Association between plasma adiponectin levels and decline in forced expiratory volume in 1 s in a general Japanese population: the Takahata study.

BACKGROUND: Adiponectin is an anti-inflammatory and cardio-protective cytokine. However, several studies have demonstrated that plasma adiponectin levels were inversely associated with pulmonary function in patients with chronic obstructive pulmonary disease, suggesting a proinflammatory or pulmonary-destructive role. It is still unclear whether adiponectin is a potent biomarker predicting declines in pulmonary function. The aim of this study was to investigate the association between adiponectin and pulmonary function among Japanese individuals who participated in an annual health check-up. METHODS: Spirometry and blood sampling, including measurements of plasma adiponectin, were performed for 3,253 subjects aged 40 years or older who participated in a community-based annual health check-up in Takahata, Japan from 2004 to 2006. In 2011, spirometry was re-performed, and the data from 872 subjects (405 men and 467 women) were available for a longitudinal analysis. RESULTS: Plasma adiponectin levels were found to be significantly associated with age, body mass index (BMI), and alanine aminotransferase (ALT), triglycerides (TG), and high-density lipoprotein-cholesterol (HDL-c) levels among both men and women in the study population. Plasma adiponectin levels were found to be associated with lifetime cigarette consumption (Brinkman index, BI) in men only. Plasma adiponectin levels were inversely correlated with forced expiratory volume in 1 s (FEV1) per forced vital capacity in both men and women. In addition, the annual change in FEV1 was inversely associated with plasma adiponectin levels in both genders. A multiple linear regression analysis revealed that this association was independent of other confounding factors such as age, BMI, BI, ALT, TG, and HDL-c. CONCLUSIONS: The results of the present study suggest that adiponectin levels are predictive of declines in FEV1 in the general population.

Hyperhomocysteinaemia predicts the decline in pulmonary function in healthy male smokers.

Hyperhomocysteinaemia is associated with chronic obstructive pulmonary disease. However, the relationship between plasma homocysteine levels and spirometric measures has not been investigated in a general population. We aimed to determine whether homocysteine levels are predictive for a rapid decline in lung function among healthy current smokers. Blood sampling and spirometry were performed on subjects participating in a community-based annual health check in Takahata, Japan, from 2004 to 2006 (n=3257). Spirometry was re-evaluated in 147 male current smokers in 2009. On initial assessment, forced vital capacity (FVC) % predicted and forced expiratory volume in 1 s (FEV1) % predicted correlated inversely with homocysteine levels and were predictive for homocysteine levels, independent of various clinical factors. Homocysteine levels were higher in subjects with restrictive, obstructive or mixed ventilatory disorders. In addition, homocysteine levels were higher in subjects with mixed ventilatory disorders, compared with restrictive or obstructive disorders. On follow-up, subjects showing a decline in FEV1 had higher homocysteine levels than those who did not. Logistic regression analysis indicated that homocysteine levels were predictive for a decline in FEV1. FVC % pred and FEV1 % pred were significantly associated with homocysteine levels, and hyperhomocysteinaemia predicted the annual rate of decline in FEV1 among male smokers.

Retrospective analysis of the relationship between decline in FEV(1) and abdominal circumference in male smokers: the Takahata study.

BACKGROUND: Metabolic syndrome (Mets) is reportedly associated with chronic obstructive pulmonary disease (COPD). However, the relationship between abdominal circumference (AC) and decline in FEV(1) has not been elucidated. We aimed to investigate this relationship among male current smokers. METHODS: Spirometry was performed on subjects (n = 3,257) ≥ 40 years of age, who participated in a community-based annual health check in Takahata, Japan, from 2004 through 2006 (visit 1). Spirometry was re-evaluated, and AC was assessed in 147 of the male current smokers in 2009 (visit 2). The diagnosis of Mets was based on the criteria used in the Hisayama Study. RESULTS: No significant relationships were observed between AC and spirometric parameters such as % predicted forced vital capacity (FVC), % predicted forced expiratory volume in 1 s (FEV(1)) and FEV(1)/FVC. However, decline in FEV(1) was significantly correlated with AC. Multivariate logistic regression analysis showed that AC was a significant discriminating factor for decline in FEV(1), independently of age, Brinkman index and change in body mass index from visit 1 to visit 2. At visit 2, there was a greater prevalence of decline in FEV(1) among subjects with Mets (n=17) than among those without Mets. Although there were no differences in % predicted FVC, % predicted FEV(1) or FEV(1)/FVC between subjects with or without Mets, the rate of decline in FEV(1) was significantly greater in subjects with Mets than in those without. CONCLUSIONS: This retrospective analysis suggested that measuring AC may be useful for discriminating male smokers who show a decline in FEV(1).

