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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.

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.

BACKGROUNDDue to the dissemination of vaccination against severe acute respiratory syndrome coronavirus 2 in the elderly, the virus-susceptible subjects have shifted to unvaccinated non-elderlies. The risk factors of COVID-19 deterioration in non-elderly patients without respiratory failure have not yet been determined. This study was aimed to create simple predicting method to identify such patients who have high risk for exacerbation.METHODSWe analyzed the data of 1,675 patients aged under 65 years who were admitted to hospitals with mild-to-moderate COVID-19. For validation, 324 similar patients were enrolled. Disease progression was defined as administration of medication, oxygen inhalation and mechanical ventilator starting one day or longer after admission.RESULTSThe patients who exacerbated tended to be older, male, had histories of smoking, and had high body temperatures, lower oxygen saturation, and comorbidities such as diabetes/obesity and hypertension. Stepwise logistic regression analyses revealed that comorbidities of diabetes/obesity, age ≥ 40 years, body temperature ≥ 38°C, and oxygen saturation < 96% (DOATS) were independent risk factors of worsening COVID-19. As a result two predictive scores were created: DOATS score, which includes all the above risk factors; and DOAT score, which includes all factors except for oxygen saturation. In the original cohort, the areas under the receiver operating characteristic curve of the DOATS and DOAT scores were 0.789 and 0.771, respectively. In the validation, the areas were 0.702 and 0.722, respectively.CONCLUSIONWe established two simple prediction scores that can quickly evaluate the risk of progression of COVID-19 in non-elderly, mild/moderate patients.SummaryThe risk stratification models using independent risks, namely comorbidity of diabetes or obesity, age ≥ 40 years, high body temperature ≥ 38□, and oxygen saturation < 96%, DOATS and DOAT scores, predicted worsening COVID-19 in patients with mild-to-moderate cases.

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.

Hyperhomocysteinemia (HHcy) was reported to enhance endoplasmic reticulum (ER) stress and subsequent apoptosis in several cells. However, the precise mechanisms of smoking susceptibility associated with HHcy has not been fully elucidated. This study included seven- to nine-week-old C57BL6 male mice induced with HHcy 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 HHcy compared to that in the control group. The apoptotic A549 cells increased as Hcy 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. HHcy exacerbated smoking-induced pulmonary emphysema and ER stress-induced alveolar cell apoptosis. ER stress in alveolar cells was reversed by vitamin B12 and folate supplementation, suggesting that HHcy could be the new therapeutic target to improve smoking susceptibility.

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.

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.

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.

Background Diabetes has been reported as a comorbidity of chronic obstructive pulmonary disease (COPD) in Western countries, but it has not been demonstrated in epidemiological reports in Japan. The purpose of this study was to clarify whether the relationship between airflow obstruction and diabetes can be confirmed in a Japanese general population. Methods From 2004 to 2006, blood sampling and pulmonary function tests were performed on 3045 people over the age of 40 years in annual health check-ups held in Takahata, Yamagata Prefecture, Japan. Pulmonary function was re-evaluated in 2009 and 2011. Results The prevalence of diabetes did not differ between subjects with and without airflow obstruction. Furthermore, although body mass index decreased, no increase in the prevalence of diabetes was observed with the progression of airflow obstruction. The annual changes in forced expiration volume in 1s (FEV1) did not differ depending on the presence or absence of diabetes in the study population. Conclusion There was no difference in the prevalence of diabetes between subjects with airflow obstruction and those without. As patients with COPD in Japan are thinner than in the West, diabetes may not be a common comorbidity in Japanese patients with COPD.

Background The designation of some cardiac-specific proteins as prognostic biomarkers in chronic obstructive pulmonary disease (COPD) exacerbations suggest that the process of exacerbation involves cardiomyocyte injury. Among these cardiac biomarkers, heart-type fatty acid binding protein (h-FABP) is considered a very sensitive diagnostic marker for cardiomyocyte injury and a prognostic marker in chronic heart failure. However, the prognostic usefulness of h-FABP in patients with COPD remains unclear. Methods Sixty-six patients were enrolled in this study. Subjects who recovered from COPD exacerbation and were discharged without needing home oxygen therapy were defined as the improved group. Those who died of the COPD exacerbations, were discharged but needed home oxygen therapy, or were transferred to a rehabilitation hospital for respiratory failure and the remaining aftereffects of exacerbation were defined as the unimproved group. Results The improved and unimproved groups included 54 and 12 subjects, respectively. Compared with the improved group, the unimproved group had significantly higher white blood cell counts and alanine aminotransferase, lactate dehydrogenase, blood urea nitrogen (BUN), uric acid, potassium, and h-FABP levels, and significantly lower total protein and total cholesterol levels and estimated glomerular filtration rates, either at admission or during the early morning within 24h after admission. A multivariate analysis revealed that higher serum h-FABP and potassium levels were independently predictive of a poor prognosis following a COPD exacerbation, and a receiver operating characteristic curve analysis yielded a cutoff of 4.5ng/ml for predicting lack of improvement. Conclusion H-FABP may predict the outcomes of COPD exacerbation.

Background: Iron is essential metal for living. We reported association of serum iron and pulmonary function in smoking man. Further, several studies show hypoironemia and anemia were associated with pulmonary function or respiratory disease. However, it is not clear how iron play role in lungs. We used cigarette smoke exposure model to evaluate influence of iron deficiency. Methods: Iron deficient (ID) or normal diet (control) were fed to C57BL/6J male mice for 3 weeks. Later, mice were exposed cigarette smoke. Bronchoalveolar lavage (BAL) and pulmonary function tests were performed after 2 weeks of cigarette exposure or 8 weeks of cigarette exposure. Results: In mice exposed to CS for 2 weeks, concentration of alveolar macrophages in BAL fluid recovered from ID mice were significantly increased compared to those from control mice. Further, interleukin (IL)-6 levels in BAL fluid were significantly increased from baseline in ID mice, but this increase of IL-6 was not observed in control mice. In mice exposed to CS for 8 weeks, total lung capacity in ID mice was significantly larger than those in control mice. Conclusion: Iron deficiency may enhance airway inflammation and worsen pulmonary function in mice exposed to cigarette smoke.

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.