Michiaki Mishima

Kyoto University, Kioto, Kyoto, Japan

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Publications (476)1567.85 Total impact

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    ABSTRACT: BACKGROUND: Matrix metalloproteinases (MMPs) are believed to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and MMP-7 has been described as a useful biomarker for IPF. However, little is known regarding the significance of MMP-10 as a biomarker for IPF. METHODS: This observational cohort study included 57 patients with IPF. Serum MMPs were comprehensively measured in all patients, and the relationships between these markers and both disease severity and prognosis were evaluated. Bronchoalveolar lavage fluid (BALF) MMP-7 and -10 levels were measured in 19 patients to investigate the correlation between these markers and their corresponding serum values. Immunohistochemical staining for MMP-10 was also performed in IPF lung tissue. RESULTS: Serum MMP-7 and -10 levels correlated significantly with both the percentage of predicted forced vital capacity (ρ = -0.31, p = 0.02 and ρ = -0.34, p < 0.01, respectively) and the percentage of predicted diffusing capacity of the lung for carbon monoxide (ρ = -0.32, p = 0.02 and ρ = -0.43, p < 0.01, respectively). BALF MMP-7 and -10 levels correlated with their corresponding serum concentrations. Only serum MMP-10 predicted clinical deterioration within 6 months and overall survival. In IPF lungs, the expression of MMP-10 was enhanced and localized to the alveolar epithelial cells, macrophages, and peripheral bronchiolar epithelial cells. CONCLUSIONS: MMP-10 may be a novel biomarker reflecting both disease severity and prognosis in patients with IPF.
    Full-text · Article · Sep 2016 · Respiratory Research
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    ABSTRACT: Background: Alpha1-antitrypsin (ΑAT) deficiency (AATD), a condition of little or no AAT in the serum, is believed to be extremely rare in Japan. However, no such nationwide epidemiological survey has been conducted. The Respiratory Research Failure Group and Japanese Respiratory Society (JRS) cooperated to conduct this survey. Methods: The survey questionnaire was sent by post to 1598 hospitals that have 200 or more beds (excluding mental hospitals), and by e-mail to members of the JRS. Hospitals failing to respond were followed-up by phone. Results: 1467 hospitals replied [response rate=91.8% (1467/1598)], and 114 members responded. Of the 14 probands registered from 10 hospitals and one local practitioner, 9 had severe and 5 had mild AATD. Eleven of these patients were diagnosed with COPD, 1 with COPD and bronchiectasis, 1 with pulmonary emphysema without airflow obstruction, and the remaining 1 with bronchiectasis without airflow obstruction. Mutation analysis of the SERPINA1 gene was performed in 7 patients, 6 of whom (85.7%) had homozygous PI*S iiyama. The prevalence of AATD in Japan was thus estimated to be 24 patients, with a 95% confidence interval (22, 27). When asked if they would prescribe AAT augmentation therapy, 6 of the 10 (60.0%) of respondent attending physicians answered affirmatively if health insurance would cover the treatment. Conclusions: This nationwide survey confirmed that AATD is extremely rare in Japan. Six of 10 care-giving physicians would offer AAT augmentation therapy if the therapy were covered by health insurance in Japan.
    No preview · Article · Jan 2016 · Respiratory Investigation
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    ABSTRACT: Background: Lung perfusions after single lung transplantation (SLT) have not been fully clarified in patients with interstitial lung disease (ILD). The present study aimed to investigate temporal changes in native lung perfusion and their associated clinical factors in patients with ILD who have undergone SLT. Methods: Eleven patients were enrolled. Perfusion scintigraphy was serially performed up to 12 months after SLT. Correlations between the postoperative perfusion ratio in the native lung and clinical parameters, including preoperative perfusion ratio and computed tomography (CT) volumetric parameters, were evaluated. Results: On average, the perfusion ratio of the native lung was maintained at approximately 30% until 12 months after SLT. However, the ratio declined more significantly in idiopathic pulmonary fibrosis (IPF) than in other ILDs (p = 0.014). The perfusion ratio before SLT was significantly correlated with that at 3 months after SLT (ρ = 0.64, p = 0.048). The temporal change of the perfusion ratio in the native lung did not correlate with those of the CT parameters. Conclusion: The preoperative perfusion ratio may predict the postoperative perfusion ratio of the native lung shortly after SLT in ILD. Perfusion of the native lung may decline faster in IPF compared with other ILDs. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Clinical Transplantation
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    ABSTRACT: Background: Lung transplantation has been established as the definitive treatment option for patients with advanced lymphangioleiomyomatosis (LAM). However, the prognosis after registration and the circumstances of lung transplantation with sirolimus therapy have never been reported. Methods: In this national survey, we analyzed data from 98 LAM patients registered for lung transplantation in the Japan Organ Transplantation Network. Results: Transplantation was performed in 57 patients as of March 2014. Survival rate was 86.7% at 1 year, 82.5% at 3 years, 73.7% at 5 years, and 73.7% at 10 years. Of the 98 patients, 21 had an inactive status and received sirolimus more frequently than those with an active history (67% vs. 5%, p<0.001). Nine of twelve patients who remained inactive as of March 2014 initiated sirolimus before or while on a waiting list, and remained on sirolimus thereafter. Although the statistical analysis showed no statistically significant difference, the survival rate after registration tended to be better for lung transplant recipients than for those who awaited transplantation (p = 0.053). Conclusions: Lung transplantation is a satisfactory therapeutic option for advanced LAM, but the circumstances for pre-transplantation LAM patients are likely to alter with the use of sirolimus.
    Full-text · Article · Jan 2016 · PLoS ONE
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    ABSTRACT: We conducted hospital-based contact investigations of 55 serial sputum smear-positive tuberculosis (TB) patients and 771 health care workers (HCWs) from 2006-2013. HCWs who made contact with TB patients in the absence of appropriate airborne precautions were evaluated using interferon gamma release assays to identify TB infection. Twenty-nine HCWs (3.8%) were newly diagnosed with TB infection. The 10 TB patients responsible for transmission had a duration of contact of >7 days by multivariate analysis.
    No preview · Article · Jan 2016 · American journal of infection control
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    Young Hak Kim · Michiaki Mishima

