Rationale: Chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and mortality from cardiovascular disease. Although a close association between COPD and atherosclerosis has been speculated, such scientific information is limited. Objectives: To evaluate subclinical atherosclerosis in smokers with airflow limitation. Methods: The subjects of this study were healthy middle-aged men. Smokers with airflow limitation (n = 61) and age-matched control smokers (n = 122) and control never-smokers (n = 122) without airflow limitation were included in the present study. Subjects with diabetes, acute infection, and respiratory disease other than COPD were excluded beforehand. All subjects underwent chest radiogram, spirometry, blood sampling, and carotid ultrasonography. We determined carotid intima-media thickness and focal atheromatous plaque as indicators of subclinical atherosclerosis. Measurements and Main Results: Mean carotid intima-media thickness was greater in smokers with airflow limitation than in control smokers (P < 0.01) and control never-smokers (P < 0.005). Focal carotid plaque was significantly more prevalent in smokers with airflow limitation than in control never-smokers (P < 0.005). Multivariate analyses showed significant associations between thickened intima-media thickness and decreased percent predicted FEV1 (P = 0.001) and between plaque and log10 C-reactive protein (P = 0.013) independent of age, pack-years of smoking, body mass index, peripheral mean arterial pressure, heart rate, glucose, and low-density lipoprotein cholesterol. Conclusions: Smokers with airflow limitation had exaggerated subclinical atherosclerosis. This study suggests that middle-aged men who are susceptible to COPD may also be susceptible to vascular atherosclerosis by smoking, and atherosclerotic change starts early in the disease process of COPD.

The pathophysiological features of chronic obstructive pulmonary disease(COPD)–asthma overlap are poorly understood and there has been no study of plasma or sputum biomarkers in overlap patients. In order to clarify the similarity and differences between overlap and COPD or asthma, we have investigated four potential biomarkers of COPD: surfactant protein A (SP-A), soluble receptor for advanced glycation end-products (sRAGE), myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL). SP-A and sRAGE are pneumocyte-derived markers. MPO and NGAL are neutrophil-derived molecules, but NGAL can also be expressed by respiratory epithelial cells.Plasma levels of SP-A and sRAGE and induced sputum levels of MPO and NGAL were measured by enzyme immunoassay/ELISA in 134 subjects: nonsmokers (n=26), smokers (n=23), asthma (n=32), COPD (n=39) and COPD–asthma overlap patients (n=14).In patients with COPD–asthma overlap, sputum MPO and plasma SP-A were significantly elevated whereas plasma sRAGE levels were reduced compared with asthma patients. Only sputum NGAL was significantly elevated in COPD–asthma overlap compared with COPD (p=0.00016) and could be used to differentiate patients with overlap from those with COPD.Increased induced sputum levels of NGAL might be a characteristic feature of overlap, suggesting enhanced neutrophilic airway inflammation and/or airway epithelial injury in COPD–asthma overlap.

Background.Recent reports indicate that matrix metalloproteinase-7 (MMP-7) and CC-chemokine ligand 18 (CCL18) are potential disease markers of idiopathic pulmonary fibrosis (IPF). The objective of this study was to perform direct comparisons of these two biomarkers with three well-investigated serum markers of IPF, Krebs von den Lungen-6 (KL-6), surfactant protein-A (SP-A), and SP-D.Methods.The serum levels of MMP-7, CCL18, KL-6, SP-A, and SP-D were evaluated in 65 patients with IPF, 31 patients with bacterial pneumonia, and 101 healthy controls. The prognostic performance of these five biomarkers was evaluated in patients with IPF.Results.The serum levels of MMP-7, KL-6, and SP-D in patients with IPF were significantly elevated compared to those in patients with bacterial pneumonia and in the healthy controls. Multivariate survival analysis showed that serum MMP-7 and KL-6 levels were independent predictors in IPF patients. Moreover, elevated levels of both KL-6 and MMP-7 were associated with poorer survival rates in IPF patients, and the combination of both markers provided the best risk discrimination using the C statistic.Conclusions.The present results indicated that MMP-7 and KL-6 were promising prognostic markers of IPF, and the combination of the two markers might improve survival prediction in patients with IPF.

Preserved ratio impaired spirometry (PRISm) is defined by reduced FEV₁ with a preserved FEV₁/FVC ratio; some individuals with PRISm can also have restrictive ventilatory abnormality. The aim of this study was to clarify clinical features of restrictive and non-restrictive PRISm. In total, 11,246 participants (mean, 49.1 years; range, 35–65 years) from five healthcare centres were included in this study. We evaluated baseline characteristics of participants with restrictive PRISm (FEV₁/FVC ≥ 0.7, FEV₁ < 80% and FVC < 80%) and non-restrictive PRISm (FEV₁/FVC ≥ 0.7, FEV₁ < 80% and FVC ≥ 80%), and airflow obstruction (FEV₁/FVC < 0.7). We examined the longitudinal risk of developing airflow obstruction by comparing spirometry results at baseline and 5 years post-baseline among 2141 participants. Multivariate analysis demonstrated that a history of asthma or smoking could constitute an independent risk factor for non-restrictive PRISm, and that non-restrictive PRISm was independently associated with the risk of developing airflow obstruction. In contrast, female sex, advanced age, and high BMI, but not history of asthma or smoking, were risk factors for restrictive PRISm. Restrictive PRISm was not associated with the development of airflow obstruction. In conclusion, our results indicate that PRISm can be categorized according to the presence or absence of restrictive abnormality. Non-restrictive PRISm, which does not meet the conventional criteria of obstructive and restrictive ventilatory abnormalities, may be a precursor of chronic obstructive pulmonary disease and merits increased monitoring.

Although currently available asthma medications are very effective in the majority of cases, there remains a subgroup for which disease control is difficult. Anticholinergics have long been used to treat asthma, although their current role in therapy is supplementary 1. Tiotropium bromide, a recently developed anticholinergic, is a long-acting bronchodilator with a well-established effectiveness for treating chronic obstructive pulmonary disease 2. Although some subgroups of asthmatics seem to respond better to anticholinergics, the pathophysiological features of these responders have yet to be established 3, 4. Previous studies that aimed to identify asthma subgroups which respond better to anticholinergics have suggested the following clinical features: patients with nocturnal symptoms, chronic asthma showing concurrent fixed airway obstruction, intrinsic asthma with longer duration of disease and nonatopic asthma 1, 5. The objective of the present study was to determine the characteristics of asthmatics which show good responses to tiotropium bromide.

The receptor for advanced glycation end-products (RAGE) is highly expressed in the lung, where it is believed to have a homeostatic role. Reduced plasma levels of soluble RAGE (sRAGE) have been reported in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the association of plasma sRAGE levels with a longitudinal decline of lung function. We have also measured plasma levels of high mobility group box 1 (HMGB1), a RAGE ligand which has been associated with chronic inflammatory diseases including COPD.