Relationship between plasma fibrinogen levels and pulmonary function in the japanese population: the Takahata study.

BACKGROUND: Plasma fibrinogen is considered a biomarker of respiratory disease, owing to the relationship between plasma fibrinogen and pulmonary function established in Western populations. However, such a relationship has not yet been confirmed in an Asian population. We assessed this relationship in the general Japanese population. METHODS: Totally, 3,257 men and women aged ≥40 years who participated in a community-based annual health checkup in Takahata, Japan, from 2004 to 2006, underwent spirometry, and their plasma fibrinogen levels were determined. RESULTS: We found an inverse relationship between spirometric measures (percent predicted forced vital capacity [%FVC] and forced expiratory volume in 1s [%FEV1], and FEV1/FVC) and plasma fibrinogen levels in men, but not in women. The plasma fibrinogen levels were significantly higher in subjects with restrictive, obstructive, and mixed ventilatory disorders than in those with normal spirometry results. Multiple linear regression analysis revealed that in men, plasma fibrinogen levels were predictive for %FVC and %FEV1 (independent of age, body mass index, and cigarette smoking) but not for FEV1/FVC. CONCLUSIONS: Plasma fibrinogen was significantly associated with pulmonary function in Japanese men, and as such, plasma fibrinogen might be a potent biomarker for pulmonary dysfunction in men.

Soluble endothelial selectin in acute lung injury complicated by severe pneumonia.

BACKGROUND: Pneumonia is still one of the most frequent causes of death in the elderly. Complication of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) by pneumonia makes patients very ill due to severe respiratory failure. Biomarkers that can discriminate the presence of complicating ALI/ARDS are required for early detection. The aim of this research was to investigate whether soluble endothelial selectin (sES) could be a biomarker for ALI. METHODS: Serum sES levels were measured in 27 pneumonia patients, who were enrolled between April 2006 and September 2007. Among these patients, six had ALI or a condition that was clinically comparable to ALI (cALI). All patients who were enrolled were successfully treated and survived. RESULTS: Circulating sES levels were elevated in pneumonia patients with ALI/cALI, and sES levels decreased following treatment of their pneumonia. Univariate and multivariate logistic regression analyses showed that sES was the only significant factor for identifying complicating ALI/cALI, independently of C-reactive protein (CRP) and lactate dehydrogenase (LDH). By receiver operating characteristic (ROC) curve analysis, the cut-off value for sES was 40.1 ng/mL, with a sensitivity of 0.8 and a specificity of 0.8. CONCLUSION: sES may be a useful biomarker for discriminating complicating ALI/cALI in patients with severe pneumonia.

Impairment of pulmonary function is an independent risk factor for atrial fibrillation: the Takahata study.

BACKGROUND: Chronic pulmonary disorders, such as chronic obstructive pulmonary disease (COPD) and fibrosing lung diseases, and atrial fibrillation (AF), are prevalent in elderly people. The impact of cardiac co-morbidities in the elderly, where pulmonary function is impaired, cannot be ignored as they influence mortality. The relationship between the prevalence of AF and pulmonary function is unclear. The aim of this study was to evaluate this relationship in participants in a health check. METHODS: Subjects aged 40 or older (n = 2,917) who participated in a community-based annual health check in Takahata, Japan, from 2004 through to 2005, were enrolled in the study. We performed blood pressure measurements, blood sampling, electrocardiograms, and spirometry on these subjects. RESULTS: The mean FEV(1) % predicted and FVC % predicted in AF subjects was significantly lower than in non-AF subjects. The prevalence of AF was higher in those subjects with airflow limitation or lung restriction than in those without. Furthermore, AF prevalence was higher in those subjects with severe airflow obstruction (FEV(1) %predicted < 50) than in those who had mild or moderate airflow obstruction (FEV(1) %predicted ≥ 50), although there was no difference between the prevalence of AF in subjects with 70≤ FVC %predicted <80 lung restriction and those with FVC %predicted <70. Multiple logistic regression analysis revealed that FEV(1) %predicted and FVC %predicted are independent risk factors for AF (independent of age, gender, left ventricular hypertrophy, and serum levels of B-type natriuretic peptide). CONCLUSION: Impaired pulmonary function is an independent risk factor for AF in the Japanese general population.

The relationship between serum uric acid and spirometric values in participants in a health check: the Takahata study.

