Nobuaki Miyahara

Okayama University, Okayama, Okayama, Japan

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Publications (116)

  • Utako Fujii · Nobuaki Miyahara · Akihiko Taniguchi · [...] · Arihiko Kanehiro
    [Show abstract] [Hide abstract] ABSTRACT: We recently reported that IL-17A plays a critical role in the development of porcine pancreatic elastase (PPE)-induced emphysema. The proliferation of T helper 17 (Th17) cells was induced by IL-23. To determine the contribution of IL-23 to the development of pulmonary emphysema a mouse model of PPE-induced emphysema was used in which responses of IL-23p19-deficient (IL-23-/-) and wild type (WT) mice were compared. Intra-tracheal instillation of PPE induced emphysematous changes in the lungs and was associated with increased levels of IL-23 in lung homogenates. Compared to WT mice, IL-23-/- mice developed significantly lower static compliance values and markedly reduced emphysematous changes on histological analyses following PPE-instillation. These changes were associated with lower levels of IL-17A and fewer Th17 cells in the lung. The neutrophilia seen in bronchoalveolar lavage (BAL) fluid of WT mice was attenuated in IL-23-/- mice, and the reduction was associated with decreased levels of KC and MIP-2 in BAL fluid. Treatment with anti-IL-23p40 monoclonal antibody significantly attenuated PPE-induced emphysematous changes in the lungs of WT mice. These data identify the important contributions of IL-23 to the development of elastase-induced pulmonary inflammation and emphysema, mediated through an IL-23-IL-17 pathway. Targeting IL-23 in emphysema is a potential therapeutic strategy for delaying disease progression.
    Article · Jun 2016 · American Journal of Respiratory Cell and Molecular Biology
  • Source
    Katsuyuki Takeda · Nobuaki Miyahara · Shigeki Matsubara · [...] · Erwin W. Gelfand
    [Show abstract] [Hide abstract] ABSTRACT: Ambroxol is used in COPD and asthma to increase mucociliary clearance and regulate surfactant levels, perhaps through anti-oxidant and anti-inflammatory activities. To determine the role and effect of ambroxol in an experimental model of asthma, BALB/c mice were sensitized to ovalbumin (OVA) followed by 3 days of challenge. Airway hyperresponsiveness (AHR), lung cell composition and histology, and cytokine and protein carbonyl levels in bronchoalveolar lavage (BAL) fluid were determined. Ambroxol was administered either before the first OVA challenge or was begun after the last allergen challenge. Cytokine production levels from lung mononuclear cells (Lung MNCs) or alveolar macrophages (AM) were also determined. Administration of ambroxol prior to challenge suppressed AHR, airway eosinophilia, goblet cell metaplasia, and reduced inflammation in subepithelial regions. When given after challenge, AHR was suppressed but without effects on eosinophil numbers. Levels of IL-5 and IL-13 in BAL fluid were decreased when the drug was given prior to challenge; when given after challenge, increased levels of IL-10 and IL-12 were detected. Decreased levels of protein carbonyls were detected in BAL fluid following ambroxol treatment after challenge. In vitro, ambroxol increased levels of IL-10, IFN-γ, and IL-12 from Lung MNCs and AM, whereas IL-4, IL-5, and IL-13 production was not altered. Taken together, ambroxol was effective in preventing AHR and airway inflammation through upregulation of Th1 cytokines and protection from oxidative stress in the airways.
    Full-text Article · Jun 2016 · Immune Network
  • [Show abstract] [Hide abstract] ABSTRACT: KL-6 is a glycoprotein found predominantly on type II pneumocytes and alveolar macrophages, and often shows increased serum levels in patients with interstitial pneumonia. We report a case of mycobacterium avium complex (MAC) infection whose disease activity was correlated with KL-6 levels in serum. During treatment of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) with prednisolone, chest image findings improved in association with decreased KL-6 levels. Following tapering of prednisolone, chest image findings deteriorated again as levels of KL-6 increased, suggesting recurrence of RA-ILD. Bronchoscopic examination revealed active MAC infection. Treatment of MAC infection not only improved chest image findings but also decreased KL-6 levels in serum, suggesting that KL-6 was increased by active MAC infection by itself, not by recurrence of RA-ILD. To the best of our knowledge, this is the first documentation of KL-6 elevation in serum in association with active MAC infection.
