Nobuaki Miyahara

Okayama University, Okayama, Okayama, Japan

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Publications (109)563.75 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The receptor for advanced glycation end products (RAGE) is a multi-ligand cell surface receptor reported to be involved in the process of acute alveolar epithelial cell injury. However, studies that address the role of RAGE in pulmonary emphysema are inconclusive. We investigated the role of RAGE in the development of elastase-induced pulmonary inflammation and emphysema in mice. RAGE sufficient (RAGE+/+) mice and RAGE deficient (RAGE-/-) mice were treated with intratracheal elastase on day 0. Airway inflammation, static compliance (Cst), lung histology and the levels of neutrophil-related chemokine and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) fluid were determined on days 4 and 21. Neutrophilia in BAL fluid, seen in elastase-treated RAGE+/+ mice, was reduced in elastase-treated RAGE-/- mice on day 4, and was associated with decreased levels of KC, MIP-2 and IL-1. Cst values and emphysematous changes in the lung tissue were decreased in RAGE-/- mice compared to RAGE+/+ mice on day 21 after elastase treatment. Experiments using irradiated, bone marrow chimeric mice showed that the mice expressing RAGE on radioresistant structural cells but not hematopoietic cells developed elastase-induced neutrophilia and emphysematous change in the lung. In contrast, mice expressing RAGE on hematopoietic cells but not radioresistant structural cells showed reduced neutrophilia and emphysematous change in the lung. These data identify the importance of RAGE expressed on lung structural cells in the development of elastase-induced pulmonary inflammation and emphysema. Thus, RAGE represents a novel therapeutic target for preventing pulmonary emphysema.
    American Journal of Respiratory Cell and Molecular Biology 09/2014; 52(4). DOI:10.1165/rcmb.2014-0027OC · 4.11 Impact Factor
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    ABSTRACT: We herein report the case of a 68-year-old man diagnosed with invasive mucinous adenocarcinoma of the lungs. Chest computed tomography showed subpleural ground-glass opacity and small nodules with cavitation. A culture of the bronchoalveolar lavage fluid resulted in the detection of Mycobacterium fortuitum. The patient's lung consolidation rapidly progressed; however, repeated bronchoscopy showed no atypical cells, thus suggesting a diagnosis of organizing pneumonia associated with M. fortuitum infection. However, the surgical biopsy specimen was diagnostic for adenocarcinoma, with no mycobacterial infection. Invasive mucinous adenocarcinoma should not be excluded in the differential diagnosis of patients with clinical features of organizing pneumonia and nontuberculous mycobacterium infection, even if a transbronchial biopsy confirms the absence of malignancy.
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    ABSTRACT: Background The incidence of overlapping bronchial asthma and chronic obstructive pulmonary disease (COPD) has increased in recent years. Cysteinyl leukotrienes (CysLTs) play an important role in asthma, and the type 1 CysLT receptor (CysLT1R) is expressed by many inflammatory cells. We evaluated the effect of montelukast, a CysLT1R antagonist, on mouse models of asthma, porcine pancreatic elastase (PPE)-induced emphysema, and asthma combined with emphysema. Methods Mice were sensitized with ovalbumin (OVA) on days 0 and 14 and subsequently challenged with OVA on days 28, 29, and 30. Pulmonary emphysema was induced by intratracheal instillation of PPE on day 25. Mice were treated subcutaneously with montelukast or vehicle from day 25 to day 31. Airway hyperresponsiveness (AHR); static compliance; the number of inflammatory cells; the levels of cytokines, chemokines, leukotrienes, and perforin in the bronchoalveolar lavage fluid; and the quantitative morphometry of lung sections were analyzed on day 32. Results Treatment with montelukast significantly attenuated the AHR and eosinophilic airway inflammation in OVA-sensitized and OVA-challenged mice. Administration of montelukast significantly reduced the AHR, static compliance, and neutrophilic airway inflammation while attenuating emphysematous lung changes in PPE-treated mice. In PPE-treated mice subjected to allergen sensitization and challenges, montelukast significantly suppressed the AHR, static compliance, and eosinophilic and neutrophilic airway inflammation in addition to the development of experimentally induced emphysema in the lungs. Conclusion Our data suggest that CysLT1R antagonists may be effective in ameliorating the consequences of PPE-induced lung damage and the changes that follow allergen sensitization and challenges.
    American Journal of Respiratory Cell and Molecular Biology 08/2013; 50(1). DOI:10.1165/rcmb.2012-0418OC · 4.11 Impact Factor
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    ABSTRACT: Background Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice. Methods BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. Results Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. Conclusion These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil- and eosinophil-dominant phases of the response to secondary allergen challenge.