BACKGROUND: Tissue hypoxia induces the degradation of adenosine triphosphate, resulting in the production of uric acid (UA). Patients with chronic obstructive pulmonary disease (COPD) have been reported to have high serum levels of UA (sUA), compared with control subjects. However, the relationship between sUA levels and spirometric measures has not been investigated in detail in a general population. METHODS: Subjects aged 40 years or older (n = 2,917), who had participated in a community-based annual health check in Takahata, Japan, in 2004 and 2005, were enrolled in the study. These subjects performed spirometry, their blood pressure was measured, and a blood sample was taken. RESULTS: sUA levels were significantly higher in males than in females. Percent predicted forced vital capacity [FVC %predicted] (r = -0.13) and forced expiratory volume in 1 s [FEV(1) %predicted] (r = -0.118) were inversely correlated with sUA levels in females but not in males. Univariate regression analysis indicated that age, body mass index (BMI), ethanol intake, mean blood pressure (BP), and serum creatinine (sCr) were significantly associated with sUA levels in males. In females, age, BMI, mean BP, hemoglobin A1c, sCr, FVC %predicted, and FEV(1) %predicted were significantly associated with sUA levels. Multiple linear regression analysis showed that for both genders, FVC %predicted and FEV(1) %predicted were predictive for sUA levels, independently of the other clinical parameters. Subjects with lung restriction had higher sUA levels than subjects without lung restriction. In addition, subjects with moderate and severe airflow limitation had higher sUA levels than subjects without airflow limitation or those with mild airflow limitation. CONCLUSION: FVC %predicted and FEV(1) %predicted were significantly associated with sUA levels in a general population.

Pneumatosis Intestinalis in Lung Cancer Induced Twice by Different Drugs: Bevacizumab and Pemetrexed.

A 72-year-old man diagnosed with stage 4 lung adenocarcinoma developed asymptomatic pneumatosis intestinalis while undergoing treatment with first-line chemotherapy, which included carboplatin, paclitaxel, and bevacizumab (BEV). He was treated conservatively. The pneumatosis recurred while the patient was undergoing treatment with the third-line chemotherapy, which included pemetrexed (PEM). His condition resolved after 4 weeks of supportive therapy. To our knowledge, this is the first case in which pneumatosis intestinalis was induced twice by two drugs in a patient with lung cancer. BEV and PEM are often administered to patients with lung cancer; thus, it should be noted that pneumatosis intestinalis may occur as an adverse event in patients treated with these drugs.

Examination of predictable factors of perioperative respiratory complications by preoperative forced oscillation technique parameters.

In this study, we investigated whether pulmonary function tests such as forced oscillation technique parameters could predict perioperative respiratory complications. In the results of our study, perioperative respiratory complications cannot be predicted using the results of preoperative pulmonary function tests and forced oscillation technique parameters. Patients who are judged by comprehensive preoperative judgment to be suitable for general anesthesia may not need to consider the risk of perioperative complications using pulmonary function test.

Predictors for mortality from respiratory failure in a general population.

Risk factors for death from respiratory failure in the general population are not established. The aim of this study was to determine the characteristics of individuals who die of respiratory failure in a Japanese general population. In total, 3253 adults aged 40 years or older participated in annual health check in Takahata, Yamagata, Japan from 2004 to 2006. Subject deaths through the end of 2010 were reviewed; 27 subjects died of respiratory failure (pneumonia, n = 22; COPD, n = 1; pulmonary fibrosis, n = 3; and bronchial asthma, n = 1). Cox proportional hazard analysis revealed that male sex; higher age, high levels of D-dimer and fibrinogen; lower body mass index (BMI) and total cholesterol; and history of stroke and gastric ulcer were independent risk factors for respiratory death. On analysis with C-statistics, net reclassification improvement, and integrated discrimination improvement, addition of the disease history and laboratory data significantly improved the model prediction for respiratory death using age and BMI. In conclusion, we identified risk factors for mortality from respiratory failure in a prospective cohort of a Japanese general population. Men who were older, underweight, hypocholesterolemic, hypercoagulo-fibrinolytic, and had a history of stroke or gastric ulcer had a higher risk of mortality due to respiratory failure.

Low arterial blood oxygenation is associated with calcification of the coronary arteries in patients with chronic obstructive pulmonary disease.