    Article · Jun 2016 · Acta medica Okayama
  • Article · Sep 2015 · European Respiratory Journal
  • Daisuke Morichika · Nobuaki Miyahara · Katsuyuki Hotta · [...] · Katsuyuki Kiura
    [Show abstract] [Hide abstract] 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.
    Article · Dec 2014 · Internal Medicine
  • Koichi Waseda · Nobuaki Miyahara · Akihiko Taniguchi · [...] · Arihiko Kanehiro
    [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.
    Article · Sep 2014 · American Journal of Respiratory Cell and Molecular Biology
  • Genyo Ikeda · Nobuaki Miyahara · Hikari Koga · [...] · Arihiko Kanehiro
    [Show abstract] [Hide abstract] 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.
    Article · Aug 2013 · American Journal of Respiratory Cell and Molecular Biology
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    Hikari Koga · Nobuaki Miyahara · Yasuko Fuchimoto · [...] · Arihiko Kanehiro
    [Show abstract] [Hide abstract] 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.
    Full-text Article · Jan 2013 · Respiratory research
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    Etsuko Kurimoto · Nobuaki Miyahara · Arihiko Kanehiro · [...] · Mitsune Tanimoto
    [Show abstract] [Hide abstract] ABSTRACT: Figure S1. Cellular composition in BAL fluid on day 2 after intratracheal instillation of PPE or saline. *p<0.05 compared to WT saline and IL-17A-/- saline. #p<0.05 versus WT PPE. n=8 in each group.
    Full-text Dataset · Jan 2013
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    Etsuko Kurimoto · Nobuaki Miyahara · Arihiko Kanehiro · [...] · Mitsune Tanimoto
    [Show abstract] [Hide abstract] 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.
    Full-text Article · Jan 2013 · Respiratory research
  • [Show abstract] [Hide abstract] 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.
    Article · Jan 2013 · Internal Medicine
  • Nobuaki Miyahara · Katsuyuki Kiura
    Article · Nov 2012 · Nippon rinsho. Japanese journal of clinical medicine
  • Etsuko Kurimoto · Arihiko Kanehiro · Nobuaki Miyahara · [...] · Mitsune Tanimoto
    Conference Paper · May 2012
  • Akihiko Taniguchi · Nobuaki Miyahara · Arihiko Kanehiro · [...] · Mitsune Tanimoto
    [Show abstract] [Hide abstract] ABSTRACT: The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE-/-) and RAGE-deficient (RAGE+/+) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE+/+ mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE-/- mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE+/+ mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses.
    Conference Paper · May 2012
  • [Show abstract] [Hide abstract] 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.
    Article · Dec 2011 · Arerugī = [Allergy]
  • [Show abstract] [Hide abstract] 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.
    Article · Dec 2011 · Acta medica Okayama
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    Yasuko Fuchimoto · Arihiko Kanehiro · Nobuaki Miyahara · [...] · Mitsune Tanimoto
    [Show abstract] [Hide abstract] 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.
    Full-text Article · Jul 2011 · American Journal of Respiratory Cell and Molecular Biology
  • [Show abstract] [Hide abstract] 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.
    Article · Jun 2011 · Acta medica Okayama
  • Conference Paper · May 2011
  • Koichi Waseda · Nobuaki Miyahara · Arihiko Kanehiro · [...] · Mitsune Tanimoto
    Conference Paper · May 2011

Publication Stats

2k Citations

Institutions

  • 2014
    • Okayama University
      Okayama, Okayama, Japan
  • 2007
    • Philipps University of Marburg
      Marburg, Hesse, Germany
    • University of Colorado
      Denver, Colorado, United States
  • 2006-2007
    • National Research Center (CO, USA)
      Boulder, Colorado, United States
  • 1998
    • Miki Sanyo Hospital
      Kōbe, Hyōgo, Japan