    Respiratory research 01/2013; 14(1):8. DOI:10.1186/1465-9921-14-8 · 3.38 Impact Factor
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    ABSTRACT: Background Pulmonary emphysema is characterized by alveolar destruction and persistent inflammation of the airways. Although IL-17A contributes to many chronic inflammatory diseases, it’s role in the inflammatory response of elastase-induced emphysema remains unclear. Methods In a model of elastase-induced pulmonary emphysema we examined the response of IL-17A-deficient mice, monitoring airway inflammation, static compliance, lung histology and levels of neutrophil-related chemokine and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Results Wild-type mice developed emphysematous changes in the lung tissue on day 21 after elastase treatment, whereas emphysematous changes were decreased in IL-17A-deficient mice compared to wild-type mice. Neutrophilia in BAL fluid, seen in elastase-treated wild-type mice, was reduced in elastase-treated IL-17A-deficient mice on day 4, associated with decreased levels of KC, MIP-2 and IL-1 beta. Elastase-treated wild-type mice showed increased IL-17A levels as well as increased numbers of IL-17A+ CD4 T cells in the lung in the initial period following elastase treatment. Conclusions These data identify the important contribution of IL-17A in the development of elastase-induced pulmonary inflammation and emphysema. Targeting IL-17A in emphysema may be a potential therapeutic strategy for delaying disease progression.
    Respiratory research 01/2013; 14(1):5. DOI:10.1186/1465-9921-14-5 · 3.38 Impact Factor
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    ABSTRACT: A 32-year-old male with CATCH22 syndrome presented with a high fever and productive cough after taking drugs for acute bronchitis, including (L)-carbocisteine. Chest radiography revealed ground-glass opacities in the bilateral lung fields. He had a history of similar pneumonia. Under the assumption of drug-induced pneumonia, or bacterial or viral pneumonia, all drugs including (L)-carbocisteine were discontinued, and antibiotics were started. A drug-induced lymphocyte stimulation test was positive only for (L)-carbocisteine. The only drug in common between this and the previous episode of pneumonia was (L)-carbocisteine. We thus concluded that this was a definite case of (L)-carbocisteine-induced pneumonia in a patient with CATCH22 syndrome.
    Internal Medicine 01/2013; 52(1):97-100. DOI:10.2169/internalmedicine.52.7882 · 0.97 Impact Factor
  • Nobuaki Miyahara, Katsuyuki Kiura
    Nippon rinsho. Japanese journal of clinical medicine 11/2012; 70 Suppl 8:545-9.
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
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    ABSTRACT: Inhaled corticosteroid (ICS) will be effective if used properly. Inadequate intake may result in insufficiency, such as for elderly asthmatics, in particular, for use of dry powder inhalers. 312 asthmatics treated with ICS for at least 6 months in the 6 facilities belonging to the Chugoku Shikoku Adult Asthma Research Forum were subject to investigation of the peak inspiratory flow (PIF) measured using In-check® and related factors. Nine (2.8%) patients were considered to have insufficient intake. By multivariate analysis, PIF (L/min) prediction formula was as follows: 79.0+0.19* peak expiratory flow (PEF: L/min)+22.9* FVC (L)-0.68* onset age (years)+34.7* gender (male, 1; female, 0)+16.1* V50/V25, [r^2=0.677, p<0.0001]. Using cluster analysis with Euclidean distance and Ward's method, the PIF without an adaptor was included in the same category as height and PEF, and the PIF with an adaptor was included in the same category as %FVC and %FEV1.0. The cases with insufficient PIF are few but present. Adequate device selection and inhalation guidance may be important. The meaning of PIF differs depending on whether or not an adaptor is present. Further investigation of intake is considered necessary.
    Arerugī = [Allergy] 12/2011; 60(12):1621-9.
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    ABSTRACT: Bronchiolitis obliterans (BO) is a disease with a poor prognosis, and a key factor that limits long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). We here report a case of a 31-year woman with acute lymphatic leukemia, which was treated by chemotherapy and HSCT, and consequently developed BO 2 years after HSCT. A non-tuberculous mycobacterial infection occurred and showed gradual exacerbation. She started taking anti-mycobacterial drugs, but lost appetite, felt tired and finally lost consciousness one month after beginning medication. Arterial blood gas revealed marked hypercapnia. Using extracorporeal life support (ECLS), the carbon dioxide concentration was reduced and her consciousness recovered. To our knowledge, this is the first case in which ECLS was successfully used for hypercapnia in a patient with BO.
