Tamaki Takahashi

Impact of COPD exacerbations on osteoporosis assessed by chest CT scan.

Abstract Background: COPD pathology involves not only the lungs but also extrapulmonary abnormalities. Osteoporosis is one of the most important abnormalities because it may cause vertebral compression fractures and deteriorate pulmonary function. COPD patients have many risk factors for osteoporosis, such as low BMI, decreased activity, systemic inflammation, and use of corticosteroids. Some of these factors have been shown to deteriorate with COPD exacerbations. We previously demonstrated the correlation between emphysema and osteoporosis and between emphysema progression and COPD exacerbations. Thus, the hypothesis that exacerbation causes osteoporosis progression in COPD patients was investigated. Methods: Forty-two COPD patients not on osteoporosis treatment for over 2 years were recruited. During follow-up, exacerbations had been prospectively recorded. Thoracic vertebral bone mineral density (BMD) was measured using chest CT, and the annual change in BMD was calculated. The change was compared between patients with and without a history of exacerbations. Results: The decrease in thoracic vertebral BMD was greater in patients with than in those without a history of exacerbations (median ΔBMD mg/ml⋅year: –3.78 versus –0.30, p = 0.02). Moreover, multivariate regression analysis showed that exacerbations and baseline PaO2 were independent predictors of the BMD decrease (R2 = 0.20, p = 0.007, and R2 = 0.09, p = 0.03, respectively) after adjustment for baseline age, smoking status, and airflow limitation. Conclusions: This is the first longitudinal study to demonstrate that COPD exacerbations are independently associated with osteoporosis progression. Osteoporosis progression should be evaluated in COPD patients, especially in those with a history of frequent exacerbations.

Oxidative stress induced Interleukin-32 mRNA expression in human bronchial epithelial cells

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and persistent inflammation in the airways and lung parenchyma. Oxidative stress contributes to the pathogenesis of COPD. Interleukin (IL)-32 expression has been reported to increase in the lung tissue of patients with COPD. Here, we show that IFNγ upregulated IL-32 expression and that oxidative stress augmented IFNγ-induced-IL-32 expression in airway epithelial cells. We further investigated transcriptional regulation responsible for IFNγ induced IL-32 expression in human airway epithelial cells.MethodsHuman bronchial epithelial (HBE) cells were stimulated with H2O2 and IFNγ, and IL-32 expression was evaluated. The cell viability was confirmed by MTT assay. The intracellular signaling pathways regulating IL-32 expression were investigated by examining the regulatory effects of MAPK inhibitors and JAK inhibitor after treatment with H2O2 and IFNγ, and by using a ChIP assay to identify transcription factors (i.e. c-Jun, CREB) binding to the IL-32 promoter. Promoter activity assays were conducted after mutations were introduced into binding sites of c-Jun and CREB in the IL-32 promoter. IL-32 expression was also examined in HBE cells in which the expression of either c-Jun or CREB was knocked out by siRNA of indicated transcription factors.ResultsThere were no significant differences of cell viability among groups. After stimulation with H2O2 or IFNγ for 48 hours, IL-32 expression in HBE cells was increased by IFNγ and synergistically upregulated by the addition of H2O2. The H2O2 augmented IFNγ induced IL-32 mRNA expression was suppressed by a JNK inhibitor, but not by MEK inhibitor, p38 inhibitor, and JAK inhibitor I. Significant binding of c-Jun and CREB to the IL-32 promoter was observed in the IFNγ + H2O2 stimulated HBE cells. Introducing mutations into the c-Jun/CREB binding sites in the IL-32 promoter prominently suppressed its transcriptional activity. Further, knocking down CREB expression by siRNA resulted in significant suppression of IL-32 induction by IFNγ and H2O2 in HBE cells.ConclusionIL-32 expression in airway epithelium may be augmented by inflammation and oxidative stress, which may occur in COPD acute exacerbation. c-Jun and CREB are key transcriptional factors in IFNγ and H2O2 induced IL-32 expression.

