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Background: Decorin is a small leucine-rich repeat proteoglycan that plays a critical role in collagen fibrillogenesis, and regulates inflammation, wound healing and angiogenesis. In idiopathic pulmonary fibrosis (IPF), decorin is expressed in fibrotic lesions; furthermore, intratracheal gene transfer of decorin has been demonstrated to inhibit bleomycin-induced pulmonary fibrosis. Although these results suggest the critical role of decorin in pulmonary fibrosis, the role of decorin in the acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) has not been clarified in detail. Thus, the goal of this study was to determine the role of decorin in AE-IIP. Methods: We retrospectively analyzed AE-IIP patients who had been admitted to our hospital. First, serum decorin levels were compared among patients with AE-IIP, patients with stable idiopathic interstitial pneumonia (SD-IIP), and healthy subjects. Next, the relationship between serum decorin levels and clinical parameters was analyzed in AE-IIP patients. Finally, the association between serum decorin levels and prognosis was evaluated in AE-IIP patients. IIP was divided into IPF and non-IPF, according to the published guidelines. Results: The serum decorin levels of AE-IIP patients were significantly lower than those of both healthy subjects and SD-IIP patients. Serum decorin levels were not related with the clinical parameters and prognosis, when all IIP patients were analyzed. In IPF patients, serum decorin levels had a significant correlation with oxygenation, and IPF patients with low serum decorin levels had a significantly higher survival rate than those with high serum decorin levels. Conclusions: Serum decorin levels are a potential prognostic biomarker in AE-IPF.

Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4&prime, s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and &alpha, smooth muscle action (&alpha, SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-&beta, expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-&beta, induced Smad3 activation, collagen and &alpha, SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-&beta, induced Smad3 activation and upregulated collagen and &alpha, SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-&beta, signaling.

A typhoon is a tropical cyclone that develops in the western Pacific or Indian Oceans and occurs yearly between September and October in Japan. In 2013, 31 typhoons developed and, of those, 10 were in close proximity to Japan and 2 struck Japan directly. Research has shown that an impending typhoon is a factor associated with asthma attacks [1]. In Okinawa, Hanashiro et al. analyzed the relationship between asthma attack outbreaks and typhoons [2]. They discovered that, as a typhoon approaches, changes in meteorological parameters, especially decreases in temperature and barometric pressure, are related to induction of asthma attacks. By contrast, in past reports, meteorological parameters of

Objective Since the term "combined pulmonary fibrosis and emphysema" (CPFE) was first proposed, the co-existence of pulmonary fibrosis and pulmonary emphysema (PE) has drawn considerable attention. However, conflicting results on the clinical characteristics of patients with both pulmonary fibrosis and PE have been published because of the lack of an exact definition of CPFE. The goal of this study was thus to clarify the clinical characteristics and phenotypes of idiopathic interstitial pneumonia (IIP) with PE. Methods We retrospectively analyzed IIP patients who had been admitted to our hospital. Their chest high-resolution computed tomography images were classified into two groups according to the presence of PE. We then performed a cluster analysis to identify the phenotypes of IIP patients with PE. Results Forty-four (53.7%) out of 82 patients had at least mild emphysema in their bilateral lungs. The cluster analysis separated the IIP patients with PE into three clusters. The overall survival rate of one cluster that consisted of mainly idiopathic pulmonary fibrosis (IPF) patients was significantly worse than those of the other clusters. Conclusion Three different phenotypes can be identified in IIP patients with PE, and IPF with PE is a distinct clinical phenotype with a poor prognosis.

