Lysophospholipid Acyltransferase 9 Promotes Emphysema Formation via Platelet-activating Factor.

Cigarette smoking is known to be the leading cause of chronic obstructive pulmonary disease (COPD). However, the detailed mechanisms have not been elucidated. PAF (platelet-activating factor), a potent inflammatory mediator, is involved in the pathogenesis of various respiratory diseases such as bronchial asthma and COPD. We focused on LPLAT9 (lysophospholipid acyltransferase 9), a biosynthetic enzyme of PAF, in the pathogenesis of COPD. LPLAT9 gene expression was observed in excised COPD lungs and single-cell RNA sequencing data of alveolar macrophages (AMs). LPLAT9 was predominant and upregulated in AMs, particularly monocyte-derived AMs, in patients with COPD. To identify the function of LPLAT9/PAF in AMs in the pathogenesis of COPD, we exposed systemic LPLAT9-knockout (LPALT9-/-) mice to cigarette smoke (CS). CS increased the number of AMs, especially the monocyte-derived fraction, which secreted MMP12 (matrix metalloprotease 12). Also, CS augmented LPLAT9 phosphorylation/activation on macrophages and, subsequently, PAF synthesis in the lung. The LPLAT9-/- mouse lung showed reduced PAF production after CS exposure. Intratracheal PAF administration accumulated AMs by increasing MCP1 (monocyte chemoattractant protein-1). After CS exposure, AM accumulation and subsequent pulmonary emphysema, a primary pathologic change of COPD, were reduced in LPALT9-/- mice compared with LPLAT9+/+ mice. Notably, these phenotypes were again worsened by LPLAT9+/+ bone marrow transplantation in LPALT9-/- mice. Thus, CS-induced LPLAT9 activation in monocyte-derived AMs aggravated pulmonary emphysema via PAF-induced further accumulation of AMs. These results suggest that PAF synthesized by LPLAT9 has an important role in the pathogenesis of COPD.

Participant Selection from the General Japanese Population for Pulmonary Function Tests Using a Questionnaire on Symptoms and Smoking Habits during Annual Health Checkups: The Yamagata-Takahata Study.

Objective Pulmonary function tests are essential for diagnosing respiratory diseases, such as chronic obstructive pulmonary disease (COPD), but are typically not performed in Japan during annual health checkups, which hinders the early diagnosis of respiratory diseases. Methods Individuals who agreed to participate in the Yamagata-Takahata study during medical checkups in Takahata (Yamagata Prefecture, Japan) in 2011 were examined. We interviewed 669 participants (49.0% men; mean age, 67.7 years old) regarding their respiratory symptoms and smoking habits and performed pulmonary function tests during the study. Results Based on pulmonary function test results, 141 participants had pulmonary dysfunction, and 115 had obstructive pulmonary dysfunction. The risk of respiratory dysfunction, particularly obstructive respiratory dysfunction, was examined by referring to a questionnaire tool for an early COPD diagnosis. The associations between age, the smoking history, respiratory symptoms, and obstructive respiratory dysfunction were evaluated. Obstructive respiratory dysfunction was found in 17.6% of participants ≥50 years old and 19.5% ≥60 years old, 30.3% had a smoking history, and 32.8% had respiratory symptoms. Furthermore, the participants with multiple factors had a higher probability of obstructive respiratory dysfunction. Conclusion Subjects with obstructive pulmonary dysfunction are expected to be efficiently identified by extracting individuals by age and smoking habit and through a respiratory symptom questionnaire, although pulmonary function tests cannot be performed for all individuals during health checkups.

On the decomposition of WKL!!

From the conceptual viewpoint, many mathematical propositions implicitly contain at least two kinds of principle. One is a logical principle such as the law-of-excluded-middle or De Morgan's law. Another is a function-existence principle. For both conceptual and practical reasons, it is an interesting enterprise to calibrate how amount of logical and function-existence principles are implicit in mathematical theorems and axioms. This is the topic of constructive reverse mathematics, which specifies necessary and sufficient axioms to prove each mathematical proposition constructively. In this paper, we decompose weak König's lemma with a uniqueness hypothesis [Formula: see text] by Moschovakis, into logical and function-existence principles in a recent framework of constructive reverse mathematics. This article is part of the theme issue 'Modern perspectives in Proof Theory'.

