Hideyuki Takeshima

TAZ contributes to pulmonary fibrosis by activating profibrotic functions of lung fibroblasts

Transcriptional coactivator with PDZ-binding motif (TAZ) regulates a variety of biological processes. Nuclear translocation and activation of TAZ are regulated by multiple mechanisms, including actin cytoskeleton and mechanical forces. TAZ is involved in lung alveolarization during lung development and Taz-heterozygous mice are resistant to bleomycin-induced lung fibrosis. In this study, we explored the roles of TAZ in the pathogenesis of idiopathic pulmonary fibrosis (IPF) through histological analyses of human lung tissues and cell culture experiments. TAZ was highly expressed in the fibroblastic foci of lungs from patients with IPF. TAZ controlled myofibroblast marker expression, proliferation, migration, and matrix contraction in cultured lung fibroblasts. Importantly, actin stress fibers and nuclear accumulation of TAZ were more evident when cultured on a stiff matrix, suggesting a feedback mechanism to accelerate fibrotic responses. Gene expression profiling revealed TAZ-mediated regulation of connective tissue growth factor (CTGF) and type I collagen. Clinical relevance of TAZ-regulated gene signature was further assessed using publicly available transcriptome data. These findings suggest that TAZ is involved in the pathogenesis of IPF through multifaceted effects on lung fibroblasts.

Interleukin-17A and Toll-Like Receptor 3 Ligand Poly(I:C) Synergistically Induced Neutrophil Chemoattractant Production by Bronchial Epithelial Cells

Chronic inflammatory airway diseases, such as bronchial asthma and chronic obstructive pulmonary disease, are common respiratory disorders worldwide. Exacerbations of these diseases are frequent and worsen patients’ respiratory condition and overall health. However, the mechanisms of exacerbation have not been fully elucidated. Recently, it was reported that interleukin (IL)-17A might play an important role in neutrophilic inflammation, which is characteristic of such exacerbations, through increased production of neutrophil chemoattractants. Therefore, we hypothesized that IL-17A was involved in the pathogenesis of acute exacerbation, due to viral infection in chronic inflammatory airway diseases. In this study, we assessed chemokine production by bronchial epithelial cells and investigated the underlying mechanisms. Comprehensive chemokine analysis showed that, compared with poly(I:C) alone, co-stimulation of BEAS-2B cells with IL-17A and poly(I:C) strongly induced production of such neutrophil chemoattractants as CXC chemokine ligand (CXCL)8, growth-related oncogene (GRO), and CXCL1. Co-stimulation synergistically induced CXCL8 and CXCL1 mRNA and protein production by BEAS-2B cells and normal human bronchial epithelial cells. Poly(I:C) induced chemokine expression by BEAS-2B cells mainly via Toll-like receptor 3/TIR-domain-containing adapter-inducing interferon-β–mediated signals. The co-stimulation with IL-17A and poly(I:C) markedly activated the p38 and extracellular-signal-regulated kinase 1/2 pathway, compared with poly(I:C), although there was little change in nuclear factor-κB translocation into the nucleus or the transcriptional activities of nuclear factor-κB and activator protein 1. IL-17A promoted stabilization of CXCL8 mRNA in BEAS-2B cells treated with poly(I:C). In conclusion, IL-17A appears to be involved in the pathogenesis of chronic inflammatory airway disease exacerbation, due to viral infection by promoting release of neutrophil chemoattractants from bronchial epithelial cells.

Guidelines-concordant empiric antimicrobial therapy and mortality in patients with severe community-acquired pneumonia requiring mechanical ventilation

BACKGROUND Community-acquired pneumonia (CAP) has high morbidity and mortality among adults. Several clinical guidelines recommend prompt administration of combined antimicrobial therapy. However, the association between guidelines concordance and mortality in patients with severe pneumonia remains unclear. The present study aimed to examine the impact of guidelines-concordant empiric antimicrobial therapy on 7-day mortality in patients with extremely severe pneumonia who required mechanical ventilation at admission, using a nationwide inpatient database in Japan. METHODS Data of CAP patients aged over 20 years who required mechanical ventilation at admission between April 2012 and March 2014 were retrospectively analyzed. Multivariable logistic regression analysis was performed to examine the association between guidelines-concordant empiric antimicrobial therapy and all-cause 7-day mortality, with adjustment for patient backgrounds and pneumonia severity. RESULTS There were a total of 3719 eligible patients, 836 (22.5%) of whom received guidelines-concordant combination therapy. Overall, 7-day mortality was 29.5%. Higher 7-day mortality was associated with advanced age, confusion, lower systolic blood pressure, malignant tumor or immunocompromised state, and C-reactive protein ≥20mg/dl or infiltration occupying two-thirds of one lung on chest radiography. After adjustment for these variables, guidelines-concordant combined antimicrobial therapy was associated with significantly lower 7-day mortality (odds ratio: 0.78; 95% confidence interval: 0.65-0.95; P=0.013). CONCLUSIONS Adherence to initial empiric treatment as recommended by the guidelines was associated with better short-term prognosis in patients with extremely severe pneumonia who required mechanical ventilation on hospital admission.