    Preview · Article · Jan 2016 · Journal of Clinical Oncology
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    ABSTRACT: Multi-ciliated airway cells (MCACs) play a role in mucociliary clearance of the lung. However, the efficient induction of functional MCACs from human pluripotent stem cells has not yet been reported. Using carboxypeptidase M (CPM) as a surface marker of NKX2-1(+)-ventralized anterior foregut endoderm cells (VAFECs), we report a three-dimensional differentiation protocol for generating proximal airway epithelial progenitor cell spheroids from CPM(+) VAFECs. These spheroids could be induced to generate MCACs and other airway lineage cells without alveolar epithelial cells. Furthermore, the directed induction of MCACs and of pulmonary neuroendocrine lineage cells was promoted by adding DAPT, a Notch pathway inhibitor. The induced MCACs demonstrated motile cilia with a "9 + 2" microtubule arrangement and dynein arms capable of beating and generating flow for mucociliary transport. This method is expected to be useful for future studies on human airway disease modeling and regenerative medicine.
    Full-text · Article · Jan 2016 · Stem Cell Reports
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    ABSTRACT: The relationship between chronic inflammation and cancer is well known. The inflammation increases the permeability of blood vessels and consequently elevates pressure in the interstitial tissues. However, there have been only a few reports on the effects of hydrostatic pressure on cultured cells, and the relationship between elevated hydrostatic pressure and cell properties related to malignant tumors is less well understood. Therefore, we investigated the effects of hydrostatic pressure on the cultured epithelial cells seeded on permeable filters. Surprisingly, hydrostatic pressure from basal to apical side induced epithelial stratification in Madin-Darby canine kidney (MDCK) I and Caco-2 cells, and cavities with microvilli and tight junctions around their surfaces were formed within the multi-layered epithelia. The hydrostatic pressure gradient also promoted cell proliferation, suppressed cell apoptosis, and increased transepithelial ion permeability. The inhibition of protein kinase A (PKA) promoted epithelial stratification by the hydrostatic pressure whereas the activation of PKA led to suppressed epithelial stratification. These results indicate the role of the hydrostatic pressure gradient in the regulation of various epithelial cell functions. The findings in this study may provide clues for the development of a novel strategy for the treatment of the carcinoma.
    Preview · Article · Dec 2015 · PLoS ONE
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    ABSTRACT: Rationale: The loss of skeletal muscle mass and physical inactivity are important manifestations of chronic obstructive pulmonary disease (COPD), and both are closely related to poor prognoses in patients with COPD. Antigravity muscles are involved in maintaining normal posture and are prone to atrophy due to inactivity. The erector spinae muscle (ESM) group is one of the antigravity muscles and can be assessed via chest computed tomography (CT). Objectives: We hypothesized that the cross-sectional area of ESM (ESMCSA) in chest CT images may serve as a predictor of mortality in patients with COPD. Methods: This study was a part of the prospective observational study undertaken at Kyoto University Hospital. ESMCSA was measured in a single axial CT image at the level of the twelfth thoracic vertebrae in patients with COPD. The cross-sectional area of the pectoralis muscles (PMCSA) was also measured. And then we evaluated the relationship between ESMCSA and clinical parameters in patients with COPD including mortality. Age- and height-matched smoking control subjects were also evaluated. Measurements and main results: In total, 130 male patients and twenty smoking control males were enrolled in this study. ESMCSA was significantly lower in patients with COPD than in the smoking control subjects and was significantly correlated with disease severity. There was a