BACKGROUND Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and glycosaminoglycan side chains of syndecan-4 bind to several proteins, suggesting several biological functions. However, the role of syndecan-4 in acute bacterial pneumonia has not yet been elucidated. METHODS Serum syndecan-4 levels were measured in patients with acute pneumonia, and the relationships between serum syndecan-4 levels and clinical parameters were analyzed. Next, we treated wild-type and syndecan-4-deficient mice with Streptococcus pneumoniae intranasally and analyzed the phenotype of syndecan-4-deficient mice. RESULTS In the patients with acute pneumonia, serum syndecan-4 levels were significantly higher than in the healthy volunteers and correlated negatively with the pneumonia severity score. In addition, in patients who improved with short-term antibiotic therapy, serum syndecan-4 levels were higher on admission and gradually increased during antibiotic therapy. Furthermore, in syndecan-4-deficient mice, the survival rate was significantly worse, and total neutrophil counts in bronchoalveolar lavage fluid, bacterial counts in blood, and plasma levels of inflammatory cytokines were significantly higher than in wild-type mice. CONCLUSIONS These results suggest that syndecan-4 has an anti-inflammatory function in acute pneumonia and could serve as a useful biomarker in these patients.

Background Idiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) turnover resulting in fibrosis. The pathogenic remodeling includes increased levels of protein synthesis and degradation mediated by proteases such as matrix metalloproteinases (MMPs). Acute exacerbations of IIP (AE-IIP) represent periods of increased disease activity. Pulmonary involvement, especially pulmonary fibrosis, is common in patients suffering from systemic sclerosis (SSc) and ankylosing spondylitis (AS) Objectives The objective was to investigate if ECM remodeling was altered during AE-IIP by serological neo-epitope biomarkers. Methods Serum samples were collected from patients with IIP at clinically stable disease (S-IIP, n=29) and at AE-IIP (n=68). Of these, 11 and 28 patients, respectively, had idiopathic pulmonary fibrosis (IPF). 28 IIP patients had paired samples. Biomarkers released from MMP-mediated degradation of collagen type I (C1M), III (C3M), IV (C4M), and VI (C6M), elastin (ELM7), versican (VCANM), biglycan (BGM), and C-reactive protein (CRPM) were assessed in serum by competitive ELISAs utilizing neo-epitope specific monoclonal antibodies. Data were analysed using Mann-Whitney test, Wilcoxon test, Spearman9s rank correlation, and Kaplan-Meier curves as appropriate. Results Mean age of patients was 71 (range 54–86) at AE-IIP and 69 (range 55–83) at S-IIP. Mean forced vital capacity in percentage of predicted value (%FVC) was 55.6% (SD 19.5) at AE-IIP and 79.0% (SD 26.5) at S-IIP. Serum levels of C4M, C6M, and CRPM at AE-IIP were positively correlated with %FVC (r=0.37, p=0.008; r=0.36, p=0.011; r=0.33, p=0.020; respectively). Serum levels of C4M (p=0.002) and C6M (p=0.024) were increased while ELM7 (p=0.024) and VCANM (p Conclusions Serological levels of neo-epitope biomarkers of ECM degradation were associated with AE-IIP and weakly with mortality outcome. These results indicate that the rate of ECM remodeling in the lungs of patients with IIP is significantly altered during periods of high disease activity such as an acute exacerbation. The difference in degradation profile for the proteins studied is intriguing and indicate activation of different processes contributing to AE-IIP. Neo-epitope biomarkers of the ECM might be useful in identifying patients diagnosed with rheumatic disease as SSc and AS with pulmonary involvement. Acknowledgements The Danish Research Foundation Disclosure of Interest None declared

Background Patients with idiopathic interstitial pneumonia can experience acute respiratory worsening, also known as acute exacerbation, with a large deterioration on prognosis. The precise mechanism remains unclear; however, syndecan-4 may be involved. Syndecan-4, a transmembrane heparan sulfate proteoglycan expressed in a variety of cells (e.g., epithelial cells, macrophages, fibroblasts, etc.), performs various biological roles by binding to several proteins through its heparan sulfate glycosaminoglycan side chains. The goal of this study was to clarify the role of syndecan-4 in acute exacerbation of idiopathic interstitial pneumonia. Methods Patients with idiopathic interstitial pneumonia who had been sequentially admitted to our hospital due to acute exacerbation were retrospectively analyzed. First, serum syndecan-4 levels in the acute exacerbation and clinically stable phases were compared. Second, the relationship between serum syndecan-4 levels and clinical parameters was analyzed. Third, the relationship between serum syndecan-4 levels and prognosis was evaluated. Results Serum syndecan-4 levels were significantly lower in patients with acute exacerbation of idiopathic interstitial pneumonia than in patients in the clinically stable phase. Serum syndecan-4 levels also showed a significant positive correlation with white blood cell count and a weak positive tendency with KL-6 and baseline %VC. Prognosis was significantly worse in patients with idiopathic interstitial pneumonia with high baseline serum syndecan-4 levels than with low baseline levels. Multiple logistic analysis indicated baseline serum syndecan-4 level as the only prognostic predictor following acute exacerbation. Conclusions Baseline serum syndecan-4 is a possible prognostic biomarker after the onset of acute exacerbation of idiopathic interstitial pneumonia.

