Tomotaka Kawayama

Periostin, a matrix protein, is a novel biomarker for idiopathic interstitial pneumonias

Idiopathic interstitial pneumonias (IIPs) are histopathologically classified into several types, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and cryptogenic organising pneumonia (COP). We investigated whether periostin, a matrix protein, could be used as a biomarker to assess histopathological types of IIPs. We performed immunohistochemical analyses in each histopathological type of IIP, examined serum levels of periostin in IIP patients and analysed the relationship between serum levels of periostin and the pulmonary functions in patients with idiopathic pulmonary fibrosis (IPF). Periostin was strongly expressed in lungs of UIP and fibrotic NSIP patients, whereas expression of periostin was weak in the lungs of cellular NSIP and COP patients, as well as in normal lungs. Serum levels of periostin in IPF were significantly higher than those of healthy subjects and COP patients. Furthermore, periostin levels in IPF patients were inversely correlated with their pulmonary functions. Thus, we have found that periostin is a novel component of fibrosis in IIP. Periostin may be a potential biomarker to distinguish IIP with fibrosis.

Interleukin-18 production and pulmonary function in COPD

Interleukin (IL)-18 production and pulmonary function were evaluated in patients with chronic obstructive pulmonary disease (COPD) in order to determine the role of IL-18 in COPD. Immunohistochemical techniques were used to examine IL-18 production in the lungs of patients with very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV, n = 16), smokers (n = 27) and nonsmokers (n = 23). Serum cytokine levels and pulmonary function were analysed in patients with GOLD stage I–IV COPD (n = 62), smokers (n = 34) and nonsmokers (n = 47). Persistent and severe small airway inflammation was observed in the lungs of ex-smokers with very severe COPD. IL-18 proteins were strongly expressed in alveolar macrophages, CD8+ T-cells, and both the bronchiolar and alveolar epithelia in the lungs of COPD patients. Serum levels of IL-18 in COPD patients and smokers were significantly higher than those in nonsmokers. Moreover, serum levels of IL-18 in patients with GOLD stage III and IV COPD were significantly higher than in smokers and nonsmokers. There was a significant negative correlation between serum IL-18 level and the predicted forced expiratory volume in one second in patients with COPD. In contrast, serum levels of IL-4, IL-13 and interferon-γ were not significantly increased in any of the three groups. In conclusion, overproduction of interleukin-18 in the lungs may be involved in the pathogenesis of chronic obstructive pulmonary disease.

Reference Ranges for Exhaled Nitric Oxide Fraction in Healthy Japanese Adult Population

BACKGROUND The measurement of the exhaled nitric oxide fraction (FE(NO)) is proposed as a useful marker of airway inflammation. In healthy adults, there have been a few studies of the reference ranges for FE(NO) in Caucasians. A community study in other regions may reveal any possible ethnic differences in the FE(NO) levels. METHODS A total of 240 healthy adults aged between 18 to 74 years were recruited from four medical centers in Japan. Current smokers and subjects having a history of atopic disease were not included. FE(NO) was measured using an online electrochemical nitric oxide analyzer according to the current guidelines. The reference ranges for FE(NO) were estimated using two different statistical methods recommended by International Federation of Clinical Chemistry and Laboratory Medicine. RESULTS The mean FE(NO) was 16.9 ppb (parts per billion) with a 95% prediction interval (2.5 to 97.5 percentiles) of 6.5 to 35.0 ppb in healthy Japanese adults. Normality assumptions were met for the logarithm-transformed FE(NO). The geometric mean FE(NO) was 15.4 ppb with a mean ± two standard deviations of 6.5 to 36.8 ppb. Age, gender, height, and past smoking history were not associated with the FE(NO) levels. CONCLUSIONS The reference ranges for FE(NO) in healthy Japanese adults were similar to those of Caucasians. It seems reasonable that the upper limit of FE(NO) for healthy adults should be set at approximately 36.0 ppb irrespective of ethnic differences.

Overexpression of CD163, CD204 and CD206 on alveolar macrophages in the lungs of patients with severe chronic obstructive pulmonary disease.