significant but only moderate correlation between ESMCSA and PMCSA. ESMCSA was significantly correlated with previously reported prognostic factors, such as body mass index (BMI), dyspnea (mMRC), %FEV1, inspiratory-to-total lung capacity ratio (IC/TLC), and emphysema severity (LAA%). Compared to PMCSA, ESMCSA was more strongly associated with mortality in patients with COPD. Among these known prognostic factors, the stepwise multivariate Cox proportional hazards analysis revealed that ESMCSA was the strongest risk factor for mortality (Hazard Ratio (HR), 0.85; 95% confidence interval (CI), 0.79-0.92; p<0.001) and mMRC was an additional factor (HR, 2.35; 95% CI, 1.51-3.65; p<0.001). Conclusions: ESMCSA assessed via chest CT may be a valuable clinical parameter, as ESACSA correlates significantly with physiological parameters, symptoms and disease prognosis.
    No preview · Article · Dec 2015 · Annals of the American Thoracic Society
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    ABSTRACT: In lymphangioleiomyomatosis (LAM), predicting lung disease progression is essential for treatment planning. However, no previous Japanese studies have attempted to predict the reductions in pulmonary function that occur in LAM patients.
    No preview · Article · Dec 2015 · Respiratory Investigation
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    ABSTRACT: Background: Health status and mortality are important outcomes in patients with advanced pulmonary diseases receiving noninvasive ventilation (NIV). However, their relationship has not been thoroughly investigated. Methods: The present study prospectively recruited 56 stable outpatients treated with NIV for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease (COPD) and/or pulmonary tuberculosis sequelae. At baseline, health status was measured by the Medical Outcomes Study 36-item short form, a generic questionnaire; the St. George's Respiratory Questionnaire (SGRQ), a respiratory-specific questionnaire; and two respiratory failure-specific questionnaires, the Maugeri Respiratory Failure questionnaire and the Severe Respiratory Insufficiency (SRI) questionnaire. Arterial blood gas, pulmonary function, dyspnea and psychological status were also measured. Results: In cross-sectional comparisons of the four health status questionnaires, the SGRQ and SRI questionnaire had lower floor and ceiling effects. During the three-year follow-up, 16 patients (29%) died. Health status shown by the SGRQ and SRI was significantly predictive of mortality, independently of the physiological measures of low body mass index (BMI), hypercapnia, and low pulmonary function. Stepwise multivariate analyses indicated that the SRI summary score was the most significant predictor of mortality (p=0.0006) followed by BMI (p=0.012). Conclusion: There was a significant relationship between health status and three-year mortality in patients with NIV, independently of under-nutrition, hypercapnia, and low pulmonary function. Health status measurement is important not only to comprehensively evaluate disease severity in relation to its close association with mortality, but also to elucidate factors that improve the survival of patients with advanced respiratory diseases. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · The Clinical Respiratory Journal
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    ABSTRACT: Cough affects all individuals at different times, and its economic burden is substantial. Despite these widespread adverse effects, cough research relies on animal models, which hampers our understanding of the fundamental cause of cough. Postnasal drip is speculated to be one of the most frequent causes of chronic cough; however, this is a matter of debate. Here we show that mechanical stimuli by postnasal drip cause chronic cough. We distinguished human cough from sneezes and expiration reflexes by airflow patterns. Cough and sneeze exhibited one-peak and two-peak patterns, respectively, in expiratory airflow, which were also confirmed by animal models of cough and sneeze. Transgenic mice with ciliary dyskinesia coughed substantially and showed postnasal drip in the pharynx; furthermore, their cough was completely inhibited by nasal airway blockade of postnasal drip. We successfully reproduced cough observed in these mice by injecting artificial postnasal drip in wild-type mice. These results demonstrated that mechanical stimulation by postnasal drip evoked cough. The findings of our study can therefore be used to develop new antitussive drugs that prevent the root cause of cough.