Emphysema distribution and annual changes in pulmonary function in male patients with chronic obstructive pulmonary disease

BackgroundThe progression of chronic obstructive pulmonary disease (COPD) considerably varies among patients. Those with emphysema identified by quantitative computed tomography (CT) are associated with the rapid progression assessed by forced expiratory volume in one second (FEV1). However, whether the rate of the decline in lung function is independently affected by the regional distribution or the severity of emphysema in the whole lung is unclear.MethodsWe followed up 131 male patients with COPD for a median of 3.7 years. We measured wall area percent (WA%) in right apical segmental bronchus, total lung volume, percent low attenuation volume (LAV%), and the standard deviation (SD) of LAV% values from CT images of 10 isovolumetric partitions (SD-LAV) as an index of cranial-caudal emphysema heterogeneity. Annual changes in FEV1 were then determined using a random coefficient model and relative contribution of baseline clinical parameters, pulmonary function, and CT indexes including LAV%, SD-LAV, and WA% to annual changes in FEV1 were examined.ResultsThe mean (SD) annual change in FEV1 was −44.4 (10.8) mL. Multivariate random coefficient model showed that higher baseline FEV1, higher LAV%, current smoking, and lower SD-LAV independently contributed to an excessive decline in FEV1, whereas ratio of residual volume to total lung capacity, ratio of diffusing capacity to alveolar ventilation, and WA% did not, after adjusting for age, height, weight, and ratio of CT-measured total lung volume to physiologically-measured total lung capacity.ConclusionsA more homogeneous distribution of emphysema contributed to an accelerated decline in FEV1 independently of baseline pulmonary function, whole-lung emphysema severity, and smoking status. In addition to whole-lung analysis of emphysema, CT assessment of the cranial-caudal distribution of emphysema might be useful for predicting rapid, progressive disease and for developing a targeted strategy with which to prevent disease progression.

Longitudinal Study of Spatially Heterogeneous Emphysema Progression in Current Smokers with Chronic Obstructive Pulmonary Disease

Background Cigarette smoke is the main risk factor for emphysema, which is a key pathology in chronic obstructive pulmonary disease (COPD). Low attenuation areas (LAA) in computed tomography (CT) images reflect emphysema, and the cumulative size distribution of LAA clusters follows a power law characterized by the exponent D. This property of LAA clusters can be explained by model simulation, where mechanical force breaks alveolar walls causing local heterogeneous lung tissue destruction. However, a longitudinal CT study has not investigated whether continuous smoking causes the spatially heterogeneous progression of emphysema. Methods We measured annual changes in ratios of LAA (LAA%), D and numbers of LAA clusters (LAN) in CT images acquired at intervals of ≥3 years from 22 current and 31 former smokers with COPD to assess emphysema progression. We constructed model simulations using CT images to morphologically interpret changes in current smokers. Results D was decreased in current and former smokers, whereas LAA% and LAN were increased only in current smokers. The annual changes in LAA%, D, and LAN were greater in current, than in former smokers (1.03 vs. 0.37%, p = 0.008; −0.045 vs. −0.01, p = 0.004; 13.9 vs. 1.1, p = 0.007, respectively). When LAA% increased in model simulations, the coalescence of neighboring LAA clusters decreased D, but the combination of changes in D and LAN in current smokers could not be explained by the homogeneous emphysema progression model despite cluster coalescence. Conversely, a model in which LAAs heterogeneously increased and LAA clusters merged somewhat in relatively advanced emphysematous regions could reflect actual changes. Conclusions Susceptibility to parenchymal destruction induced by continuous smoking is not uniform over the lung, but might be higher in local regions of relatively advanced emphysema. These could result in the spatially heterogeneous progression of emphysema in current smokers.

Computed tomography assessment of pharmacological lung volume reduction induced by bronchodilators in COPD

