Kazuto Hirata

Irisin, a newly discovered myokine, is a novel biomarker associated with physical activity in patients with chronic obstructive pulmonary disease

Irisin is a recently identified hormone secreted by skeletal myocytes, which has been proposed to mediate the beneficial effects of exercise. Physical activity has been emphasized as one of the principal targets of the treatment for chronic obstructive pulmonary disease (COPD). This study was designed to evaluate the possibility of using serum irisin level as a novel biomarker associated with physical activity in patients with COPD.

Epistatic effects of multiple receptor genes on pathophysiology of asthma - its limits and potential for clinical application.

To date, genome-wide association studies (GWAS) permit a comprehensive scan of the genome in an unbiased manner, with high sensitivity, and thereby have the potential to identify candidate genes for the prevalence or development of multifactorial diseases such as bronchial asthma. However, most studies have only managed to explain a small additional percentage of hereditability estimates, and often fail to show consistent results among studies despite large sample sizes. Epistasis is defined as the interaction between multiple different genes affecting phenotypes. By applying epistatic analysis to clinical genetic research, we can analyze interactions among more than 2 molecules (genes) considering the whole system of the human body, illuminating dynamic molecular mechanisms. An increasing number of genetic studies have investigated epistatic effects on the risk for development of asthma. The present review highlights a concept of epistasis to overcome traditional genetic studies in humans and provides an update of evidence on epistatic effects on asthma. Furthermore, we review concerns regarding recent trends in epistatic analyses from the perspective of clinical physicians. These concerns include biological plausibility of genes identified by computational statistics, and definition of the diagnostic label of ‘physician-diagnosed asthma’. In terms of these issues, further application of epistatic analysis will prompt identification of susceptibility of diseases and lead to the development of a new generation of pharmacological strategies to treat asthma.

Impaired nuclear factor erythroid 2-related factor 2 expression increases apoptosis of airway epithelial cells in patients with chronic obstructive pulmonary disease due to cigarette smoking

BackgroundCigarette smoking-induced oxidative stress is known to be a key mechanism in COPD pathogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central transcription factor that regulates the antioxidant defense system. The aim of this study was to compare Nrf2 expression in COPD subjects and control subjects, and to determine the role of Nrf2 in protecting against oxidative stress-induced apoptosis.MethodsWe enrolled 8 COPD subjects and 7 control subjects in this study. We performed bronchial brushing by bronchoscopy and obtained bronchial epithelial cells from the airways. Nrf2 expression in bronchial epithelial cells was evaluated by real-time PCR and Western blotting. We examined the effect of 10 or 15xa0% cigarette smoke extract (CSE) induced A549 cells apoptosis using a time-lapse cell imaging assay with caspase-3/7 activation detecting reagent and performed Terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling assay for confirming A549 cells apoptosis. We also examined the effects of Nrf2 knockdown and, 0.1, 0.5, and 1.0xa0mMxa0N-acetyl cysteine on CSE-induced apoptosis. Statistical analyses were performed using t-test, paired t-test or an analysis of variance followed by the Tukey-Kramer method.ResultsNrf2 mRNA expression in COPD subjects was significantly lower than that in control subjects and Nrf2 mRNA were negatively correlated with pack year. Nrf2 protein in COPD subjects was significantly lower than that in control subjects. CSE-induced A549 cells apoptosis was increased in a time-, concentration-dependent manner, and was significantly increased by Nrf2 knockdown. N-acetyl cysteine significantly ameliorated CSE-induced apoptosis.ConclusionsNrf2 expression was lower in COPD patients than in control subjects. Nrf2 might have a protective role against apoptosis caused by CSE-induced oxidative stress. These results suggest an involvement of Nrf2 in COPD and administration of antioxidants to patients with COPD might be a basic therapeutic option.

Decreased levels of irisin, a skeletal muscle cell-derived myokine, are related to emphysema associated with chronic obstructive pulmonary disease

Background Cigarette smoking-induced oxidant–antioxidant imbalance is a factor that contributes to the pathogenesis of COPD through epithelial cell apoptosis. Irisin is a skeletal muscle cell-derived myokine associated with physical activity. Irisin is also known to decrease oxidant-induced apoptosis in patients with diabetes mellitus. However, the correlation between irisin and emphysema in COPD and its role in epithelial cell apoptosis remains unknown. Subjects and methods Forty patients with COPD were enrolled in this study. Pulmonary function tests and measurements of the percentage of low-attenuation area on high-resolution computed tomography images were performed, and the results were evaluated for correlation with serum irisin levels. The effect of irisin on cigarette-smoke extract-induced A549 cell apoptosis and the expression of Nrf2, a transcription factor for antioxidants, was also examined in vitro. Results Serum irisin levels were significantly correlated with lung diffusing capacity for carbon monoxide divided by alveolar volume (r=0.56, P<0.01) and percentage of low-attenuation area (r=−0.79, P<0.01). Moreover, irisin significantly enhanced Nrf2 expression (P<0.05) and reduced cigarette-smoke extract-induced A549 cell apoptosis (P<0.05). Conclusion Decreased serum irisin levels are related to emphysema in patients with COPD and involved in epithelial apoptosis, resulting in emphysema. Irisin could be a novel treatment for emphysema in patients with COPD.