    Preview · Article · Nov 2015 · PLoS ONE
  • Satoshi Hamada · Ryosuke Takahashi · Michiaki Mishima · Kazuo Chin
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    ABSTRACT: A 70-year-old man (case 1) and a 64-year-old woman (case 2) with multiple system atrophy (MSA) and snoring were admitted for polysomnography. Their awake PaCO2 indicated normocapnia. Apnoea-hypopnoea index (AHI), max transcutaneous carbon dioxide partial pressure (PtcCO2) and ΔPtcCO2 (max PtcCO2 (during sleep)-baseline PtcCO2 (while awake)) were 11.4/h, 63 mm Hg and 18 mm Hg, respectively, in case 1 and 53.1/h, 59 mm Hg and 13 mm Hg, respectively, in case 2. Their sleep-disordered breathing (SDB) was diagnosed as obstructive sleep apnoea with hypoventilation. We thought that variable expiratory positive airway pressure and pressure support ventilation (advanced-adaptive servo ventilation (ASV)) might be favourable for their SDB. Polysomnography after introducing advanced-ASV revealed that AHI, max PtcCO2 and ΔPtcCO2 were 0.2/h, 53 mm Hg and 5 mm Hg, respectively, in case 1 and 1.5/h, 56 mm Hg and 9 mm Hg, respectively, in case 2. Advanced-ASV for treating Cheyne-Stokes breathing may be helpful in SDB in patients with MSA.
    No preview · Article · Nov 2015 · Case Reports
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    ABSTRACT: Introduction: Association of knee and low back pain with sleep disturbance is poorly understood. We aimed to clarify the independent and combined effects of these orthopedic symptoms on sleep in a large-scale general population. Methods: Cross-sectional data about sleep and knee/low back pain were collected for 9,611 community residents (53±14 years old) by a structured questionnaire. Sleep duration less than 6 h/d was defined as short sleep. Sleep quality and the presence of knee and low back pain were evaluated by dichotomous questions. Subjects who complained about knee or low back pains were graded by tertiles of a numerical response scale (NRS) score and a Roland-Morris disability questionnaire (RDQ) score respectively. Multivariate regression analyses were performed to determine the correlates of short sleep duration and poor sleep quality. Results: Frequency of participants who complained of the orthopedic symptoms was as follows; knee pain, 29.0%; low back pain, 42.0% and both knee and low back pain 17.6%. Both knee and low back pain were significantly and independently associated with short sleep duration (knee pain: odds ratio (OR) = 1.19, p<0.01; low back pain: OR = 1.13, p = 0.01) and poor sleep quality (knee pain: OR = 1.22, p<0.01; low back pain; OR = 1.57, p<0.01). The group in the highest tertile of the NRS or RDQ score had the highest risk for short sleep duration and poor sleep quality except for the relationship between the highest tertile of the RDQ score and short sleep duration.(the highest tertile of the NRS: OR for short sleep duration = 1.31, p<0.01; OR for poor sleep quality = 1.47, p<0.01; the highest tertile of the RDQ: OR for short sleep duration = 1.11, p = 0.12; OR for poor sleep quality = 1.81, p<0.01) Further, coincident knee and low back pain raised the odds ratios for short sleep duration (either of knee or low back pain: OR = 1.10, p = 0.06; both knee and low back pain: OR = 1.40, p<0.01) and poor sleep quality (either of knee or low back pain: OR = 1.61, p<0.01; both knee and low back pain: OR = 2.17, p<0.01). Conclusion: Knee and low back pains were independently associated with short sleep duration and poor sleep quality. Further, they additively increased the correlation with these sleep problems in the general population.
    Preview · Article · Oct 2015 · PLoS ONE