Effect of hyperhomocysteinemia on a murine model of smoke-induced pulmonary emphysema.

Hyperhomocysteinemia was reported to enhance endoplasmic reticulum (ER) stress and subsequent apoptosis in several cells. However, the precise mechanisms of smoking susceptibility associated with hyperhomocysteinemia has not been fully elucidated. This study included 7- to 9-week-old C57BL6 male mice induced with hyperhomocysteinemia and were exposed to cigarette smoke (CS). A549 cells (human alveolar epithelial cell line) were cultured with homocysteine and were exposed to cigarette smoke extract (CSE) to observe cell viability and expression of proteins related to the ER stress. After 6 months of CS exposure, pulmonary emphysema was more severely induced in the group under the condition of hyperhomocysteinemia compared to that in the control group. The apoptotic A549 cells increased as homocysteine concentration increased and that was enhanced by CSE. Protein expression levels of ER stress markers were significantly increased after simultaneous stimulation. Notably, vitamin B12 and folate supplementation improved ER stress after simultaneous stimulation of A549 cells. In this study, we showed that hyperhomocysteinemia exacerbates CS exposure-induced emphysema in mice, suggesting that hyperhomocysteinemia and CS stimulation enhance ER stress and subsequent induced apoptosis in alveolar epithelial cells. It was suggested that there is a synergistic effect between homocysteine and CS.

Role of CC Chemokine Ligand 17 in Mouse Models of Chronic Obstructive Pulmonary Disease.

Lung function deterioration is significantly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). We previously reported that CC chemokine ligand 17/thymus and activation-regulated chemokine (CCL17/TARC) could be a predictive factor of lung function decline in patients with COPD. However, the role of CCL17 in the pathogenesis of COPD is unclear. Here we examined the role of CCL17 in lung inflammation using mouse COPD models. Exposure to cigarette smoking induced CCL17 production in bronchial epithelial cells and accumulation of alveolar macrophages in the lungs. Intranasal administration of recombinant CCL17 further enhanced cigarette smoke-induced macrophage accumulation and also aggravated elastase-induced pulmonary emphysema. We confirmed that cigarette smoke (CS) extract as well as hydrogen peroxide upregulated CCL17 in BAES-2B cells. Of note, macrophages of both M1 and M2 surface markers were accumulated by cigarette smoke. Both alveolar macrophage accumulation via exposure to cigarette smoking and emphysematous changes induced by elastase administration were significantly reduced in CCL17-deficient mice. We further demonstrated that CCL17 strongly induced the expression of CC chemokine ligand 2 (CCL2), a chemoattractant for macrophages, in RAW264.7 cells, and its production was inhibited by knockdown of CCR4, the receptor of CCL17. Collectively, the present results demonstrate that CCL17 is produced by lung epithelial cells upon CS exposure. Furthermore, CCL17 is involved in CS-induced accumulation of alveolar macrophages and development of elastase-induced pulmonary emphysema, possibly through CCL17-induced production of CCL2 by macrophages. Our findings may provide a new insight into the pathogenesis of COPD.

The Incidence and Risk Analysis of Lung Cancer Development in Patients with Chronic Obstructive Pulmonary Disease: Possible Effectiveness of Annual CT-Screening.

PURPOSE: Lung cancer is a serious complication in patients with chronic obstructive pulmonary disease (COPD) and accounts for approximately 15% of deaths in patients with COPD. However, with the exception of emphysema, few reports to date have been published on the factors that predict lung cancer development in COPD patients. It has been reported that patients with COPD develop lung cancer at a rate of 0.8% - 1.7%/year, but the incidence may be higher in the Japanese population. Therefore, we investigated the incidence of lung cancer and the lung cancer mortality rate in Japanese COPD patients, as well as factors that are associated with the development of lung cancer in COPD patients. PATIENTS AND METHODS: We followed up 224 patients with stable COPD and performed CT examinations at least once per year. The incidence of lung cancer was recorded and data at enrollment were compared with data of the group that did not develop lung cancer. RESULTS: Over a median follow-up period of 4.58 years, lung cancer was newly diagnosed in 19 patients; the incidence of lung cancer in this population was 1.85%/year. Patients who developed lung cancer had more severe emphysema assessed by CT and GOLD classification and were more likely to be current smokers than those who did not develop lung cancer. No other significant differences were observed between these two groups. Mortality was significantly increased in patients who developed lung cancer compared with those who did not. CONCLUSION: In COPD patients, the incidence of lung cancer is higher and the development of lung cancer worsens the prognosis; however, lung cancer development is unpredictable and attention should be paid to all patients. Annual CT screening is important for early detection of lung cancer.

Association between low mean corpuscular hemoglobin and prognosis in patients with exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Several studies have demonstrated the association between mean corpuscular hemoglobin concentration (MCHC), a hematological index used for the assessment of anemia, and the prognosis of patients with heart disease. While the red cell distribution width (RDW) is known to be related to the prognosis of patients with chronic obstructive pulmonary disease (COPD), few studies have focused on the association between the MCHC and COPD. Therefore, we examined the association between the MCHC and prognosis in patients with exacerbation of COPD. METHODS: We examined the association between the 30-day mortality and clinical findings in patients with COPD exacerbation who were hospitalized between October 2008 and December 2018. RESULTS: We enrolled 195 patients with COPD exacerbation (average age: 76.4 years; 181 men, 14 women). The MCHC was significantly lower, while the RDW was significantly higher in the 27 patients (13.8%) who died during the 30-day observation period compared to those in the patients who survived. Multivariate logistic regression analysis revealed that the MCHC was independently associated with 30-day mortality. The area under the curve calculated from the MCHC obtained from peripheral blood was 0.688 and the cutoff value was 31.6 g/dL, with a sensitivity of 0.593 and specificity of 0.810 (p = 0.0001). CONCLUSION: The MCHC might be a valuable biomarker for evaluating the prognosis of patients with COPD exacerbation.

Thymus and activation-regulated chemokine (TARC/CCL17) predicts decline of pulmonary function in patients with chronic obstructive pulmonary disease.

BACKGROUND: The deterioration of pulmonary function, such as FEV1-decline, is strongly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). However, few investigations shed light on useful biomarkers for predicting the decline of pulmonary function. We evaluated whether thymus and activation-regulated chemokine (TARC), a Th2 inflammation marker, could predict rapid FEV1-decline in COPD patients. METHODS: We recruited 161 patients with stable COPD and performed pulmonary function test once every six months. At the time of registration, blood tests, including serum levels of TARC were performed. We assessed the correlation between changes in parameters of pulmonary function tests and serum levels of TARC. The rapid-decline in pulmonary function was determined using 25th percentile of change in FEV1 or FEV1 percent predicted (%FEV1) per year. RESULTS: In the FEV1-rapid-decline group, the frequency of exacerbations, the degree of emphysema, and serum levels of TARC was higher than in the non-rapid-decline group. When using %FEV1 as a classifier instead of FEV1, age, the frequency of exacerbations, the degree of emphysema and serum levels of TARC in the rapid-decline group was significantly greater than those in the non-rapid-decline group. In univariate logistic regression analysis, TARC was the significant predictive factor for rapid-decline group. In multivariate analysis adjusted for emphysema, serum levels of TARC are independently significant predicting factors for the rapid-decline group. CONCLUSIONS: TARC is an independent predictive biomarker for the rapid-decline in FEV1. Measuring serum TARC levels may help the management of COPD patients by predicting the risk of FEV1 decline.

Examination of predictable factors of perioperative respiratory complications by preoperative forced oscillation technique parameters.

In this study, we investigated whether pulmonary function tests such as forced oscillation technique parameters could predict perioperative respiratory complications. In the results of our study, perioperative respiratory complications cannot be predicted using the results of preoperative pulmonary function tests and forced oscillation technique parameters. Patients who are judged by comprehensive preoperative judgment to be suitable for general anesthesia may not need to consider the risk of perioperative complications using pulmonary function test.