Development of a nomogram for predicting in-hospital mortality of patients with exacerbation of chronic obstructive pulmonary disease

Background and objectives Patients with chronic obstructive pulmonary disease (COPD) often experience exacerbations of their disease, sometimes requiring hospital admission and being associated with increased mortality. Although previous studies have reported mortality from exacerbations of COPD, there is limited information about prediction of individual in-hospital mortality. We therefore aimed to use data from a nationwide inpatient database in Japan to generate a nomogram for predicting in-hospital mortality from patients’ characteristics on admission. Methods We retrospectively collected data on patients with COPD who had been admitted for exacerbations and been discharged between July 1, 2010 and March 31, 2013. We performed multivariable logistic regression analysis to examine factors associated with in-hospital mortality and thereafter used these factors to develop a nomogram for predicting in-hospital prognosis. Results The study comprised 3,064 eligible patients. In-hospital death occurred in 209 patients (6.8%). Higher mortality was associated with older age, being male, lower body mass index, disturbance of consciousness, severe dyspnea, history of mechanical ventilation, pneumonia, and having no asthma on admission. We developed a nomogram based on these variables to predict in-hospital mortality. The concordance index of the nomogram was 0.775. Internal validation was performed by a bootstrap method with 50 resamples, and calibration plots were found to be well fitted to predict in-hospital mortality. Conclusion We developed a nomogram for predicting in-hospital mortality of exacerbations of COPD. This nomogram could help clinicians to predict risk of in-hospital mortality in individual patients with COPD exacerbation.

Effect of outpatient therapy with inhaled corticosteroids on decreasing in-hospital mortality from pneumonia in patients with COPD.

Background and objectives Inhaled corticosteroids (ICS) and long-acting inhaled bronchodilators (IBD) are beneficial for the management of COPD. Although ICS has been reported to increase the risk of pneumonia in patients with COPD, it remains controversial whether it influences mortality. Using a Japanese national database, we examined the association between preadmission ICS therapy and in-hospital mortality from pneumonia in patients with COPD. Methods We retrospectively collected data from 1,165 hospitals in Japan on patients with COPD who received outpatient inhalation therapy and were admitted with pneumonia. Patients were categorized into those who received ICS with IBD and those who received IBD alone. We performed multivariate logistic regression analysis to examine the association between outpatient ICS therapy and in-hospital mortality, adjusting for the patients’ backgrounds. Results Of the 7,033 eligible patients, the IBD alone group (n=3,331) was more likely to be older, have lower body mass index, poorer general conditions, and more severe pneumonia than the ICS with IBD group (n=3,702). In-hospital mortality was 13.2% and 8.1% in the IBD alone and the ICS with IBD groups, respectively. After adjustment for patients’ backgrounds, the ICS with IBD group had significantly lower mortality than the IBD alone group (adjusted odds ratio, 0.80; 95% confidence interval, 0.68–0.94). Higher mortality was associated with older age, being male, lower body mass index, poorer general status, and more severe pneumonia. Conclusion Outpatient inhaled ICS and IBD therapy was significantly associated with lower mortality from pneumonia in patients with COPD than treatment with IBD alone.

Mortality associated with bone fractures in COPD patients

Background and objective COPD is well known to frequently coexist with osteoporosis. Bone fractures often occur and may affect mortality in COPD patients. However, in-hospital mortality related to bone fractures in COPD patients has been poorly studied. This retrospective study investigated in-hospital mortality of COPD patients with bone fractures using a national inpatient database in Japan. Methods Data of COPD patients admitted with bone fractures, including hip, vertebra, shoulder, and forearm fractures to 1,165 hospitals in Japan between July 2010 and March 2013, were extracted from the Diagnosis Procedure Combination database. The clinical characteristics and mortalities of the patients were determined. Multivariable logistic regression analysis was also performed to determine the factors associated with in-hospital mortality of COPD patients with hip fractures. Results Among 5,975 eligible patients, those with hip fractures (n=4,059) were older, had lower body mass index (BMI), and had poorer general condition than those with vertebral (n=1,477), shoulder (n=281), or forearm (n=158) fractures. In-hospital mortality was 7.4%, 5.2%, 3.9%, and 1.3%, respectively. Among the hip fracture group, surgical treatment was significantly associated with lower mortality (adjusted odds ratio, 0.43; 95% confidence interval, 0.32–0.56) after adjustment for patient backgrounds. Higher in-hospital mortality was associated with male sex, lower BMI, lower level of consciousness, and having several comorbidities, including pneumonia, lung cancer, congestive heart failure, chronic liver disease, and chronic renal failure. Conclusion COPD patients with hip fractures had higher mortality than COPD patients with other types of fracture. Surgery for hip fracture was associated with lower mortality than conservative treatment.