Down-Regulation of Soluble α-Klotho is Associated with Reduction in Serum Irisin Levels in Chronic Obstructive Pulmonary Disease.

PurposeThe klotho gene was originally identified as a putative aging-suppressor gene. Klotho-depleted mice display a shortened life span and exhibit a variety of premature aging-related phenotypes such as pulmonary emphysema and sarcopenia. This study was designed to determine the roles of secreted-type klotho protein on lung and skeletal muscle in chronic obstructive pulmonary disease (COPD).MethodsSerum α-klotho and irisin levels were assayed in 16 non-smokers, 13 smokers without COPD, and 24 smokers with COPD. Moreover, we examined correlations between soluble α-klotho levels and the results of lung function test, cardiopulmonary exercise test (CPET), and skeletal muscle function in smokers with COPD.ResultsSoluble α-klotho levels were significantly lower in smokers with COPD compared to non-smokers and smokers without COPD. In smokers with COPD, those levels did not significantly correlate with any parameters of lung function test. In CPET, peak VO2 significantly correlated with FEV1 (% predicted) (rxa0=xa00.76, pxa0=xa00.0003) and DLCO (% predicted) (rxa0=xa00.62, pxa0=xa00.003). In contrast, soluble α-klotho levels did not significantly correlate with peak VO2. Irisin levels were also significantly lower in smokers with COPD. Moreover, there was a significant correlation between soluble α-klotho and serum irisin levels (rxa0=xa00.61, pxa0=xa00.004).ConclusionsOur findings could provide a critical first step to understanding the impacts of soluble α-klotho on skeletal muscle in COPD and may lead to the identification of new molecular targets for the treatment of COPD.

Potential role of pentosidine on susceptibility to small airway closure in elderly and smoking asthma

BACKGROUNDnSmall airway closure in asthma is determined by a complex interaction of structural and functional characteristics including lung elastic recoil. Recently, we determined that loss of elastic recoil might be attributable to pentosidine level in the airways. This study was designed to investigate the influences of aging and smoking on small airway closure in asthma.nnnMETHODSnSixty-one patients with asthma (20 non-smoking young adult, 23 non-smoking elderly, and 18 smoking young adult) and 36 control subjects (12 non-smoking young adult, 11 non-smoking elderly, and 13 smoking young adult) were included. We assessed airway responses during methacholine provocation and calculated the closing index. In addition, we measured pentosidine levels in induced sputum from all study subjects.nnnRESULTSnPentosidine levels in induced sputum were markedly higher in asthmatic patients than in controls. In control subjects, the intergroup differences in pentosidine level among 3 subgroups were significant. Similarly, pentosidine levels were significantly higher in non-smoking elderly and smoking young adult asthmatics than in non-smoking young adult asthmatics. There was no significant difference in pentosidine levels between non-smoking elderly and smoking young adult asthmatics. The closing index was also significantly higher in non-smoking elderly and smoking young adult asthmatics than in non-smoking young adult asthmatics. Moreover, pentosidine levels in non-smoking elderly and smoking young adult asthmatics were closely correlated with closing index.nnnCONCLUSIONSnWe determined the correlation of pentosidine level with susceptibility to small airway closure in elderly and smoking asthmatics. Our results might facilitate the understanding of elderly and smoking asthma.

Application of a new parameter in the 6-minute walk test for manifold analysis of exercise capacity in patients with COPD

Background New parameters in the 6-minute walk test (6MWT) are required for comprehensive analysis of exercise capacity in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to apply a novel index, the desaturation distance ratio (DDR), to clinical research on COPD as an estimate of exercise capacity and to examine whether DDR is a potential parameter for manifold analysis of exercise capacity in patients with COPD. Methods A total of 41 patients with COPD (median age [interquartile range] =75 [68–79] years; and body mass index [BMI] =22.3 [19.4–23.8] kg/m2) participated in the study. The 6MWT was performed along with anthropometric measurements and a pulmonary function test. The “desaturation area” was measured as the total area above the curve created using peripheral oxygen saturation (SpO2) values observed at each minute during the 6MWT. Then the DDR was calculated as the ratio of the desaturation area to the 6-minute walk distance (6MWD). Results The 6MWD was 370 (328–445) m, and the decline in SpO2 values (ΔSpO2) was −5.0% (−8.0% to −1.5%). The DDR correlated modestly with baseline pulmonary function in patients with COPD (forced expiratory volume in 1 second [% of predicted value]: r=−0.658, P<0.001; and diffusing capacity of the lung for carbon monoxide [DLCO]: r=−0.470, P=0.002), comparable with the findings of the 6MWD. The DDR correlated well with ΔSpO2 (r=−0.656, P<0.001) and with the increase in subjective sense of dyspnea during the 6MWT, as assessed by Borg scale scores (ΔBorg) (r=0.486, P=0.001), in contrast with the 6MWD, which was not significantly correlated with ΔSpO2 and ΔBorg scale scores. Conclusion The DDR is more informative for manifold analysis of exercise capacity associated with oxygen desaturation and subsequent sense of dyspnea by exercise in patients with COPD.