Effect of Iron Deficiency on a Murine Model of Smoke-induced Emphysema.

Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Smoking susceptibility is important for the onset and development of COPD. We previously reported an association between serum iron concentrations and pulmonary function in male smokers. However, the mechanism governing smoking susceptibility in relation to iron deficiency is unclear; this study aimed to elucidate this mechanism. C57BL/6 male mice were fed an iron-deficient or normal diet and then exposed to cigarette smoke. BAL, histological analysis, and pulmonary function tests were performed after cigarette smoke exposure. Human alveolar type II epithelial A549 cells were treated with an iron chelator. Subsequently, A549 cells were exposed to cigarette smoke extract. In mice exposed to cigarette smoke for 2 weeks, the concentration of alveolar macrophages in the BAL fluid recovered from iron-deficient mice was significantly higher than that in normal diet mice. IL-6 and MCP-1 (monocyte chemotactic protein 1) concentrations in the BAL fluid increased significantly from baseline in iron-deficient mice, but not in normal diet mice. In mice exposed to cigarette smoke for 8 weeks, the pathological mean linear intercepts, physiological total lung capacity, and functional residual capacity in the lungs of iron-deficient mice were significantly greater than in normal diet mice. Phosphorylation of NF-κB was enhanced in the lungs of iron-deficient mice exposed to cigarette smoke and in the iron-chelating A549 cells exposed to cigarette smoke extract. Iron deficiency exaggerated cigarette smoke-induced pulmonary inflammation, suggesting that it may accelerate COPD development.

E-selectin as a prognostic factor of patients hospitalized due to acute inflammatory respiratory diseases: a single institutional study.

When examining patients with acute inflammatory respiratory diseases, it is difficult to distinguish between infectious pneumonia and interstitial pneumonia and predict patient prognosis at the beginning of treatment. In this study, we assessed whether endothelial selectin (E-selectin) predicts the outcome of patients with acute inflammatory respiratory diseases. We measured E-selectin serum levels in 101 patients who were admitted to our respiratory care unit between January 2013 and December 2013 because of acute inflammatory respiratory diseases that were eventually diagnosed as interstitial pneumonia (n = 38) and lower respiratory tract infection (n = 63). Seven of these patients (n = 101) died. The pneumonia severity score was significantly higher and the oxygen saturation of arterial blood measured by pulse oximeter (SpO2)/fraction of inspiratory oxygen (FiO2) was significantly lower in the deceased patients than in the surviving patients. There were significantly fewer peripheral lymphocytes and significantly higher E-selectin serum levels in the deceased patients than in the surviving patients. In the multiple logistic regression analysis, the E-selectin serum levels and SpO2/FiO2 ratio were independent predictive factors of prognosis. The risk of death during acute respiratory disease was determined using a receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) was 0.871 as calculated from the ES, and the cutoff value was 6453.04 pg/ml, with a sensitivity of 1.00 and a specificity of 0.72 (p = 0.0027). E-selectin may be a useful biomarker for predicting the prognosis of patients with acute inflammatory respiratory diseases.

Smaller erector spinae muscle size is associated with inability to recover activities of daily living after pneumonia treatment.

BACKGROUND: Elderly patients who are hospitalized due to pneumonia experience deterioration of their activities of daily living (ADL) during this period; in some cases, this loss of ADL is not recovered at the end of antibiotic treatment. In this study, we examined whether erector spinae muscle cross-sectional area (ESMCSA) measured by computed tomography (CT) could predict a low level of ADL at the end of antibiotic treatment for pneumonia. METHODS: Eighty patients (mean age 74.8 years) with pneumonia, who were admitted to Yamagata university hospital between 2015 and 2016, were analyzed retrospectively. In all cases, chest CT was performed on admission and ESMCSA was measured at the level of the 12th thoracic vertebra. Patient levels of ADL were also measured, both on admission and at the end of treatment, using the Barthel Index. RESULTS: Patients with lower levels of ADL at the end of treatment were significantly older and tended to have a lower body mass index, poorer nutritional status, and more severe pneumonia than did patients who were self-reliant. Significantly smaller ESMCSAs were noted in patients who required assistance at the end of treatment than in those who were self-reliant. In multivariate logistic regression analysis, smaller ESMCSA was significantly associated with a lower level of ADL at the end of treatment, independent of age, sex, severity of pneumonia, nutritional status, or dehydration status. CONCLUSION: These results suggest that ESMCSA can predict ADL level after antibiotic treatment of pneumonia.

