Search

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disorder. It often causes weight loss, which is considered a poor prognostic factor. A Japanese herbal Kampo medicine, Hochuekkito (TJ-41), has been reported to prevent systemic inflammation and weight loss in COPD patients, but the underlying biological mechanisms remain unknown. In the present study, we investigated the role of TJ-41 in vivo using a mouse model of lung emphysema. We used lung epithelium-specific Taz conditional knockout mice (Taz CKO mice) as the lung emphysema model mimicking the chronic pulmonary inflammation in COPD. Acute inflammation was induced by intratracheal lipopolysaccharide administration, simulating COPD exacerbation. Mice were fed a diet containing 2% TJ-41 or a control diet. Taz CKO mice showed increased numbers of inflammatory cells in the bronchoalveolar lavage fluid compared to control mice. This effect was reduced by TJ-41 treatment. In the acute exacerbation model, TJ-41 mitigated the increased numbers of inflammatory cells in the bronchoalveolar lavage fluid and attenuated lung inflammation in histopathological studies. Additional in vitro experiments using the human macrophage cell line U-937 demonstrated that lipopolysaccharide-induced tumor necrosis factor-alpha expression was significantly downregulated by TJ-41. These results suggest that TJ-41 has anti-inflammatory effects in lung emphysema both in the chronic phase and during an acute exacerbation. In conclusion, our study sheds light on the anti-inflammatory effects of TJ-41 in lung emphysema. This establishes its potential as a new anti-inflammatory therapy and a preventive medicine for exacerbations during the long-time maintenance of COPD patients.

The mTOR pathway is one of the key signal cascades in the pathogenesis of idiopathic pulmonary fibrosis. Previous studies have mainly focused on this pathway in the fibroblasts and/or myofibroblasts, but not in the epithelial cells. In this study, we sought to investigate the role of the mTOR pathway in lung epithelial cells in lung fibrosis. Using Sftpc-mTORSL1+IT transgenic mice, in which active mTOR is conditionally expressed in lung epithelial cells, we assessed the effects of chronically activated mTOR in lung epithelial cells on lung phenotypes as well as bleomycin-induced lung fibrosis. Furthermore, we isolated alveolar epithelial cell type 2 from mice and performed RNA sequencing. Sftpc-mTORSL1+IT transgenic mice had no obvious abnormal findings, but, after bleomycin administration, showed more severe fibrotic changes and lower lung compliance than control mice. RNA sequencing revealed Angptl4 (angiopoietin-like protein 4) as a candidate downstream gene of the mTOR pathway. In vitro studies revealed that ANGPTL4, as well as mTOR, promoted tight junction vulnerability and epithelial-mesenchymal transition. mTOR activation in lung epithelial cells promoted lung fibrosis and the expression of ANGPTL4, a novel downstream target of the mTOR pathway, which could be related to the etiology of fibrosis.

Background Obstructive lung disease (OLD) is a risk factor for postoperative pulmonary complications (PPC) and is incidentally discovered during preoperative evaluation. The key treatments for OLD are inhaled long-acting bronchodilators (LAB). However, the advantage of preoperative bronchodilator treatment for patients with OLD remains unclear. The aim of this study is to elucidate the effect of preoperative LAB treatment in patients with untreated OLD on postoperative outcomes. Methods In this propensity-matched cohort study, we included patients who were referred to the pulmonologists for untreated OLD. The patients were either treated with LAB or left untreated. The primary outcome was the incidence of prolonged oxygen therapy (>3 days) in the postoperative period. We evaluated patients' characteristics with and without the use of LAB using propensity score (PS) matching weight. Subsequently, the outcomes in the two groups were compared. Results We analysed 614 patients; 132 patients were part of the LAB group and 482 were included in the control group. In the crude analysis, the incidence of prolonged oxygen therapy was higher in the LAB group than in the control group (odds ratio [OR] = 1.35; P = 0.04). However, after PS matching weight, no statistically significant differences in prolonged oxygen therapy (OR = 1.15), incidence of prolonged intensive care unit stay, endotracheal re-intubation postoperatively and in-hospital death between the groups were identified. Conclusion There is a limited benefit of preoperative treatment with inhaled LAB for the reduction of PPC in patients with untreated OLD.

