDs and normal lung was calculated (R_SI = SI_PD/SI_normal). Total lung volume (TLV), total emphysema volume (TEV) and emphysema index (EI) were obtained from volumetric CT data. For “at risk for COPD,” the positive rate of PDs on MR perfusion images was higher than that of abnormal changes on non-enhanced CT images (p < 0.05). Moderate-to-strong positive correlations were found between all the PFT parameters and SI_PD, or R_SI (r range 0.445～0.683, p ≤ 0.001). TEV and EI were negatively correlated better with FEV₁/FVC than other PFT parameters (r range ?0.48 –?0.63, p < 0.001). There were significant differences in R_SI and SI_PD between “at risk for COPD” and “very severe COPD,” and between “mild COPD” and “very severe COPD”. Thus, MR perfusion imaging may be a good approach to identify early evidence of COPD and may have potential to assist in classification of COPD.     

Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization

Factors modulating the variable progression of chronic obstructive pulmonary disease (COPD) are largely unknown, but infectious agents may play a role. Because Pneumocystis has previously been shown to induce a CD8(+) lymphocyte- and neutrophil-predominant response similar to that in COPD, we explored the association of the organism with accelerated disease progression. We examined Pneumocystis colonization rates in lung tissue obtained during lung resection or transplantation in smokers with a range of airway obstruction severity and in a control group with lung diseases other than COPD. Using nested polymerase chain reaction, Pneumocystis colonization was detected in 36.7% of patients with very severe COPD (Global Health Initiative on Obstructive Lung Disease [GOLD] Stage IV) compared with 5.3% of smokers with normal lung function or less severe COPD (Stages 0, I, II, and III) (p = 0.004) and with 9.1% of control subjects (p = 0.007). Colonized subjects exhibited more severe airway obstruction (median FEV(1) = 21% predicted versus 62% in noncolonized subjects, p = 0.006). GOLD IV was the strongest predictor of Pneumocystis colonization (odds ratio = 7.3, 95% confidence interval = 2.4-22.4, p < 0.001) and was independent of smoking history. We conclude that there is a strong association between Pneumocystis colonization and severity of airflow obstruction in smokers, suggesting a possible pathogenic link with COPD progression.     

Matrix metalloproteinase-9 promoter polymorphism associated with upper lung dominant emphysema

RATIONALE: Matrix metalloproteinase 9 (MMP-9) has proteolytic activity against connective tissue proteins and appears to play an important role in the development of chronic obstructive pulmonary disease (COPD). The functional polymorphism of MMP-9 (C-1562T) is considered as one of the candidate genes in the susceptibility to COPD. OBJECTIVES: To determine if MMP-9 (C-1562T) is related to the development of COPD in the Japanese population and whether it is associated with development of pulmonary emphysema assessed by high-resolution computed tomographic (HRCT) parameters. METHODS: MMP-9 (C-1562T) genotypes of 84 patients with COPD and 85 healthy smokers (control subjects) were determined by the restriction fragment length polymorphism method. We investigated the relationship between the genotypes using automatically analyzed HRCT parameters, such as percentage of low attenuation area (LAA%) and average computed tomography (CT) value density (Hounsfield units; mean CTv) in upper, middle, and lower lung fields in all patients with COPD. MEASUREMENTS AND MAIN RESULTS: There was no difference in polymorphism of MMP-9 (C-1562T) between patients with COPD and control subjects. In the HRCT study, patients with COPD with a T allele (C/T or T/T) showed larger LAA% (95% confidence interval of difference, 0.5-18.7; p = 0.04), and smaller mean CTv (confidence interval, -34.3 to -1.0; p = 0.04) in the upper lung compared with patients without T alleles (C/C). However, pulmonary function tests showed no difference between the two patient groups. Patients with a T allele showed a decrease in LAA% and an increase in mean CTv from upper to lower lung fields (p = 0.006 and p = 0.002, respectively). CONCLUSIONS: Polymorphism of MMP-9 (C-1562T) was associated with upper lung dominant emphysema in patients with COPD.     