Influence of Parkinsonism on outcomes of elderly pneumonia patients

INTRODUCTION Pneumonia is one of the most frequent reasons for hospitalization in patients with Parkinsons disease. The present study aimed to evaluate the impact of Parkinsonism on the clinical courses of elderly patients hospitalized for pneumonia. METHODS We conducted a retrospective cohort study of patients aged ≥60 years who were hospitalized for pneumonia, using data from a national inpatient database in Japan. We performed one-to-four matching for age and sex between patients with and without Parkinsonism. Multivariable regression analyses were carried out for in-hospital mortality, length of stay, and discharge to home. RESULTS Patients with Parkinsonism had significantly lower in-hospital mortality than those without Parkinsonism (odds ratio, 0.81; 95% confidence interval, 0.74-0.89). Length of stay was 8.1% longer in patients with Parkinsonism. Patients with Parkinsonism were less likely to be discharged to home (odds ratio, 0.62; 95% confidence interval, 0.58-0.67). CONCLUSION Parkinsonism was not an independent predictor of in-hospital mortality, but was related to prolonged length of stay and discharge other than to home in patients with pneumonia.

Mechanism of Periostin Production in Human Bronchial Smooth Muscle Cells

Background: Asthma is a chronic airway inflammatory disease characterized by airway remodeling, in which the bronchial smooth muscle (BSM) cells play an important role. Periostin, a biomarker that reflects Th2-driven inflammatory diseases such as asthma, may play an important role in the asthmatic airway. Although periostin is mainly produced in airway epithelial cells and fibroblasts after interleukin (IL)-13 stimulation, whether BSM cells produce periostin remains unclear. Therefore, we investigated periostin production in BSM cells and the mechanisms involved. Methods: Human BSM cells were cultured, and the effect of IL-13 stimulation on periostin production was evaluated using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). We evaluated the phosphorylation of signal transducer and activator of transcription factor 6 (STAT6), extracellular signal-regulated kinase (ERK)1/2, and Akt after IL-13 stimulation. Furthermore, using ELISA, we evaluated the influence of several phosphorylation inhibitors on periostin production. Results: Periostin mRNA expression increased in a dose- and time-dependent manner after IL-13 stimulation; periostin production was induced 24 and 48 h after stimulation. IL-13 stimulation induced the phosphorylation of STAT6, ERK1/2, and Akt. IL-13-induced periostin production was attenuated by inhibiting STAT6 phosphorylation and strongly suppressed by inhibiting mitogen-activated protein kinase kinase 1/2 phosphorylation or phosphatidylinositol 3-kinase (PI3K) phosphorylation. Conclusions: BSM cells produced periostin after IL-13 stimulation, via the JAK/STAT6, ERK1/2, and PI3K/Akt pathways. Understanding the mechanism of periostin production in BSM cells may help to clarify asthma pathogenesis.

Cerebral Arterial Air Embolism after Diagnostic Flexible Fiberoptic Bronchoscopy: A Case Report and Review of the Literature

Cerebral arterial air embolism (CAAE) is an extremely rare complication of diagnostic flexible fiberoptic bronchoscopy, reported to occur once about every 103978 examinations. In all the eight cases of CAAE reported previously, the patients had undergone transbronchial lung biopsy (TBLB) or transbronchial needle aspiration (TBNA) prior to the onset of CAAE. Herein, we describe the case of a 77-year-old patient with double primary lung cancer who developed CAAE after bronchial curette cytology, which is considered to be less invasive than TBLB or TBNA. The patient was treated with supplemental oxygen, but paresis of the left upper arm and left spatial neglect remained. This is the first report of CAAE occurring after bronchial curettage during diagnostic flexible fiberoptic bronchoscopy.

Oral fluorouracil vs vinorelbine plus cisplatin as adjuvant chemotherapy for stage II-IIIA non-small cell lung cancer: Propensity score-matched and instrumental variable analyses

Adjuvant chemotherapy with vinorelbine plus cisplatin (VNR/CDDP) is a standard regimen for treatment of postoperative stage II‐IIIA non‐small cell lung cancer (NSCLC). However, oral fluorouracil offers a feasible alternative adjuvant chemotherapeutic regimen. We compared the prognoses of patients with NSCLC treated with adjuvant chemotherapy with either VNR/CDDP or oral fluorouracil.