Impact of cigarette smoking on decline in forced expiratory volume in 1s relative to severity of airflow obstruction in a Japanese general population: The Yamagata-Takahata study.

BACKGROUND: Few studies are available regarding the annual decline of forced expiratory volume in 1s (FEV1) in chronic obstructive pulmonary disease patients with mild airflow obstruction. This study sought to clarify to what extent cigarette-smoking individuals with mild airflow obstruction lose pulmonary function annually. METHODS: From 2004 to 2006, pulmonary function tests were performed on people >40 years of age, during the annual health checkup held in Takahata, Yamagata, Japan (initial study population, n=3253). In 2011, pulmonary function tests were performed again on participants who agreed to undergo reexamination (follow-up study population, n=838). RESULTS: Smokers have decreased pulmonary function in terms of percent forced vital capacity (FVC), %FEV1, and FEV1/FVC; the stages of airflow obstruction were also more severe in smokers than never-smokers. The annual decline in FEV1 was significantly greater in smokers than in never-smokers. The median annual decline in FEV1 was most significant in individuals with mild airflow obstruction. The annual decline in FEV1 was greater in smokers with mild airflow obstruction than in smokers with moderate airflow obstruction. In analyzing the decline in %FEV1, the annual change in smokers with mild airflow obstruction was greater than that in smokers with normal spirometric values. CONCLUSION: The annual decline in FEV1 was most significant in smokers with mild airflow obstruction in a Japanese general population. This highlights the importance of early detection of chronic obstructive pulmonary disease patients among the general population in order to prevent disease progression in undiagnosed patients.

MafB enhances efferocytosis in RAW264.7 macrophages by regulating Axl expression.

The transcription factor MafB is involved in cellular differentiation and phagocytosis in macrophages. Macrophages phagocytose apoptotic cells in vivo; this process, which is known as efferocytosis, requires Axl receptor tyrosine kinase (Axl) activity. However, the association between MafB and efferocytosis, as well as that between MafB and Axl, in macrophages is unknown. We hypothesized that MafB modulates macrophage efferocytosis by regulating Axl expression. Fluorescent-labeled apoptotic thymocytes were added to RAW264.7-MafB-shRNA and control cells, and the proportion of phagocytosis-positivey fluorescence microscopy and flow cytometry. In addition, Axl mRNA and protein were quantified by real-time PCR and western blotting in each group. RAW264.7-MafB-shRNA cells were transfected with a plasmid expressing green fluorescent protein (GFP)-tagged Axl or a control empty plasmid expressing only GFP. The capacity for phagocytosis of apoptotic cells was assessed in GFP-positive cells gated based on fluorescence intensity. In RAW264.7-MafB-shRNA cells, capacity for phagocytosis of apoptotic thymocytes was significantly reduced compared with that of control cells, as determined by fluorescence microscope and flow cytometry. Axl mRNA and protein expression was significantly reduced in RAW264.7-MafB-shRNA cells relative to control cells. Furthermore, the capacity of RAW264.7-MafB-shRNA cells, transfected with an Axl-expressing plasmid, for phagocytosis of apoptotic thymocytes was significantly greater than that of cells transfected with the control plasmid. Collectively, the present findings indicate that MafB enhances efferocytosis by regulating Axl expression in RAW264.7 macrophages.

MafB silencing in macrophages does not influence the initiation and growth of lung cancer induced by urethane.