BACKGROUND: Cigarette smoking is a well-known major cause of both chronic obstructive pulmonary disease (COPD) and atherosclerosis. However, few studies have investigated the correlation between COPD and coronary atherosclerosis. METHODS: We recruited 54 patients with stable COPD (51 men, 3 women) but without angina symptoms. Arterial blood gas analyses were performed, pulmonary function was assessed, and calcification of the coronary arteries was evaluated by computed tomography (CT). RESULTS: Calcification of the coronary arteries was noted in 25 patients. There were no significant differences in age, body mass index, respiratory function, and levels of low-density lipoprotein cholesterol, hemoglobin A1c, glucose, or C-reactive protein between patients with or without calcification of the coronary arteries. Arterial blood oxygenation was significantly lower in patients with calcification of the coronary arteries. On both univariate and multivariate analyses, low arterial blood oxygenation was an independent risk factor for calcification of the coronary arteries. CONCLUSIONS: In patients with COPD, low arterial blood oxygenation was strongly associated with calcification of the coronary arteries and may be a significant predictor of cardiovascular disease.

Relationship between Serum Level of Lymphatic Vessel Endothelial Hyaluronan Receptor-1 and Prognosis in Patients with Lung Cancer.

BACKGROUND: Lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) is a hyaluronic acid receptor that is selectively expressed in the endothelia of lymphatic capillaries. The density of lymphatic vessels expressing LYVE-1 on immunohistochemistry negatively correlates with prognosis of patients with non-small-cell lung cancer. However, the relationship between LYVE-1 serum levels and lung cancer staging is unknown. METHODS: We collected blood samples from 58 lung cancer patients before treatment and measured LYVE-1 serum levels using an enzyme-linked immunosorbent assay. RESULTS: Mean serum LYVE-1 levels were 1,420 pg/mL. Serum LYVE-1 levels correlated positively with serum albumin levels, but inversely with primary tumor size, leukocyte counts, and platelet counts by Pearson's product-moment correlation coefficient. A high cancer staging, occurrence of lymph-node metastases, and occurrence of distant metastases were significantly associated with low LYVE-1 levels. Moreover, multiple logistic regression analyses revealed that LYVE-1 levels were predictive of the presence of lymph node and distant metastases, independently of the other factors. Kaplan-Meier analysis showed that the survival of patients with serum LYVE-1 ≤1,553 pg/mL was significantly poorer than that of patients with serum LYVE-1 >1,553 pg/mL. This survival difference relative to LYVE-1 levels remained statistically significant after adjusting for age and gender by the Cox proportional-hazard analysis. CONCLUSION: Serum LYVE-1 is significantly low in lung cancer patients with metastasis, compared with those without. Measuring LYVE-1 levels in lung cancer patients may be useful for evaluating lung cancer progression.

Inhibition of elastase-pulmonary emphysema in dominant-negative MafB transgenic mice.

Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke. The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema. Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages. We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12. Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice. AMs with projected pseudopods were decreased in DN-MafB Tg mice. The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice. Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice. Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression.

Relationships between values of antibodies to several connective tissue disease autoantigens and pulmonary function in a Japanese general population: the Takahata study.

BACKGROUND: Accumulating evidence suggests the involvement of an autoimmune mechanism in the pathogenesis of respiratory dysfunction. The aim of this study was to investigate the relationship between pulmonary function and serum antibodies to several connective tissue disease autoantigens (ACTDA) levels, which has not been investigated in a general population. METHODS: Blood sampling and spirometry were performed for subjects (n = 3,257) aged ≥40 years who participated in a community-based annual health check in Takahata, Japan, from 2004 to 2006. ACTDA was measured by enzyme immunoassay, and subjects with ACTDA values ≥20 were defined as positive. RESULTS: In males, there were significant inverse relationships between logarithmically transformed ACTDA values and spirometric parameters, including % predicted values for forced expiratory volume in 1 s (FEV1) and maximal midexpiratory flow (MMF) as well as FEV1/forced vital capacity (FVC). Multiple linear regression analysis revealed that except for the relationship between ACTDA and FEV1/FVC, these relationships were still significant after adjustment for Brinkman index (a measure of inhaled cigarette consumption). The prevalence of positive ACTDA was greater in male never-smokers with mixed ventilation disorders and relatively severe airflow obstruction (% predicted FEV1 below the median value). CONCLUSIONS: Autoimmunity may be involved in the mechanism of impaired pulmonary function in the general population.

A lower level of forced expiratory volume in 1 second is a risk factor for all-cause and cardiovascular mortality in a Japanese population: the Takahata study.