慢性阻塞性肺疾病病患的认知功能探讨

目的评估慢性阻塞性肺疾病(慢阻肺)病患的认知功能状态,以及与临床资料的相关性。方法从2014年10月-2018年12月,160例符合标准的受试者入组;认知评估使用蒙特利尔(MoCA)量表,获取临床资料并完成相关性分析。结果约46%的慢阻肺病患存在认知功能障碍。四组受试者的MOCA总分为:健康对照组26.47±1.31、慢阻肺病患轻度组24.77±2.61、中度组22.39±3.64、重度组21.92±2.65;相比对照组,慢阻肺受试者的认知得分降低(p<0.05),表现在注意、定向、抽象思维、延迟记忆、视空间与执行功能。组间比较亦有统计学差异;同时慢阻肺受试者的MoCA总分和肺功能中FEV 1有正相关(r=0.377,P<0.001),与血气分析中PaO 2有正相关性(r=0.295,P<0.05),与PaCO 2无相关性(r=0.059,P>0.05)。结论慢阻肺病患存在特定的认知障碍。低氧血症、肺功能中的FEV 1降低可能是造成慢阻肺认知障碍的病理生理学机制。     

A distinctive alveolar macrophage activation state induced by cigarette smoking

RATIONALE: Macrophages are believed to play a central role in emphysema based largely on data from mouse models. However, the relevance of these models to smoking-related lung disease in humans is uncertain. OBJECTIVES: We sought to comprehensively characterize the effects of smoking on gene expression in human alveolar macrophages and to compare these with effects seen in transgenic mouse models of emphysema. METHODS: We used DNA microarrays with genomewide coverage to analyze alveolar macrophages from 15 smokers, 15 nonsmokers, and 15 subjects with asthma (disease control). Selected gene expression changes were validated by polymerase chain reaction and ELISA. Expression changes were compared with those identified by microarray analysis of interleukin-13-overexpressing and integrin-beta6-deficient mice, which both develop emphysema. MEASUREMENTS AND MAIN RESULTS: All 15 smokers shared a common pattern of macrophage gene expression that distinguished them from nonsmokers, a finding not observed in subjects with asthma. We identified 110 genes as differentially expressed in smokers despite using conservative statistical methods. Matrix metalloproteinase 12, a proteinase that plays a critical role in mouse models, was the third most highly induced gene in smokers (ninefold, p < 0.0001). However, most changes in smokers were not reflected in mouse models. One such finding was increased osteopontin expression in smokers (fourfold, p = 0.006), which was confirmed at the protein level and correlated with the degree of airway obstruction. CONCLUSIONS: Smoking induces a remarkably consistent and distinctive pattern of alveolar macrophage activation. These studies identify aspects of mouse models that are directly relevant to human smokers and also reveal novel potential mediators of smoking-related diseases.     

Subphenotypes of Mild-to-Moderate COPD by Factor and Cluster Analysis of Pulmonary Function,CT Imaging and Breathomics in a Population-Based Survey

Abstract

Introduction: Classification of COPD is currently based on the presence and severity of airways obstruction. However, this may not fully reflect the phenotypic heterogeneity of COPD in the (ex-) smoking community. We hypothesized that factor analysis followed by cluster analysis of functional, clinical, radiological and exhaled breath metabolomic features identifies subphenotypes of COPD in a community-based population of heavy (ex-) smokers. Methods: Adults between 50–75 years with a smoking history of at least 15 pack-years derived from a random population-based survey as part of the NELSON study underwent detailed assessment of pulmonary function, chest CT scanning, questionnaires and exhaled breath molecular profiling using an electronic nose. Factor and cluster analyses were performed on the subgroup of subjects fulfilling the GOLD criteria for COPD (post-BD FEV₁/FVC < 0.70). Results: Three hundred subjects were recruited, of which 157 fulfilled the criteria for COPD and were included in the factor and cluster analysis. Four clusters were identified: cluster 1 (n = 35; 22%): mild COPD, limited symptoms and good quality of life. Cluster 2 (n = 48; 31%): low lung function, combined emphysema and chronic bronchitis and a distinct breath molecular profile. Cluster 3 (n = 60; 38%): emphysema predominant COPD with preserved lung function. Cluster 4 (n = 14; 9%): highly symptomatic COPD with mildly impaired lung function. In a leave-one-out validation analysis an accuracy of 97.4% was reached. Conclusions: This unbiased taxonomy for mild to moderate COPD reinforces clusters found in previous studies and thereby allows better phenotyping of COPD in the general (ex-) smoking population.     