Abstract Pharmacological lung volume reduction in COPD is an important goal in treatment with long-acting bronchodilators because in addition to airflow limitation, lung hyperinflation considerably affects COPD symptoms. Quantitative computed tomography (CT) simultaneously provides structural information about airway dimensions, emphysematous changes, and lung volumes, some of which are difficult to be evaluated by pulmonary function. Here, we evaluated changes in CT parameters and pulmonary function in 30 patients with COPD who underwent CT scans before and one year after starting tiotropium treatment and in 12 patients with COPD who were not treated with long-acting bronchodilators. Baseline pulmonary function and CT parameters did not differ between the two groups. One-year tiotropium therapy improved physiological-indices including residual volume (RV) and ratio of RV to total lung capacity (RV/TLC) (−235 mL, p = 0.005, and −2.9%, p = 0.0001, respectively), and CT-indices including wall area percent (WA%) and inner luminal area in right upper lobe apical and lower lobe basal segmental bronchi (−1.59%, p = 0.01, 2.27 mm2, p = 0.0005; and −1.33%, p = 0.0008, 3.42 mm2, p < 0.0001, respectively), low attenuation volume (LAV) and total lung volume (CT-TLV) (−92 mL, p = 0.0003, and −211 mL, p = 0.002, respectively). Changes in LAV, CT-TLV, RV, and RV/TLC were significantly greater in the tiotropium, than the non-bronchodilator group. The tiotropium-induced reduction in LAV correlated with the decrease in RV (ρ = 0.45, p = 0.01). Our findings not only indicate the value of the comprehensive CT measurements in assessing the effects of bronchodilators, including pharmacological lung volume reduction, but also further understanding of the structural changes underlying physiological improvements induced by bronchodilators.

Relationship between periodontitis-related antibody and frequent exacerbations in chronic obstructive pulmonary disease.

Background To identify patients with chronic obstructive pulmonary disease (COPD) who are susceptible to frequent exacerbations is important. Although periodontitis aggravated by poor oral hygiene might increase the risk of lower respiratory tract infection, the relationship between periodontitis and COPD exacerbations remains unknown. This prospective cohort study investigates the relationship between periodontitis-related antibody and exacerbation frequency over a one-year period. Methods We assessed an IgG antibody titer against Porphyromonas gingivalis, which is a major pathogen of periodontitis, and then prospectively followed up 93 individuals over one year to detect exacerbations. Results The numbers of exacerbations and the rate of individuals with frequent exacerbations (at least two per year) were significantly lower in patients with higher IgG titer than those with normal IgG titer (0.8 vs. 1.2 per year, p  = 0.045 and 14.3 vs. 38.6%, p  = 0.009, respectively). Multivariate logistic regression analysis showed that being normal-IgG titer for periodontitis-related antibody significantly increased the risk of frequent exacerbations (relative risk, 5.27, 95% confidence interval, 1.30–25.7; p  = 0.019) after adjusting for other possible confounders, such as a history of exacerbations in the past year, disease severity, COPD medication and smoking status. Conclusions Normal-IgG titer for periodontitis-related antibody can be an independent predictor of frequent exacerbations. Measuring periodontitis-related antibody titers might be useful to identify patients with susceptibility to frequent exacerbations so that an aggressive prevention strategy can be designed.

Peri-diaphragmatic lung volume assessed by computed tomography correlates with quality of life in patients with chronic obstructive pulmonary disease

Background and objective:  Health‐related quality of life (HRQoL) is important in the management of chronic obstructive pulmonary disease (COPD). In patients with emphysema, lung hyperinflation identified radiologically as shortening and flattening of the diaphragm is associated with impaired HRQoL. It remains unclear whether shortening of the diaphragm and/or alteration in chest wall shape are associated with reduced pulmonary function and HRQoL.

Annual decline in arterial blood oxygen predicts development of chronic respiratory failure in COPD with mild hypoxaemia: A 6-year follow-up study: Annual decline in PaO2 in COPD patients

Chronic respiratory failure (CRF) with hypoxaemia is an important pathophysiology in patients with chronic obstructive pulmonary disease (COPD), and existing mild hypoxaemia may be a sign of future CRF development. However, little is known about the trajectory of partial arterial pressure of oxygen (PaO2) decline in patients with COPD. We assessed decline in PaO2 and the impact of short‐term reductions in PaO2 to predict future decline in PaO2.

Efficacy of Budesonide in Combination with Formoterol in Patients with Inadequately Controlled Asthma on Fluticasone in Combination with Salmeterol

Global Initiative for Asthma ( GINA ) guidelines (GINA 2010) advocate the use of inhaled corticosteroids combined with a long-acting inhaled β2-agonist in a single inhaler (ICS LABA) in Treatment Steps 3 through 5 for bronchial asthma.1 Fluticasone in combination with salmeterol (FP SM) is effective in patients with moderate to severe asthma,2 but some patients do not resolve the persistent symptoms and require step up treatments. Therefore, the efficacy of budesonide in combination with formoterol (BUD FM) was assessed in patients with inadequately controlled asthma on FP SM.