An increased number of tumor-associated macrophages (TAMs) that exhibit the M2 macrophage phenotype is related to poorer prognosis in cancer patients. MafB is a transcription factor regulating the differentiation of macrophages. However, involvement of MafB for the development of TAMs is unknown. This study was designed to investigate the role of MafB in a murine urethane-induced lung cancer model. Urethane was injected intraperitoneally into wild-type and dominant-negative MafB transgenic mice. Twenty-four weeks later, mice were sacrificed and their lungs removed for pathological analysis. The numbers and mean areas of lung cancer were evaluated. In addition, the numbers of Mac-3-positive macrophages were evaluated in each tumor. The numbers and mean areas of lung cancer induced by urethane administration were not significantly different between wild-type and dominant-negative MafB transgenic mice. The numbers of TAMs in lung cancer tissue were not significantly different between the two groups. MafB silencing using dominant-negative MafB did not influence the initiation and growth of lung cancer in mice exposed to urethane. These data suggest that MafB may not be related to the development of TAMs.

Decreased left ventricular stroke volume is associated with low-grade exercise tolerance in patients with chronic obstructive pulmonary disease.

BACKGROUND: Low-grade exercise tolerance is associated with a poor prognosis in patients with chronic obstructive pulmonary disease (COPD). The 6 min walk test (6MWT) is commonly used to evaluate exercise tolerance in patients with COPD. However, little is known regarding the relationship between cardiac function and exercise tolerance in patients with COPD. The aim of this study was to identify predictive factors in cardiac function for low-grade exercise tolerance in patients with stable COPD. METHODS: We recruited 57 patients with stable COPD (men 54, women 3) to perform the 6MWT. Patients with underlying orthopaedic disease or heart failure were excluded. Cardiac function was evaluated by echocardiography and contrast-enhanced cardiac CT. We also measured pulmonary function and the 6MWT distance. RESULTS: Forced expiratory volume in 1 s (FEV1) and per cent predicted FEV, along with left ventricular end diastolic volume and left ventricular cardiac output as measured by cardiac CT, were significantly related to the 6MWT distance. On multivariate analysis, left ventricular stroke volume was the factor most closely associated with a decreased walked distance in the 6MWT. CONCLUSIONS: Decreased left ventricular stroke volume was associated with low-grade exercise tolerance in patients with stable COPD without heart failure.

MafB enhances the phagocytic activity of RAW264.7 macrophages by promoting Fcgr3 expression.

This study was designed to investigate whether MafB influences the phagocytic activity of macrophages by modulating the expression of the Fc receptors for IgG (FcγRs), Fcgr2b and Fcgr3. In macrophages, FcγRs are critical for the phagocytosis of opsonized pathogens. Of these receptors, Fcgr3 has been shown to play an important role in host defense. As a model to evaluate the mechanism by which MafB influences phagocytosis, we utilized a macrophage cell-line that constitutively expresses a MafB-specific short hairpin (sh)RNA (RAW264.7-MafB-shRNA). Specifically, the levels of Fc receptor mediated-phagocytosis and the levels of FcγRs surface expression were evaluated by flow cytometry analysis, while quantitative real-time PCR analysis was utilized to examine the mRNA expression levels of FcγRs. Compared to the control cell population, RAW264.7-MafB-shRNA cells exhibited significant reductions in Fcgr3 expression and Fc receptor-mediated phagocytosis, but no difference in Fcgr2b expression. Likewise, there was markedly decreased surface expression of Fcgr3 antigen, but not Fcgr2b antigen, in RAW264.7-MafB-shRNA, compared to the control cells. Meanwhile, the observed reduction in the phagocytic activity of the MafB-shRNA-expressing cells was attenuated by ectopic expression of Fcgr3. Together, the results presented here indicate that MafB influences the phagocytic activity of macrophages by promoting Fcgr3, but not Fcgr2b, expression.

Role of chemokine C-C motif ligand-1 in acute and chronic pulmonary inflammations.