Prevalence and underdiagnosis of COPD by disease severity and the attributable fraction of smoking Report from the Obstructive Lung Disease in Northern Sweden Studies

BACKGROUND: There is a lack of epidemiological data on COPD by disease severity. We have estimated the prevalence and underdiagnosis of COPD by disease severity defined by the British Thoracic Society (BTS) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. The impact of smoking was evaluated by the population attributable fraction of smoking in COPD. METHODS: A random sample of 1500 responders of the third postal survey performed in 1996 of the Obstructive Lung Disease in Northern Sweden (OLIN) Studies' first cohort (6610 subjects recruited in 1985) were invited to structured interview and spirometry. One thousand two hundred and thirty-seven subjects (82%) performed spirometry. RESULTS: The prevalence of mild BTS-COPD was 5.3%, moderate 2.2%, and severe 0.6% (GOLD-COPD: mild 8.2%, moderate 5.3%, severe 0.7%, and very severe 0.1%). All subjects with severe COPD were symptomatic, corresponding figures among mild COPD were 88% and 70% (BTS and GOLD), Subjects with severe BTS-COPD reported a physician-diagnosis consistent with COPD in 50% of cases, in mild BTS-COPD 19%, while in mild GOLD-COPD only 5% of cases. The major risk factors, age and smoking, had a synergistic effect on the COPD-prevalence. The Odds Ratio (OR) for having COPD among smokers aged 76-77 years was 59 and 34 (BTS and GOLD) when non-smokers aged 46-47 was used as reference population. CONCLUSIONS: Most subjects with COPD have a mild disease. The underdiagnosis is related to disease-severity. Though being symptomatic, only a half of the subjects with severe COPD are properly labelled. Smoking and increasing age were the major risk factors and acted synergistic.     

All-trans retinoic acid modulates the balance of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with emphysema

STUDY OBJECTIVE: The balance between proteases and antiproteases plays an essential role in the pathogenesis of emphysema. This study was designed to evaluate the impact of all-trans retinoic acid (ATRA) on the balance of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with emphysema. DESIGN AND SETTING: As part of a clinical study, ATRA was administered to 20 patients with emphysema for 12 weeks and evaluated for its effects on plasma levels of MMP-9 and TIMP-1. Plasma MMP-9 levels were also measured in a separate cohort of patients with emphysema and matched control subjects to evaluate the relationship of circulating enzyme levels to lung disease. To further investigate the effects of ATRA on protease activity within the lung microenvironment, alveolar macrophages (AM) recovered from the lungs of active smokers with COPD were cultured with ATRA in vitro. MEASUREMENTS AND RESULTS: Administration of ATRA to patients with emphysema produced a 45 +/- 14% reduction (mean +/- SEM) in plasma MMP-9 by enzyme-linked immunosorbent assay and a similar reduction in MMP-9 enzyme activity, while having little effect on TIMP-1 levels. Baseline MMP-9 levels were higher in patients with emphysema compared to nonsmoking control subjects, suggesting a relationship between plasma levels and the presence of lung disease. In vitro, concentrations of ATRA similar to those achieved in the plasma of study subjects significantly reduced both the production and enzyme activity of MMP-9 by AM. In the same experiments, TIMP-1 levels increased significantly, resulting in a marked reduction in the MMP-9/TIMP-1 molar ratio. CONCLUSION: We conclude that ATRA can modulate protease/antiprotease balance in a manner that may impact on disease pathogenesis.     