Background: Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) are key downstream effectors of the Hippo pathway. TAZ is considered as a homolog of YAP. Recent studies revealed that TAZ knockout mice exhibit lung emphysema, while YAP knockout mice show abnormalities in bronchial morphogenesis, and the cause of these differences remains unknown. Objective: To compare the role of TAZ and YAP in lung development, by generating lung epithelial-specific conditional knockout mice (cKO mice) of Taz and Yap. Methods: Taz and Yap cKO mice were generated by using a surfactant protein C-driven Cre recombinase allele. To identify genes affected by Yap ablation from lung epithelial cells, RNA-seq analysis was performed in Yap cKO embryo lung. We confirmed our in vivo findings by using human lung epithelial cell lines, which YAP and TAZ were suppressed by siRNA. Results: In lung development, Yap was highly expressed in embryonic stage of lung development, conversely Taz was highly expressed in the early alveolar stage. Taz cKO adult mice exhibited lung emphysema in adults, whereas Yap cKO mice were lethal at birth and showed bronchial branching abnormalities. RNA-seq analysis revealed that YAP ablation decreased Sonic hedgehog (Shh) expression, which is essential in proper branching morphogenesis. We also found that TGF-beta stimulation induces Shh expression in cell lines, which was suppressed by knockdown of TAZ or YAP. Conclusion: Our results indicate that TAZ and YAP function at different stages of lung development in lung epithelial cells and essential for proper lung development. Our results suggested the existence of a novel pathway between TGF-beta and Shh.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a systemic inflammatory disease, and often causes weight loss, which is considered as a poor prognostic factor. A Japanese herbal medicine, Hochu-ekki-to (TJ-41), was reported to prevent weight loss in a small study of COPD patients, while its biological mechanism is unknown. Objective: The objective of our study was to evaluate the role of TJ-41 using mouse lung emphysema model, and to investigate its biological mechanism in vivo and in vitro. Methods: We used lung epithelial specific Taz conditional knockout mice (Taz CKO mice) as emphysema model mice, and fed a diet containing 2% TJ-41 or a control diet for 12 weeks. During administration, body weights were measured. After seeding, Taz CKO mice and control mice were subjected to BALF analysis, and lung mRNA expressions of inflammatory cytokines were analysed by RT-PCR. Results: After treatment, Taz CKO mice showed higher body weights in TJ-41 group compared to control diet group. BALF analysis showed decreased number of inflammatory cells in TJ-41 group, and among inflammatory cytokines, IL-8 expression was also significantly decreased. Conclusion: Our results suggest the possibility that TJ-41 attenuates lung inflammation, and thereby prevents weight loss of COPD patients. Among inflammatory cytokines, IL-8 is downregulated by administration of TJ-41, which coincided with decreased number of inflammatory cells in BALF in TJ-41 group. Our study sheds light on the biological mechanism of TJ-41 in lung emphysema, and suggests its potential for anti-inflammatory therapy for COPD patients.

Backgrounds: Ｃhronic obstructive pulmonary disease (COPD) is a pulmonary disease with permanent airflow obstruction and emphysema, and acute exacerbation of COPD is often induced by infection often resulting in a poor prognosis. Reactive oxygen species (ROS), producted in mitochondria, has been reported to accelerate the establishment of COPD. Sirtuin3(SIRT3) is the mitochondrial NAD(+)-dependent deacetylase, which regulates ROS formation and proinflammatory responses. It is also reported to be related with lifespan longevity. Aims: The aim of our study was to investigate the role of SIRT3 in COPD exacerbation mouse model generated by porcine pancreatic elastase(PPE) and lipopolysaccharide(LPS). Methods: PPE followed by LPS was administered intratracheally to wild-type (WT) or SIRT3 overexpressing transgenic(SIRT3 OE), SIRT3 knockout (SIRT3 KO) male mice. The next day (early phase) and 4weeks later (late phase) after LPS administration, BALF analysis and lung function test was conducted. Results: In early phase, the BALF cell count of SIRT3 OE mice was significantly increased compared to control WT mice, whereas that of SIRT3 KO mice was significantly decreased. In late phase, the lung compliance was increased in SIRT3 OE mice compared to WT mice, and decreased in SIRT3 KO mice. Conclusions: Our study showed that SIRT3 surpressed acute lung injury and emphysematous worsening in COPD model mice. SIRT3 would serve as a new therapeutic target to COPD and COPD exacerbation.

Background/aim Cytological analysis for diagnosing malignant pleural effusion associated with lung adenocarcinoma (Ad-MPE) shows limited sensitivity and novel diagnostic biomarkers are needed. The aim of this study was to evaluate the profile of four microRNAs (miRNAs) in exosomes in Ad-MPE and benign (non-neoplastic) pleural effusion (BPE). Materials and methods A total of 56 pleural effusion samples from patients with lung adenocarcinoma and benign diseases were collected. Exosomal miRNA expressions were evaluated using real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). Results The expression levels of miR-182 and miR-210 were significantly higher in the Ad-MPE than in the BPE samples. The receiver operating characteristics curve analyses of miR-182 and miR-210 for diagnosis of Ad-MPE yielded areas under the receiver operating characteristic curves of 0.87 and 0.81, respectively. Conclusion These miRNA signatures may have a diagnostic potential for differentiating Ad-MPE from BPE.

Background: COPD and Bronchial asthma (BA) are implicated in increased risk of postoperative pulmonary complications (PPC). Risks of PPC in patients with FEV1/FVC Aims and Objectives: The aim was to elucidate the risk of PPC in patients with FEV1/FVC Methods: We retrospectively evaluated patients consulted to the Department of Respiratory Medicine for FEV1/FVC Results: Out of 408 incidentally detected FEV1/FVC 3 days (P=0.03) and oxygen therapy >4 days (P=0.02) after surgery. Whereas, patients without CADs fulfilling FEV1%pred 3 days (P=0.04). Conclusions: Depending on severity of airway obstruction, patients with FEV1/FVC