Background: Cough is a major symptom of asthma. Cough frequency monitoring devices are now available to objectively measure cough and they have the potential to assess the severity of asthma and monitor the response to treatment. Objective: Firstly, we examined whether there is a difference in cough frequency pattern between asthmatic and non-asthmatic cough. Secondary, cough frequency monitoring could be applicable for assess the response to asthma therapy. Methods: Forty eight asthmatic subjects and 64 non-asthmatic subjects who were suffering from cough were enrolled in the study. They wore the automated Leicester cough monitor (LCM), which is a validated cough monitoring tool, for 24 hours before treatment. At the same time Visual Analog Scale (VAS) and Leicester cough questionnaire (LCQ) were completed. 17 asthmatic subjects, also completed LCM and questionnaires after asthma treatment. Results: Cough frequency while sleeping was significantly higher in asthmatic subjects than in non-asthmatic subjects (14 vs 4c/hr; p=0.01). Cough frequency significantly correlated with VAS (cough severity, frequency) and LCQ scores (r=0.50, 0.43, -0.57, respectively; p Conclusions: LCM appears useful to objectively assess cough in asthma management. Furthermore, a raised cough frequency during sleep may raise the possibility of allergy induced cough.

Background: We have reported serum and sputum hydrogen sulfide (H 2 S) could be a marker of neutrophilic dominant obstructive asthma (Saito JACI 2013). However, relationship between H 2 S and disease activities in asthma remained unclear. Objectives: Serum and sputum H 2 S levels during a stable and an exacerbation state were compared. Additionally, differences in H 2 S levels between controlled and uncontrolled asthmatics were examined. Finally, we evaluated the associations between H 2 S and parameters related to disease activities. Methods: Fifty five stable asthmatics (s-BA), 23 asthmatics with exacerbation (AE-BA), and 15 healthy subjects (HS) were recruited in the study. In 13 asthmatics, paired serum samples during a stable and an exacerbation state were obtained.Serum and sputum H 2 S levels were measured using the ion electrode method as previously reported. Results: Serum H 2 S levels in s-BA were significantly higher compared to those in HS whereas serum H 2 S levels in AE-BA were significantly lower than those in s-BA and similar to HS. Sputum H 2 S levels in AE-BA were higher compared to s-BA and HS. In comparison with serum H 2 S levels between a stable and an exacerbation state obtained from the same subjects, serum H 2 S levels during exacerbation state were significantly lower than those during stable state. When classified s-BA into control status, serum H 2 S levels in uncontrolled asthmatics were significantly lower than those in controlled asthmatics. Finally, the only association between sputum H 2 S levels and sputum neutrophil percentages could be seen in this population. Conclusions: Serum and sputum H 2 S may provide better information on predicting uncontrolled and/or exacerbated asthmatic subjects.