Correlation of C-reactive protein with disease severity in CT diagnosed emphysema

Background and objective:   Recent studies suggest that CRP levels are related to airflow obstruction. However, limited data exist on the relevance of CRP levels in individuals with or without emphysema. The aim of this study was to assess the relationship between the extent of emphysema, COPD severity and serum CRP levels.
Methods:   Lung function tests and high-sensitivity CRP were examined in 651 males with stable disease who underwent CT screening for lung cancer. CRP levels were examined cross-sectionally in individuals with various degrees of emphysema and in those without emphysema.
Results:   Emphysema was detected in 179 (34.7%) of 516 current smokers. Airflow obstruction was observed in 47 (28.8%) of 163 smokers with mild emphysema, in eight (57.1%) of 14 smokers with moderate emphysema, and in two of two individuals with severe emphysema. CRP levels were not higher in individuals with mild or moderate emphysema compared with individuals without emphysema. Among 98 individuals with airflow obstruction (19.0% of the 516 current smokers), there was a modest correlation between CRP levels and FEV₁%.
Conclusions:   The severity of COPD varied in individuals with similar degrees of emphysema. CRP levels were not significantly higher in individuals with mild or moderate emphysema compared with individuals without emphysema but CRP levels were modestly correlated with FEV₁% among individuals with airflow obstruction.     

Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema

The lung pathology of severe chronic obstructive pulmonary disease (COPD) has been poorly investigated. We examined surgical specimens obtained from patients with severe (forced expiratory volume in 1 second [FEV(1)] = 29 +/- 3% predicted, n = 9) or mild/no airflow limitation (FEV(1) = 86 +/- 5% predicted, n = 9) and similar smoking history. With histochemical and immunohistochemical methods we quantified the structural changes and the inflammatory cells in small airways and in muscular pulmonary arteries. As compared with smokers with mild/no COPD, smokers with severe COPD had an increased number of leukocytes in the small airways, which showed a positive correlation with the radiologic score of emphysema and with the value of residual volume, and a negative correlation with the values of FEV(1) and carbon monoxide diffusing capacity. The inflammatory process was characterized by an increase in CD8(+) and CD4(+) T-lymphocytes in the airway wall and by an increase in macrophages in the airway epithelium. When all smokers were considered together, the smoking history was correlated with both the airway wall and smooth muscle thickness, suggesting that smoking itself may play a role in the development of structural changes. No structural and cellular differences were observed in pulmonary arteries between smokers with severe COPD and smokers with mild/no COPD. In conclusion, in the small airways of smokers with severe COPD, there is an increased number of leukocytes, which is correlated with reduced expiratory flow, lung hyperinflation, carbon monoxide diffusion impairment, and radiologic emphysema, suggesting a role for this inflammatory response in the clinical progression of the disease.     

Pathophysiology of Evolution of Small Airways Disease to Overt COPD

ABSTRACT

Background: The slope of phase III (single breath nitrogen test), an index of ventilation inhomogeneity, has been used for early detection of COPD. Tidal airway closure (cyclic opening and closure of the peripheral airways during tidal breathing; AC_T) and expiratory flow limitation (attainment of maximal expiratory flow during tidal expiration; EFL_T) cause small airways disease (SAD). The relationships of these indices with COPD severity may reflect the progress from SAD to overt COPD. Methods: In this cross-sectional study we have assessed for the first time the phase III slope, AC_T and EFL_T in 10 smokers with normal spirometry (group O) and 40 COPD patients with GOLD scores from I to IV. Results: In most group O smokers the phase III slope was increased, and further increased with GOLD severity (up to 800%pred in GOLD IV). A close correlation was found of slope with GOLD (r = 0.77). AC_T was absent in smokers with normal spirometry and in most patients with mild COPD. EFL_T first appeared in GOLD II patients and its prevalence progressively increased in GOLD III and IV patients. Conclusions: Most group O smokers exhibit increased phase III. With overt COPD there is a progressive increase in phase III and reduction of FEV₁/FVC ratio from GOLD I to IV. A reduction of FEV₁ occurs from GOLD stage II. As the disease progresses from moderate to severe, there is an increasing presence of AC_T. Tidal EFL, with dynamic hyperinflation and severe dyspnea is present only in GOLD III and IV.     