We have previously reported that the lungs of patients with very severe chronic obstructive pulmonary disease (COPD) contain significantly higher numbers of alveolar macrophages than those of non-smokers or smokers. M1 and M2 macrophages represent pro- and anti-inflammatory populations, respectively. However, the roles of M1 and M2 alveolar macrophages in COPD remain unclear. Immunohistochemical techniques were used to examine CD163, CD204 and CD206, as M2 markers, expressed on alveolar macrophages in the lungs of patients with mild to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I (mild) n = 11, II (moderate) n = 9, III (severe) n = 2, and IV (very severe) n = 16). Fifteen smokers and 10 non-smokers were also examined for comparison. There were significantly higher numbers of alveolar macrophages in COPD patients than in smokers and non-smokers. The numbers and percentages of CD163+, CD204+ or CD206+ alveolar macrophages in patients with COPD at GOLD stages III and IV were significantly higher than in those at GOLD stages I and II, and those in smokers and non-smokers. In patients with COPD, there was a significant negative correlation between the number of CD163+, CD204+ or CD206+ alveolar macrophages and the predicted forced expiratory volume in one second. Overexpression of CD163, CD204 and CD206 on lung alveolar macrophages may be involved in the pathogenesis of COPD.

Development of the Japanese version of the COPD Assessment Test

BACKGROUND We aimed to develop the Japanese version of the COPD Assessment Test (TM) (CAT), which was recently developed in overseas countries, to measure the health status of patients with chronic obstructive pulmonary disease (COPD) and to validate its psychometric properties. METHODS The original CAT was translated to Japanese through linguistic validation. Then, an Internet-based survey was conducted by including 301 Japanese patients with COPD who were over 40 years of age and had a history of smoking, to assess the reliability and validity of the translated CAT. RESULTS The Japanese CAT was shown to have high internal consistency (Cronbachs α coefficient: 0.891). The assessment using the Japanese CAT was highly correlated with assessment using the COPD-specific St. Georges Respiratory Questionnaire (r = 0.820). The assessment also showed correlation between the Japanese CAT and a generic health-related quality of life (QOL) questionnaire (SF-12v2). CONCLUSION The Japanese version of the CAT has high reliability and validity, and can be expected to serve as a short and simple questionnaire for precise assessment of the health status of Japanese patients with COPD.

Interleukin-18 in Pulmonary Inflammatory Diseases

The proinflammatory cytokine interleukin (IL)-18 was originally discovered as an interferon-γ-inducing factor in 1995. IL-18 is known to play an important role in Th1/Tc1 polarization and promoting the production of Th2 cytokines (e.g., IL-4, IL-5, IL-9, and IL-13) by T cells, NK cells, basophils, and mast cells. IL-18 can act as a cofactor for Th2 cell development and IgE production, and also plays an important role in the differentiation of Th17 cells. IL-18 is a key player in the pathogenesis of inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, adult-onset Stills disease, Sjögrens syndrome, and inflammatory bowel diseases. Furthermore, many lines of evidence suggest that IL-18 plays a key role in the pathogenesis of pulmonary inflammatory diseases, including bronchial asthma and chronic obstructive pulmonary disease. Here, we review the pathological roles of IL-18 in pulmonary inflammatory diseases.

Serum level of periostin can predict long-term outcome of idiopathic pulmonary fibrosis

BACKGROUND KL-6 and surfactant proteins A and D are the only established serum biomarkers of idiopathic pulmonary fibrosis (IPF). We have previously shown that serum levels of periostin, a unique matricellular protein, are elevated and correlated with pulmonary function in patients with IPF. We sought to determine whether the serum periostin levels correlate with overall survival (OS) and time-to-event (TTE), as a parameter reflecting long-term outcome, and with the extent of abnormality on chest high-resolution computed tomography (HRCT) scores in patients with IPF. METHODS Twenty-nine patients with IPF were analyzed retrospectively. The mean observation period was 1035.2 ± 663.1 days (range, 112-1800 days). High-resolution computed tomography (HRCT) scores were calculated based on the extent of abnormality evidenced by HRCT. We evaluated if there were any correlations between the serum periostin levels and clinical parameters, including HRCT score, using Spearmans rank correlation coefficients and analyzed predictors of OS and TTE using the log-rank tests. RESULTS We showed that the serum periostin levels significantly correlated with the increase of honeycombing score on HRCT during a 6-month period. Log-rank tests showed that a higher serum periostin level was a predictor of a shortened OS and TTE. Greater extents of fibrotic lesions on HRCT scan were predictors of shortened OS and TTE. CONCLUSIONS In IPF patients, the serum periostin level may be a good predictive biomarker for an increase in the radiological fibrotic area and long-term outcome.