RATIONALE: We have reported that diurnal variation of fractional exhaled nitric oxide (FeNO) could be useful in the assessment of asthma control and future risks of asthma exacerbation (Saito J, ERJ 2014). However, it is unclear how asthma treatment influences diurnal variation of FeNO. OBJECTIVES: To compare diurnal variation of FeNO before and after intensive asthma treatment. METHODS: Sixteen healthy subjects and ten uncontrolled or partially controlled asthmatic subjects were enrolled in the study. In asthmatic subjects, FeNO and peak expiratory flow (PEF) were measured twice daily using portable monitors (NObreath® and PIKO®) for 1 week before starting intensive treatment and for 2 weeks thereafter. In healthy subjects, FeNO and PEF were also measured for 2 weeks as a normal control. Asthma control questionnaire (ACQ) and spirometry before and after treatment were also performed to assess the treatment effect. RESULTS: Diurnal FeNO variation and mean FeNO levels in asthmatic subjects were significantly greater than in healthy subjects, whereas mean PEF levels, but not diurnal PEF variation, were significantly lower compered to healthy subjects. For the FeNO and PEF levels before and after treatment, only diurnal FeNO variation in the 2nd week after treatment decreased significantly than before treatment. Other parameters including mean FeNO levels, mean PEF levels and diurnal PEF variation showed no significant change after 2 weeks of treatment, although 9 of 10 asthmatic subjects achieved good control by ACQ scores and spirometry. CONCLUSIONS: These results suggest thatdiurnal FeNO variation is useful for predicting short-term treatment effect in asthmatic patients.

Background: The cardio-ankle vascular index (CAVI) is an index of the overall stiffness of the artery from the origin of the aorta to the ankle. Aims and objectives: The aim of this study was to investigate CAVI and its relationships to clinical parameters in adult asthmatics. Methods: Adult asthmatics underwent CAVI measurement at Fukushima Medical University Hospital. We calculated normal values of CAVI based on the linear regression equation consisting of age and sex in healthy Japanese individuals without coronary risk factors. We defined the percent-predicted CAVI (%CAVI) as the ratio of CAVI in asthmatics to a normal value. Asthmatics with higher than 100% of %CAVI were defined as the high CAVI group and those with 100% or lower of %CAVI were defined as the low CAVI group. Asthmatics who smoked more than 10 pack-years were excluded from the study. Results: A total of 52 asthmatics (29–80 years, female/male = 41/11) were included. Mean (±SD) %CAVI was 98.4 ± 11.7 %. The prevalence in the high CAVI group was 52% (27 out of 52 asthmatics). In this group, age, age at asthma onset, and serum IgE level were significantly higher, and forced expiratory volume in one-second percent (FEV1/FVC) at stable condition was significantly lower than in the low CAVI group. No significant differences were observed in the severity of asthma, incidence of asthma attacks, and annual decline in forced expiratory volume in one second between both groups. In 31 asthmatics without diabetes mellitus and dyslipidemia, there was a significant negative correlation between %CAVI and FEV1/FVC at stable condition. Conclusions: These results suggest a possible relation between CAVI and airway remodeling in asthma.

背景．小細胞肺癌（SCLC）に対して外科切除と化学療法施行15年目に，肺扁平上皮癌を発症した症例を報告する．症例．80歳，男性．66歳時小細胞肺癌で外科切除後にシスプラチン，エトポシドとドキソルビシンの化学療法を施行．15年目に喘鳴，息切れが出現し，受診．右主気管支に扁平上皮癌を認め，放射線治療を施行．症状軽快され，奏効が得られた．結論．I期小細胞肺癌は手術療法と術後化学療法を併用することにより予後が期待できる．小細胞肺癌長期生存中に新たに肺癌が合併する可能性があり，注意深い経過観察が必要と考えられた．

We observed cholesterol-like crystals (Crystal X) in the bronchoalveolar lavage fluid (BALF) smears of patients with diffuse pulmonary disease. We analyzed the clinical data of patients with and without crystals, and elucidated the structure of Crystal X and its concentration in the BALF.Two hundred eighty-nine patients with diffuse pulmonary disease who underwent bronchoalveolar lavage (BAL) were analyzed. The relationships between the presence and number of Crystal X in BALF smears and clinical parameters were investigated. Furthermore, structure determination and quantitative analyses of the crystals were performed.Seventy-five (26.0%) patients had Crystal X in their BALF. The crystals were frequently observed in patients with chronic interstitial pneumonia (CIP, 60/160=35.3%). Patients with Crystal X exhibited significantly higher serum Kerbs von Lungren 6 antigen and surfactant protein-D levels (P0.01) and lower percentage vital capacity (P0.05) than patients without Crystal X. The number of crystals was significantly correlated with these parameters. The presence of crystals was also associated with a lower survival rate at 1 year after the BAL. The interfacial angles of the crystals were 126±2° and 144±2°, different from those of cholesterol monohydrate crystals. Infrared absorption spectrometry showed Crystal X was cholesteryl palmitate. Its concentration was significantly higher in BALF with crystals than in BALF without crystals (P0.01).Crystal X in the BALF of patients with diffuse pulmonary disease was identified as cholesteryl palmitate, which may be a useful prognostic biomarker for CIP.