Chronic obstructive pulmonary disease is a known risk factor for cardiovascular death in Western countries. Because Japan has a low cardiovascular death rate, the association between a lower level of forced expiratory volume in 1 s (FEV1) and mortality in Japan's general population is unknown. To clarify this, we conducted a community-based longitudinal study. This study included 3253 subjects, who received spirometry from 2004 to 2006 in Takahata, with a 7-year follow-up. The causes of death were assessed on the basis of the death certificate. In 338 subjects, airflow obstruction was observed by spirometry. A total of 127 subjects died. Cardiovascular death was the second highest cause of death in this population. The pulmonary functions of the deceased subjects were significantly lower than those of the subjects who were alive at the end of follow-up. The relative risk of death by all causes, respiratory failure, lung cancer, and cardiovascular disease was significantly increased with airflow obstruction. The Kaplan-Meier analysis showed that all-cause and cardiovascular mortality significantly increased with a worsening severity of airflow obstruction. After adjusting for possible factors that could influence prognosis, a Cox proportional hazard model analysis revealed that a lower level of FEV1 was an independent risk factor for all-cause and cardiovascular mortality (per 10% increase; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.82-0.98; and HR, 0.72; 95% CI, 0.61-0.86, respectively). In conclusion, airflow obstruction is an independent risk factor for all-cause and cardiovascular death in the Japanese general population. Spirometry might be a useful test to evaluate the risk of cardiovascular death and detect the risk of respiratory death by lung cancer or respiratory failure in healthy Japanese individuals.

Elevated serum iron is a potent biomarker for spirometric resistance to cigarette smoke among Japanese males: the Takahata study.

Chronic obstructive pulmonary disease is a common disability among elderly subjects with a heavy cigarette smoking habit. In contrast to the population that is susceptible to smoking, in whom pulmonary function worsens with the length of exposure to cigarette smoke, there are elderly individuals whose pulmonary function is not impaired. However, to date, the characteristics of this resistant smoking population have not been investigated. We aimed to identify a biomarker in individuals in whom lung health is maintained despite smoking. Blood sampling and spirometry were performed on 3,257 subjects who participated in a community-based annual health check in Takahata, Japan, from 2004 to 2006. We selected 117 elderly smokers (age ≥70, Brinkman index ≥600, smoking years ≥30). The 'smoking resistant' group met the following criteria: FEV1/FVC ≥0.7, and FEV1%predicted ≥80. Spirometry was re-evaluated in 147 male, current smokers in 2009. Baseline serum iron (sFe) levels were higher in the smoke resistant group compared with the non-resistant group. In those with low sFe levels, FEV1/FVC was reduced in male subjects. These spirometric measures were positively associated with sFe levels in men. Multiple linear regression analysis revealed that sFe levels were predictive for spirometric values, independent of other clinical factors. In addition, sFe levels were predictive for a decline in FEV1.Serum iron levels may be a biomarker for the spirometric susceptibility of individuals to cigarette smoke.

Impact of cigarette smoking on maximal expiratory flows in a general population: the Takahata study.

BACKGROUND: Maximal expiratory flows (MEFs) depend on the elastic recoil pressure in the alveoli, airway resistance and bronchial collapsibility. MEFs at lower levels of vital capacity [MEFs at x% FVC (MEF(x))] would indicate the patency of peripheral airways. In Japan, a ratio of MEF(50) to MEF(25) (MEF(50)/MEF(25)) greater than 4.0 is used as an index of injury to the small airways in subjects without airflow limitation. However, to date there have been no epidemiological investigations relating to this index. The aim of this study was to evaluate the impact of cigarette smoking on MEFs in a general population, and to assess the validity of using this index to evaluate injury to the small airways. METHODS: Subjects aged 40 years or older (n=2,917), who had participated in a community-based annual health-check in Takahata, Japan, were enrolled in the study. MEF(75), MEF(50) and MEF(25) were measured in these subjects. RESULTS: In smokers, as compared with never-smokers, the percentage predicted MEFs (%MEFs) decreased according to the aging of the population, except in the case of %MEF(25) in females. In males, but not in females, %MEFs decreased significantly with an increase in cigarette consumption. In both genders, MEF(50)/MEF(25) was slightly, but significantly, elevated with aging of the population. In addition, 36.5% of subjects who participated in this health-check had MEF(50)/MEF(25) values greater than 4.0. No difference in MEF(50)/MEF(25) was observed between smokers and never-smokers. CONCLUSION: Cigarette smoking enhanced the age-related decline in MEFs. Since many healthy subjects aged 40 years or older have MEF(50)/MEF(25) values greater than 4.0, the use of this criterion may over-estimate the presence of small airway disease.