BACKGROUND: Chemokine C-C motif ligand 1 (CCL1) accumulates C-C motif chemokine receptor 8 positive leukocytes to the inflammatory sites. Single-nucleotide polymorphisms in the chemokine CCL1 gene are associated with exacerbation of chronic obstructive lung disease. However, it is unclear whether CCL1 has immunomodulatory functions during pulmonary inflammation. This study aimed to elucidate this issue using newly generated transgenic mice that express CCL1 in the lungs (SPC-CCL1 mice). METHODS: To evaluate the phenotypes of these mice, lung section and bronchoalveolar lavage (BAL) fluid analyses were performed. We intratracheally administered lipopolysaccharide (LPS) or Mycobacterium bovis as a model of acute or chronic lung inflammation, respectively. RESULTS: No histological differences were observed between lung tissue from SPC-CCL1 Tg and wild-type mice in the resting condition and after LPS administration. In the resting condition, the total BAL cell concentration was lower in SPC-CCL1 Tg mice than in wild-type mice (P = 0.0097). Flow cytometric analyses showed that SPC-CCL1 Tg mice had fewer F4/80-positive cells than wild-type mice (P = 0.0278). After intratracheal LPS administration, CCL1 overexpression changed neither the total numbers nor population of BAL cells. After mycobacterial administration, pulmonary granuloma formation was significantly enhanced. The degree of Immunostaining for endoplasmic reticulum to nucleus signaling 1, a molecule associated with granuloma formation and endoplasmic reticulum stress, was significantly enhanced in the granuloma regions of SPC-CCL1 mice treated with Mycobacterium, compared to those of wild-type mice. CONCLUSIONS: CCL1 overexpression in the lungs did not change the acute inflammatory response induced by LPS, but enhanced granuloma formation after mycobacterial treatment, possibly through enhancing endoplasmic reticulum stress.

Predictors for mortality from respiratory failure in a general population.

Risk factors for death from respiratory failure in the general population are not established. The aim of this study was to determine the characteristics of individuals who die of respiratory failure in a Japanese general population. In total, 3253 adults aged 40 years or older participated in annual health check in Takahata, Yamagata, Japan from 2004 to 2006. Subject deaths through the end of 2010 were reviewed; 27 subjects died of respiratory failure (pneumonia, n = 22; COPD, n = 1; pulmonary fibrosis, n = 3; and bronchial asthma, n = 1). Cox proportional hazard analysis revealed that male sex; higher age, high levels of D-dimer and fibrinogen; lower body mass index (BMI) and total cholesterol; and history of stroke and gastric ulcer were independent risk factors for respiratory death. On analysis with C-statistics, net reclassification improvement, and integrated discrimination improvement, addition of the disease history and laboratory data significantly improved the model prediction for respiratory death using age and BMI. In conclusion, we identified risk factors for mortality from respiratory failure in a prospective cohort of a Japanese general population. Men who were older, underweight, hypocholesterolemic, hypercoagulo-fibrinolytic, and had a history of stroke or gastric ulcer had a higher risk of mortality due to respiratory failure.

Reference values of MostGraph measures for middle-aged and elderly Japanese individuals who participated in annual health checkups.

BACKGROUND: The forced oscillation technique (FOT) can measure respiratory system resistance and reactance under tidal volume respiration. MostGraph is a device that incorporates the FOT and enables the immediate, three-dimensional visualization of resistance and reactance parameters. The aim of this study was to establish MostGraph reference values for middle-aged and elderly Japanese individuals. METHODS: From 2004 to 2006, 3253 subjects living in Takahata, Yamagata underwent spirometry. Of these, 872 again underwent spirometry in 2011, and 784 (368 men, ages 46-89 years; 416 women, ages 47-90 years) underwent FOT examinations using MostGraph-01. RESULTS: In this study population, 19.0% of the men and 91.5% of the women were life-long never smokers. Abnormal spirometric findings were observed in 30.2% of the men and 14.6% of the women. Although the respiratory system resistance and reactance parameters obtained using MostGraph were not distributed normally, normal distribution was achieved via natural logarithm (R5, R20, Fres, and ALX), square root (R5-R20), or exponential (X5) transformation. Furthermore, the transformed values were converted back to the actual values after determining the values representing one and two standard deviations from the mean. CONCLUSION: Respiratory system resistance and reactance reference values were determined using MostGraph in middle-aged and elderly Japanese individuals who participated in annual health checkups.