Clara cell 16 protein in COPD sputum: A marker of small airways damage?

RATIONALE: The development of chronic obstructive pulmonary disease (COPD) in smokers and their susceptibility to infections is not fully understood. Recent evidences suggest that Clara cells play a part in host defense, immunomodulatory response and airways remodelling through the production of specific factors such as Clara cell 16 (CC-16). This protein has never been related to patients' lung function tests, blood gases parameters and diseases severity. OBJECTIVES: To evaluate a possible correlation between CC-16 expression in sputum, measured by a new methodological approach, and the degree of severity in patients with moderate and severe COPD. We also analyzed possible correlations between CC-16 and cytological sputum population, arterial blood gases and lung function. MAIN FINDINGS: We analyzed 20 patients, mean age 72.95, classified on the basis of the global initiative for chronic obstructive lung disease guidelines (GOLD 2006). The samples were processed for cytological analysis and CC-16 levels were assessed by Western blot. We found lower levels of CC-16 in severe COPD compared to moderate ones (p<0.027). No statistically significant differences were found between CC-16 expression and sputum cellularity (except for macrophages), arterial blood gases, and spirometric parameters. Multiple linear regression analysis of CC-16 versus functional and cytological parameters showed no significance. CONCLUSIONS: We found a significantly different expression of CC-16 in COPD patients, according to their stage of severity, as defined by the GOLD 2006 guidelines. Considering CC-16 properties in innate immunity, a possible link between protein expression, innate immune system, and COPD infectious exacerbations may be hypothesized but further investigation are needed.     

Alphabet Soup: Assessment of Dyspnea

Abstract

The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring. Methods: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9–11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements. Results: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively. Conclusions: Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.     

Alveolar cell senescence in patients with pulmonary emphysema

RATIONALE AND OBJECTIVES: The prevalence of chronic obstructive pulmonary disease (COPD) is age-dependent, suggesting an intimate relationship between the pathogenesis of COPD and aging. In this study we investigated whether the senescence of alveolar epithelial and endothelial cells is accelerated in emphysematous lungs. METHODS: Samples of lung tissue were obtained from patients with emphysema, asymptomatic smokers, and asymptomatic nonsmokers. Paraffin-embedded lung tissue sections were evaluated for cellular senescence by quantitative fluorescence in situ hybridization to assess telomere shortening, and by immunohistochemistry to assess the expression of senescence-associated cyclin-dependent kinase inhibitors. Tissue sections were also immunostained for proliferating cell nuclear antigen (PCNA), surfactant protein A, and CD31. MAIN RESULTS: The patients with emphysema had significantly higher percentages of type II cells positive for p16INK4a and p21CIP1/WAF1/Sdi1 than the asymptomatic smokers and nonsmokers. They had also significantly higher percentages of endothelial cells positive for p16INK4a than the asymptomatic smokers and nonsmokers, and higher percentages of endothelial cells positive for p21CIP1/WAF1/Sdi1 than the asymptomatic nonsmokers. Telomere length in alveolar type II cells and endothelial cells was significantly shorter in the patients with emphysema than in the asymptomatic nonsmokers. The level of p16INK4a expression was negatively correlated with the level of PCNA expression. The level of alveolar cell senescence was positively correlated with airflow limitation. CONCLUSIONS: These results suggest that the senescence of alveolar epithelial and endothelial cells is accelerated in patients with emphysema. Cellular senescence may explain the abnormal cell turnover that promotes the loss of alveolar cells in emphysematous lungs.