Midkine is a low‐molecular‐weight heparin‐binding protein that is strongly expressed mainly in the midgestation period and has various physiological activities such as in development and cell migration. Midkine has been reported to be strongly expressed in cancer cells and in inflammation and repair processes, and to be involved in the pathogenesis of various diseases. However, its role in the lung is poorly understood. In this study, we analyzed the clinical characteristics of idiopathic pulmonary fibrosis patients in relation to midkine expression and used a mouse bleomycin‐induced pulmonary fibrosis model to investigate the role of midkine in pulmonary fibrosis. In the idiopathic pulmonary fibrosis patients, the serum midkine level was significantly higher than in healthy subjects, and midkine levels in the serum and bronchoalveolar lavage (BAL) fluid correlated positively with the percentage of inflammatory cells in the BAL fluid. In wild‐type mice, intratracheal bleomycin administration increased midkine expression in lung tissue. Additionally, compared with wild‐type mice, midkine‐deficient mice showed low expression of both collagen and α‐smooth muscle actin, as well as a low value for the pathological lung fibrosis score after bleomycin administration. Furthermore, the total cell count and lymphocyte percentage in the BAL fluid, as well as TNF‐α and transforming growth factor‐β expression in lung tissue, were significantly lower in the midkine‐deficient mice compared with wild‐type mice. These results suggest that midkine is involved in the development of pulmonary fibrosis by regulating inflammatory cell migration into the lung, and TNF‐α and transforming growth factor‐β expression.

Krebs von den Lungen-6 (KL-6) is a high-molecular-weight glycoprotein which is elevated in serum of patients with interstitial pneumonia (IP). Serum KL-6 level is clinically used for the diagnosis of IP as well as the evaluation of its disease activity. KL-6 is originally identified when exploring novel soluble antigens in patients with lung cancer, and is known to be elevated in patients with several malignant tumors. The risk of malignant tumors is high in IP patients with polymyositis and dermatomyositis (PM/DM), and follow-up of KL-6 levels may allow earlier detection of such tumors. However, to date, there are only a few reports showing the usefulness of following-up serum KL-6 levels for finding malignant tumors in IP patients with PM/DM. Here, we described the first patient in whom increased serum KL-6 led to the diagnosis of colon cancer during follow-up of DM-associated IP.

Secretoglobin (SCGB) 3A2, previously known as uteroglobin-related protein 1, is a secreted protein highly expressed in the epithelial cells of the airways. It has been demonstrated that SCGB3A2 is involved in allergic airway inflammation such as bronchial asthma. However, the role of SCGB3A2 in lipopolysaccharide (LPS)-induced airway inflammation has yet to be reported. The goal of this study was therefore to clarify the role of SCGB3A2 in LPS-induced airway inflammation. We stimulated BEAS-2B, human bronchial epithelial cells, with LPS and analyzed messenger RNA (mRNA) expression of tumor necrosis factor (TNF)-α and CXCL8 with or without pre-incubation of SCGB3A2. The mRNA expression of TNF-α and CXCL8 was clearly upregulated 3 h after LPS stimulation, and pre-incubation of SCGB3A2 significantly inhibited the upregulation of the mRNA expression. The pre-incubation of SCGB3A2 also inhibited LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein kinase in BEAS-2B cells. Furthermore, PD98059, a specific inhibitor for ERK, as well as SP600125, a specific inhibitor for JNK, inhibited LPS-induced mRNA upregulation of inflammatory mediators. These results demonstrate the novel biological activity of SCGB3A2, which is that it attenuates LPS-induced inflammation in bronchial epithelial cells through inhibition of ERK and JNK activation.