    Acta medica Okayama 12/2011; 65(6):403-6. · 0.75 Impact Factor
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    ABSTRACT: Chemokine receptor (CCR) 5 is expressed on dendritic cells, macrophages, CD8 cells, memory CD4 T cells, and stromal cells, and is frequently used as a marker of T helper type 1 cells. Interventions that abrogate CCR5 or interfere with its ligand binding have been shown to alter T helper type 2-induced inflammatory responses. The role of CCR5 on allergic airway responses is not defined. CCR5-deficient (CCR5(-/-)) and wild-type (CCR5(+/+)) mice were sensitized and challenged with ovalbumin (OVA) and allergic airway responses were monitored 48 hours after the last OVA challenge. Cytokine levels in lung cell culture supernatants were also assessed. CCR5(-/-) mice showed significantly lower airway hyperresponsiveness (AHR) and lower numbers of total cells, eosinophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid compared with CCR5(+/+) mice after sensitization and challenge. The levels of IL-4 and IL-13 in BAL fluid of CCR5(-/-) mice were lower than in CCR5(+/+) mice. Decreased numbers of lung T cells were also detected in CCR5(-/-) mice after sensitization and challenge. Transfer of OVA-sensitized T cells from CCR5(+/+), but not transfer of CCR5(-/-) cells, into CCR5(-/-) mice restored AHR and numbers of eosinophils in BAL fluid after OVA challenge. Accordingly, the numbers of airway-infiltrating donor T cells were significantly higher in the recipients of CCR5(+/+) T cells. Taken together, these data suggest that CCR5 plays a pivotal role in allergen-induced AHR and airway inflammation, and that CCR5 expression on T cells is essential to the accumulation of these cells in the airways.
    American Journal of Respiratory Cell and Molecular Biology 07/2011; 45(6):1248-55. DOI:10.1165/rcmb.2010-0465OC · 4.11 Impact Factor
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    ABSTRACT: Churg-Strauss syndrome (CSS) is a granulomatous necrotizing vasculitis of unknown etiology associated with bronchial asthma. Despite affecting small to medium-sized vessels, necrosis of the digits due to vasculitis is extremely rare. We report a case of CSS with necrosis of the toe tips. A 37-year-old woman with asthma, who had been diagnosed with CSS 2 years ago, was admitted to our hospital with an exacerbation of CSS. The patient had a high grade fever and complained of abdominal pain and numbness of the lower extremities. Blood examination revealed marked eosinophilia. The fever pattern, abdominal pain and blood eosinophilia showed improvement by combination treatment with prednisolone and cyclophosphamide. However, the color of her right toe tips changed, and necrosis finally resulted despite antithrombotic therapy. Arteriography showed narrowing of the dorsalis pedis artery and of the more peripheral arteries of her right leg. Stump plasty with negative pressure dressing therapy for the toe tips, but not amputation, was done to preserve the leg function. While numbness of the extremities remained, no recurrence of necrosis was seen. Clinicians need to be aware that rare complications of CSS, including necrosis of the digits, can occur.
    Acta medica Okayama 06/2011; 65(3):215-8. · 0.75 Impact Factor
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • Satoko Miyahara, Nobuaki Miyahara, Shigeki Matsubara
    Folia Pharmacologica Japonica 03/2011; 137(3):141-5. DOI:10.1254/fpj.137.141
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    ABSTRACT: Most of the studies investigating the effectiveness of blocking the leukotriene B4 (LTB4) receptor 1 (BLT1) have been performed in models of primary or acute allergen challenge. The role of the LTB4-BLT1 pathway in secondary challenge models, where airway hyperresponsiveness (AHR) and airway inflammation have been established, has not been defined. We investigated the effects of blocking BLT1 on early- and late-phase development of AHR and airway inflammation in previously sensitized and challenged mice. Female BALB/c mice were sensitized (Days 1 and 14) and challenged (primary, Days 28-30) with ovalbumin. On Day 72, mice were challenged (secondary) with a single OVA aerosol, and the early and late phases of AHR and inflammation were determined. Specific blockade of BLT1 was attained by oral administration of a BLT1 antagonist on Days 70 through 72. Administration of the antagonist inhibited the secondary ovalbumin challenge-induced alterations in airway responses during the late phase but not during the early phase, as demonstrated by decreases in AHR and in bronchoalveolar lavage neutrophilia and eosinophilia 6 and 48 hours after secondary challenge. The latter was associated with decreased levels of KC protein, macrophage inflammatory protein 2, and IL-17 in the airways. These data identify the importance of the LTB4-BLT1 pathway in the development of late-phase, allergen-induced airway responsiveness after secondary airway challenge in mice with established airway disease.
