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 [FEV1 %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 FEV1 %predicted were significantly associated with sUA levels. Multiple linear regression analysis showed that for both genders, FVC %predicted and FEV1 %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 FEV1 %predicted were significantly associated with sUA levels in a general population.

Background Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation. The prevalence of airflow limitation in Japan is 10.9% (16.4% of males and 5.0% of females). Cigarette smoking is well known as a major cause of COPD. However, few epidemiological studies have evaluated the effects of cigarette smoking on pulmonary function in healthy subjects. Methods Subjects aged 40 years or older (n=2,917), who had participated in a community-based annual health check in Takahata, Japan, from 2004 through 2005, were enrolled in the study. The smoking histories of these subjects were investigated using a self-reported questionnaire. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and forced expiratory flow at 25-75% of FVC (FEF25-75) were measured by standard procedures using spirometric machines. Results There were 554 current smokers (18.6%) and 403 former smokers (13.8%). The prevalence of airflow limitation defined by FEV1/FVC <0.7 in this population was 10.6%, and prevalence of airflow limitation defined by 5th percentile lower limit of normal was 6.4%. In smokers, percent predicted values of measured spirometric parameters (%FVC, %FEV1 and %FEF25-75) decreased significantly with age, except for male %FVC. Also, percent predicted values of measured spirometric parameters decreased significantly with increasing pack-years, except for female %FEF25-75. Conclusion Cigarette smoking increased the prevalence and severity of airflow limitation. It is concluded that cigarette smoking increases the risk of airflow limitation in a healthy Japanese population.

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.

Azithromycin (AZM), a 15-member macrolide antibiotic, possesses anti-inflammatory activity. Macrophages are important in innate and acquired immunity, and produce pro-inflammatory cytokines such as interleukin (IL)-12, which are composed of subunit p40 and p35. The key function of IL-12 is the induction and maintenance of T-helper-1 responses, which is associated with the pathogenesis of chronic inflammatory diseases. We investigated the effect of azithromycin on IL-12p40 production in macrophages after lipopolysaccharide (LPS)/interferon (IFN)-γ stimulation. RAW264.7 macrophage cell line was pre-treated with vehicle or AZM, followed by the stimulation with LPS/IFN-γ. We measured IL-12 production by RT-PCR and ELISA. IL-12 transcriptional regulation was assessed by electrophoretic mobility shift assay and reporter assay. Phosphorylation of activator protein (AP)-1 and interferon consensus sequence binding protein (ICSBP) was assessed by immunoprecipitation using phosphotyrosine antibody, and immunoblotting using specific antibodies against JunB and ICSBP. AZM reduced the induction of IL-12p40 by LPS/IFN-γ in a dose dependent manner. AZM inhibited the binding of AP-1, nuclear factor of activated T cells (NFAT), and ICSBP, to the DNA binding site in the IL-12p40 promoter. AZM also reduced LPS/IFN-γ-induced IL-12p40 promoter activity. Phosphorylation of JunB and ICSBP was inhibited by azithromycin-treatment in stimulated cells. In conclusion, AZM reduced IL-12p40 transcriptional activity by inhibiting the binding of AP-1, NFAT, and ICSBP to the promoter site. This may represent an important mechanism for regulating the anti-inflammatory effects of AZM in macrophages.

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 (MEFx)] would indicate the patency of peripheral airways. In Japan, a ratio of MEF50 to MEF25 (MEF50/MEF25) 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. MEF75, MEF50 and MEF25 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 %MEF25 in females. In males, but not in females, %MEFs decreased significantly with an increase in cigarette consumption. In both genders, MEF50/ MEF25 was slightly, but significantly, elevated with aging of the population. In addition, 36.5% of subjects who participated in this health-check had MEF50/MEF25 values greater than 4.0. No difference in MEF50/ MEF25 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 MEF50/MEF25 values greater than 4.0, the use of this criterion may over-estimate the presence of small airway disease.

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.

Recently, propylthiouracil (PTU) has been thought to be one of the possible causes of antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis syndrome, resulting in glomerulonephritis and, infrequently, diffuse alveolar haemorrhage (DAH). The mechanism of ANCA-positive vasculitis during PTU therapy is still unknown. Herein, we describe the case of a 59-year-old woman who developed myeloperoxidase (MPO)- and proteinase 3 (PR3)-ANCA positive DAH, without any other organ system involvement, during PTU therapy. Diminution and discontinuation of PTU resulted in a positive response. To our knowledge, this is the first documentation of both MPO- and PR3-ANCA-positive DAH, without systemic manifestations, developing during PTU therapy.

Background: The Gly80Ser polymorphism in phospholipase A2-IID (PLA2G2D, NCBI SNP reference: rs584367) is associated with a loss in body weight in patients with chronic obstructive pulmonary disease (COPD). The T allele missense mutation results in the 80th amino acid of the PLA2G2D protein changing from a glycine (Gly; C allele) to a serine (Ser; T allele). COPD patients carrying Ser lose a significant amount of weight compared with those carrying Gly. The mechanism for this weight loss following carriage of this Ser allele has not been clarified. Objectives: We aimed to evaluate whether this allelic change alters PLA2 enzymatic activity and/or pro-inflammatory cytokine inducibility. Methods: A549 cells (a human pulmonary epithelial cell line) were transfected with PLA2G2D-Gly or PLA2G2D-Ser. We evaluated PLA2 activity and cytokine expressions in these cells. Results: The enzymatic activity of sPLA2 in A549-PLA2G2D-Ser cells did not differ from the A549-PLA2G2D-Gly cells. A549-PLA2G2D-Ser cells spontaneously produced higher levels of interleukin (IL)-6 and IL-8 than A549-PLA2G2D-Gly cells. Upon tumor necrosis factor-α stimulation, IL-6 and IL-8 mRNA and protein levels in A549-PLA2G2D-Ser cells were elevated compared with those of A549-PLA2G2D-Gly cells. Upon hydrogen peroxide stimulation, IL-8 mRNA and protein levels in A549-PLA2G2D-Ser cells were higher than those of A549-PLA2G2D-Gly cells. Conclusions:PLA2G2D-Ser enhances the expression of IL-6 and IL-8 compared with PLA2G2D-Gly. This enhanced cytokine expression observed with the allelic change in PLA2G2D may be associated with the body weight loss seen in COPD patients.