Interleukin-18 expression, CD8(+) T cells, and eosinophils in lungs of nonsmokers with fatal asthma.

BACKGROUND The process of airway inflammation in the lungs of nonsmokers who die of asthma (fatal asthma) has not been reported in detail. OBJECTIVE To examine nonsmokers who had died of asthma to exclude chronic obstructive pulmonary disease and investigate pulmonary inflammatory cells and the expression of interleukin-18 (IL-18) and its receptor in lung tissues compared with those in patients with well-controlled mild asthma and nonsmokers. METHODS Lung tissues were obtained at autopsy examination from 12 nonsmokers with fatal asthma, excluding cases of chronic obstructive pulmonary disease, and from 5 nonsmokers with well-controlled mild asthma and 10 nonsmokers who had undergone surgical resection for lung cancer. Pulmonary inflammatory cells were examined and the expression of the proinflammatory cytokine IL-18 and its receptor in the lungs was evaluated. RESULTS The numbers of eosinophils and lymphocytes, but not basophils or macrophages, were significantly increased in the lungs of patients with fatal asthma compared with the other 2 groups. The lung neutrophil count did not differ significantly between the fatal and mild asthma groups but was significantly higher in the fatal asthma group than in nonsmokers. CD8(+) T cells, but not CD4(+) T cells, were significantly increased in the lungs of the fatal asthma group compared with the other 2 groups. IL-18 protein and IL-18 receptor were strongly expressed in the lungs in the fatal asthma group. CONCLUSION Caspase-1 inhibitors, anti-IL-18 antibodies, anti-IL-18 receptor antibodies, IL-18 binding protein, or inhibitors of genes downstream of the IL-18 signal transduction pathway may be of clinical benefit for the treatment of patients with severe asthma.

IL-18 Induces Airway Hyperresponsiveness and Pulmonary Inflammation via CD4+ T Cell and IL-13

IL-18 plays a key role in the pathogenesis of pulmonary inflammatory diseases including pulmonary infection, pulmonary fibrosis, lung injury and chronic obstructive pulmonary disease (COPD). However, it is unknown whether IL-18 plays any role in the pathogenesis of asthma. We hypothesized that overexpression of mature IL-18 protein in the lungs may exacerbate disease activities of asthma. We established lung-specific IL-18 transgenic mice on a Balb/c genetic background. Female mice sensitized– and challenged– with antigen (ovalbumin) were used as a mouse asthma model. Pulmonary inflammation and emphysema were not observed in the lungs of naïve transgenic mice. However, airway hyperresponsiveness and airway inflammatory cells accompanied with CD4+ T cells, CD8+ T cells, eosinophils, neutrophils, and macrophages were significantly increased in ovalbumin-sensitized and challenged transgenic mice, as compared to wild type Balb/c mice. We also demonstrate that IL-18 induces IFN-γ, IL-13, and eotaxin in the lungs of ovalbumin-sensitized and challenged transgenic mice along with an increase in IL-13 producing CD4+ T cells. Treatment with anti-CD4 monoclonal antibody or deletion of the IL-13 gene improves ovalbumin-induced airway hyperresponsiveness and reduces airway inflammatory cells in transgenic mice. Overexpressing the IL-18 protein in the lungs induces type 1 and type 2 cytokines and airway inflammation, and results in increasing airway hyperresponsiveness via CD4+ T cells and IL-13 in asthma.

Depression, but not sleep disorder, is an independent factor affecting exacerbations and hospitalization in patients with chronic obstructive pulmonary disease.

Background and objective:  Patients with chronic obstructive pulmonary disease (COPD) may experience depression and sleep disorders, which can adversely affect their health‐related quality of life (HRQOL). The aim of this study was to investigate depression and sleep disorders among 85 COPD patients and 46 control subjects, aged 40 years and over.