    American Journal of Respiratory Cell and Molecular Biology 03/2011; 45(4):851-7. DOI:10.1165/rcmb.2010-0455OC · 4.11 Impact Factor
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    ABSTRACT: Invariant NKT cells (iNKT cells) play a pivotal role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation. However, it is unclear what role they play in the initiation (sensitization) phase as opposed to the effector (challenge) phase. The role of iNKT cells during sensitization was examined by determining the response of mice to intratracheal transfer of OVA-pulsed or OVA-alpha-galactosylceramide (OVA/alphaGalCer)-pulsed bone marrow-derived dendritic cells (BMDCs) prior to allergen challenge. Wild-type (WT) recipients of OVA-BMDCs developed AHR, increased airway eosinophilia, and increased levels of Th2 cytokines in bronchoalveolar lavage fluid, whereas recipients of OVA/alphaGalCer BMDCs failed to do so. In contrast, transfer of these same OVA/alphaGalCer BMDCs into IFN-gamma-deficient (IFN-gamma(-/-)) mice enhanced the development of these lung allergic responses, which was reversed by exogenous IFN-gamma treatment following OVA-BMDC transfer. Further, Jalpha18-deficient recipients, which lack iNKT cells, developed the full spectrum of lung allergic responses following reconstitution with highly purified WT liver or spleen iNKT cells and transfer of OVA-BMDCs, whereas reconstituted recipients of OVA/alphaGalCer BMDCs failed to do so. Transfer of iNKT cells from IFN-gamma(-/-) mice restored the development of these responses in Jalpha18-deficient recipients following OVA-BMDC transfer; the responses were enhanced following OVA/alphaGalCer BMDC transfer. iNKT cells from these IFN-gamma(-/-) mice produced higher levels of IL-13 in vitro compared with WT iNKT cells. These data identify IFN-gamma as playing a critical role in dictating the consequences of iNKT cell activation in the initiation phase of the development of AHR and airway inflammation.
    The Journal of Immunology 07/2010; 185(1):253-62. DOI:10.4049/jimmunol.0902301 · 5.36 Impact Factor
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    ABSTRACT: Montelukast and S-carbocysteine have been used in asthmatic patients as an anti-inflammatory or mucolytic agent respectively. S-carbocysteine also exhibits anti-inflammatory properties. Ovalbumin (OVA) sensitized BALB/c mice were challenged with OVA for 3 days followed by single OVA re-challenge (secondary challenge) 2 weeks later. Forty-eight hours after secondary challenge, mice were assessed for airway hyperresponsiveness (AHR) and cell composition in bronchoalveolar lavage (BAL) fluid. Suboptimal doses of 10 mg.kg(-1) of S-carbocysteine by intraperitoneal injection (ip), 20 mg.kg(-1) of montelukast by gavage, the combination of S-carbocysteine and montelukast or 3 mg.kg(-1) of dexamethasone as a control were administered from 1 day before the secondary challenge to the last experimental day. Isolated lung cells were cultured with OVA and montelukast to determine the effects on cytokine production. Treatment with S-carbocysteine or montelukast reduced both AHR and the numbers of eosinophils in BAL fluid. Neutralizing IFN-gamma abolished the effects of S-carbocysteine on these airway responses. Combination of the two drugs showed further decreases in both AHR and eosinophils in the BAL fluid. Goblet cell metaplasia and Th2-type cytokines, interleukin (IL)-4, IL-5 and IL-13, in BAL fluid were decreased with montelukast treatment. Conversely, S-carbocysteine increased Th1-type cytokines, IFN-gamma and IL-12 in BAL fluid. The combination of two agents, montelukast and S-carbocysteine, demonstrated additive effects on AHR and airway inflammation in a secondary allergen model most likely through independent mechanisms of action.
    British Journal of Pharmacology 07/2010; 160(6):1399-407. DOI:10.1111/j.1476-5381.2010.00797.x · 4.99 Impact Factor

Publication Stats

2k Citations
563.75 Total Impact Points

Institutions

  • 2002–2013
    • Okayama University
      Okayama, Okayama, Japan
  • 2011
    • Kawasaki Medical University
      • Department of Respiratory Medicine
      Kurasiki, Okayama, Japan
  • 2009–2010
    • National Jewish Health
      • Department of Pediatrics
      Denver, CO, United States
  • 2006–2008
    • National Research Center (CO, USA)
      Boulder, Colorado, United States
  • 2007
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2005
    • Massachusetts General Hospital
      • Center for Immunology and Inflammatory Diseases
      Boston, Massachusetts, United States
  • 2000–2001
    • National Hospital Organization Yamaguchi-Ube Medical Center
      Ubi, Yamaguchi, Japan
  • 1998–2000
    • Miki Sanyo Hospital
      Kōbe, Hyōgo, Japan