  • No preview · Article · Oct 2015 · Respiratory Investigation
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    ABSTRACT: Purpose: Acute kidney injury (AKI) is a common and serious adverse effect of cisplatin-based chemotherapy. However, traditional markers of kidney function, such as serum creatinine, are suboptimal, because they are not sensitive measures of proximal tubular injury. We aimed to determine whether the new urinary biomarkers such as kidney injury molecule-1 (KIM-1), monocyte chemotactic protein-1 (MCP-1), and neutrophil gelatinase-associated lipocalin (NGAL) could detect cisplatin-induced AKI in lung cancer patients in comparison with the conventional urinary proteins such as N-acetyl-β-D-glucosaminidase (NAG) and β2-microglobulin. Methods: We measured KIM-1, MCP-1, NGAL, NAG, and β2-microglobulin concentrations in urine samples from 11 lung cancer patients, which were collected the day before cisplatin administration and on days 3, 7, and 14. Subsequently, we evaluated these biomarkers by comparing their concentrations in 30 AKI positive (+) and 12 AKI negative (-) samples and performing receiver operating characteristic (ROC) curve analyses. Results: The urinary levels normalized with urine creatinine of KIM-1 and MCP-1, but not NGAL, NAG, and β2-microglobulin in AKI (+) samples were significantly higher than those in AKI (-) samples. In addition, ROC curve analyses revealed that KIM-1 and MCP-1, but not NGAL, could detect AKI with high accuracy (area under the curve [AUC] = 0.858, 0.850, and 0.608, respectively). The combination of KIM-1 and MCP-1 outperformed either biomarker alone (AUC = 0.871). Conclusions: Urinary KIM-1 and MCP-1, either alone or in combination, may represent biomarkers of cisplatin-induced AKI in lung cancer patients.
    No preview · Article · Sep 2015 · Cancer Chemotherapy and Pharmacology
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    ABSTRACT: Background: Decreased bone mineral density (BMD) has been reported in patients with interstitial lung disease. However, BMD has not been evaluated in steroid-naïve patients with idiopathic pulmonary fibrosis (IPF). We aimed to measure vertebral BMD and investigate its relationship with clinical features in steroid-naïve patients with IPF. Methods: We recruited 55 consecutive male patients with steroid-naïve IPF; 55 male smokers without chronic obstructive pulmonary disease or interstitial lung disease, matched by age, body mass index, and pack-years of smoking (control smokers); and 27 healthy young adults. Thoracic vertebral BMD was measured by computed tomography (CT). We further investigated the relationship of BMD with clinical features and quantitative CT indices of lung density in patients with IPF. Results: The thoracic vertebral BMD of patients with IPF was significantly lower than that of control smokers (139.9 ± 28.5 mg/mL vs 160.9 ± 39.5 mg/mL, p < 0.01). Fifteen patients (27.2%) had BMD more than 2.5 SD below the mean BMD of young adults. In patients with IPF, emphysema volume (EV) and its ratio to total lung volume (EV%) had a significantly negative correlation with BMD (r = -0.28, p = 0.04 and r = -0.39, p < 0.01, respectively). In stepwise multiple regression analysis, EV% was an independent explanatory variable for thoracic vertebral BMD. Conclusion: A substantial percentage of steroid-naïve IPF patients had decreased BMD, and a significant association was observed between the extent of emphysema and BMD in IPF.
    Full-text · Article · Sep 2015 · Respiratory medicine

  • No preview · Article · Sep 2015 · European Respiratory Journal

  • No preview · Article · Sep 2015 · European Respiratory Journal

  • No preview · Article · Aug 2015 · Cancer Research

Publication Stats

8k Citations
1,567.85 Total Impact Points


  • 1993-2016
    • Kyoto University
      • • Department of Respiratory Medicine
      • • Primate Research Institute
      Kioto, Kyoto, Japan
  • 2013
    • Khon Kaen University
      • Centre for Research and Development of Medical Diagnostic Laboratories
      Kawn Ken, Khon Kaen, Thailand
  • 2011
    • Hospital Universitari Germans Trias i Pujol
      Badalona, Catalonia, Spain
  • 2010
    • Chiba University
      • Department of Respirology
      Chiba-shi, Chiba-ken, Japan
  • 2006
    • Nagai Internal Medicine Clinic
      Okayama, Okayama, Japan
  • 2005
    • Kyoto Sangyo University
      Kioto, Kyōto, Japan
  • 1992
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan