研究者詳細 - 宮原　信明

論文 - 宮原　信明

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Practical Guidelines for Asthma Management (PGAM): Digest edition. 国際誌

Jun Tamaoki, Hiroyuki Nagase, Hiroyuki Sano, Takeshi Kaneko, Yasuhiro Gon, Nobuaki Miyahara, Hironori Sagara, Akihiko Tanaka, Takahiko Horiguchi, Etsuko Tagaya, Tomohiro Akaba, Yuji Tohda

Respiratory investigation 63 ( 3 ) 405 - 421 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

The international and national guidelines for asthma management are typically comprehensive and designed for respiratory specialists, making them less practical for primary care physicians who handle most asthma cases. Recognizing the need for more accessible guidelines, the Japan Asthma Society developed the Practical Guidelines for Asthma Management (PGAM). PGAM aims to provide a concise summary of key asthma management principles, increasing awareness, education, and support among nonspecialists and patients alike. It includes user-friendly tables and lists outlining common symptoms, triggers, diagnostic criteria, and basic management strategies, along with frequently encountered treatable traits and comorbidities. These elements are presented through simple, clinically relevant algorithms. A notable feature of PGAM is the "Basic Roadmap for Asthma Management," which outlines a clear sequence for patient assessment, diagnosis, and treatment from initial consultation onward, offering an easy-to-follow visual guide. Additionally, the guidelines include methods for assessing airway inflammation, enabling patient phenotyping and endotyping. This supports a personalized treatment approach, particularly with biologics, aimed at achieving clinical remission.

DOI： 10.1016/j.resinv.2025.03.009

Refractory phenotype of Aspergillus-sensitized asthma with bronchiectasis and allergic bronchopulmonary aspergillosis. 国際誌

Natsuko Nomura, Hisako Matsumoto, Koichiro Asano, Yusuke Hayashi, Akihito Yokoyama, Yoshihiro Nishimura, Naozumi Hashimoto, Takuro Sakagami, Koichi Fukunaga, Nobuyuki Hizawa, Akira Yamasaki, Hiroyuki Nagase, Noboru Hattori, Mitsuko Kondo, Norihiro Harada, Hisatoshi Sugiura, Mari Miki, Tomoki Kimura, Mikio Toyoshima, Osamu Matsuno, Hidefumi Koh, Toshiyuki Kita, Hiromi Tomioka, Keisuke Tomii, Hisashi Ohnishi, Shohei Takata, Kazunori Tobino, Shiro Imokawa, Hironobu Sunadome, Tadao Nagasaki, Tsuyoshi Oguma, Naoya Tanabe, Toyohiro Hirai

The journal of allergy and clinical immunology. Global 4 ( 1 ) 100364 - 100364 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Sensitization to Aspergillus, mucus plugs, and bacterial colonization may coexist and relate to a refractory phenotype during follow-up in asthma with bronchiectasis and allergic bronchopulmonary aspergillosis (ABPA). OBJECTIVE: This study aimed to clarify the features of Aspergillus-sensitized refractory asthma with bronchiectasis and determine the refractory phenotype in this population and ABPA. METHODS: This study included cases of the oldest available Aspergillus fumigatus-specific IgE data and chest computed tomography images from a nationwide survey of refractory asthma with bronchiectasis. The characteristics of the A fumigatus-IgE positive (Af sIgE+) group were investigated and compared with its nonsensitized counterpart (Af sIgE-) and ABPA group. Cluster analysis was conducted to determine the refractory phenotype. RESULTS: The Af sIgE+ group (n = 35) demonstrated type 2 inflammation levels intermediate between the ABPA (n = 42) and Af sIgE- (n = 38) groups while exhibiting higher blood monocyte counts than the Af sIgE- group. Cluster analysis conducted in patients with ABPA and Af sIgE+ newly determined 2 clusters: one was characterized by a younger age of asthma onset with fungal detection in sputum, and the other was characterized by mucus plugs and inflammation with eosinophils and monocytes, which was significantly related to mucus plugs, airflow limitation, and trend to show exacerbation. In the latter cluster, mucus plugs persisted, and 30% yielded Pseudomonas aeruginosa in the sputum <5 years later. CONCLUSION: The refractory phenotype with persistent mucus plugs was identified in Aspergillus-sensitized refractory asthma with bronchiectasis and ABPA. Mucus plug prevention is warranted.

DOI： 10.1016/j.jacig.2024.100364

Advantage of spirometry over oscillometry to detect dupilumab’s effect on small airway dysfunction. 査読

Toshihiro Shirai, Keita Hirai, Taisuke Akamatsu, Kenji Mizumura, Hitoshi Sasano, Norihiro Harada, Akihiko Tanaka, Hironori Sagara, Katsunori Masaki, Koichi Fukunaga, Konomi Kobayashi, Hiroyuki Nagase, Nobuaki Miyahara, Arihiko Kanehiro, Noboru Kitamura, Naruhiko Sugihara, Junko Terada-Hirashima, Masayuki Hojo, Kazuyuki Chibana, Etsuko Tagaya, Yasuhiro Gon

Allergology International 2024年12月

The Clinical Significance of Interstitial Pneumonia with Autoimmune Features in Cryptogenic Organizing Pneumonia: A Prospective Multicenter Observational Study. 査読国際誌

Hisao Higo, Hirohisa Ichikawa, Yukako Arakawa, Yoshihiro Mori, Tomoki Tamura, Shoichi Kuyama, Chiaki Matsumoto, Keisuke Sugimoto, Noboru Hamada, Toshimitsu Suwaki, Junko Itano, Yasushi Tanimoto, Satoru Senoo, Akihiko Taniguchi, Yumi Inukai, Machiko Arita, Satoko Makimoto, Katsuhide Kojima, Takashi Matsushita, Yoshinobu Maeda, Nobuaki Miyahara

Journal of clinical medicine 13 ( 22 ) 2024年11月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Background: There are cases of idiopathic interstitial pneumonias (IIPs) that do not meet the diagnostic criteria for connective tissue disease but have clinical features suggestive of autoimmune process. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept for these patients. Although several prospective studies on IPAF have been conducted, its clinical significance in cryptogenic organizing pneumonia (COP) remains unclear. Methods: Patients aged ≥20 years with suspected COP were prospectively enrolled between June 2018 and December 2022. Among the enrolled patients, those diagnosed with COP based on computed tomography (CT) and bronchoalveolar lavage (BAL) findings were compared between the IPAF and non-IPAF groups. Results: A total of 56 patients were enrolled in this study. Of these, 30 were diagnosed with COP and included in the analysis. Clinical and serological features were positive in two and six patients, respectively. Each feature was exclusive, and eight patients (26.7%) were diagnosed with IPAF. There were no differences between the IPAF and non-IPAF groups in terms of clinical features, including BAL findings, laboratory data, CT findings, and clinical course. During the one-year follow-up period, the frequency of COP exacerbation did not differ between the IPAF and non-IPAF groups, and no cases of systemic autoimmune disease or death occurred in either group. Conclusions: The COP characteristics of the IPAF and non-IPAF groups are similar in all aspects, and distinguishing between the two groups may be of little significance.

DOI： 10.3390/jcm13226870

Predicting dupilumab effectiveness with Type-2 biomarkers: A real-world study of severe asthma. 査読国際誌

Kenji Mizumura, Yasuhiro Gon, Norihiro Harada, Shiho Yamada, Asami Fukuda, Ryosuke Ozoe, Shuichiro Maruoka, Sumiko Abe, Kazuhisa Takahashi, Akihiko Tanaka, Hironori Sagara, Taisuke Akamatsu, Toshihiro Shirai, Katsunori Masaki, Koichi Fukunaga, Konomi Kobayashi, Hiroyuki Nagase, Nobuaki Miyahara, Arihiko Kanehiro, Noboru Kitamura, Naruhiko Sugihara, Fumio Kumasawa, Junko Terada-Hirashima, Masayuki Hojo, Kazuyuki Chibana, Etsuko Tagaya

Allergology international : official journal of the Japanese Society of Allergology 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The therapeutic effectiveness of dupilumab for severe asthma in real-world settings is yet to be prospectively investigated across multiple institutions, and uncertainties persist regarding predictive factors for its effectiveness. We aimed to assess the effectiveness of dupilumab and identify predictors of its effectiveness in real-world settings using two type-2 biomarkers: FeNO concentration and blood eosinophil count. METHODS: This prospective multicenter study included 103 patients with severe asthma. Exacerbations and respiratory functions were monitored for 24 weeks. Asthma control was evaluated using the Asthma Control Questionnaire-5. Clinical symptoms and their impact on cough and sputum were assessed using the Cough and Sputum Assessment Questionnaire (CASA-Q). Subgroup analyses of type-2 biomarkers were conducted based on FeNO levels and blood eosinophil counts at baseline. RESULTS: Treatment with dupilumab led to a reduction in exacerbations and enhancement in asthma control, FEV1, and CASA-Q scores. FEV1 improvement was correlated with enhancement in the sputum domain of the CASA-Q. Patients exhibiting elevated FeNO levels and blood eosinophil counts demonstrated more significant enhancements in FEV1. CASA-Q sputum domain scores were significantly higher in the group with elevated eosinophil counts. Regression analysis revealed that FeNO levels and blood eosinophil counts are significant predictors of FEV1 improvement, with blood eosinophil counts also predicting sputum improvement in patients treated with dupilumab. CONCLUSIONS: Type-2 biomarkers may act as indicators of improvement in FEV1 and sputum outcomes among patients with severe asthma undergoing dupilumab treatment in real-world settings.

DOI： 10.1016/j.alit.2024.08.005

A Case of Single-lung Transplant in a Patient with Mycobacterium avium Pulmonary Disease Successfully Treated with Amikacin Liposome Inhalation Suspension. 査読

Taichi Ozeki, Hisao Higo, Hiroki Omori, Shunta Mori, Shin Tanaka, Go Makimoto, Kiichiro Ninomiya, Akihiko Taniguchi, Masanori Fujii, Kentaro Miyoshi, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Seiichiro Sugimoto, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Nobuaki Miyahara

Internal medicine (Tokyo, Japan) 2024年9月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

A 55-year-old man presented to our hospital with idiopathic pulmonary fibrosis (IPF). He was registered with the Japan Organ Transplant Network the following year due to disease progression. Treatment with clarithromycin, ethambutol, and rifampicin for complications of Mycobacterium avium pulmonary disease was initiated, but sputum conversion could not be achieved. The administration of an amikacin liposome inhalation suspension (ALIS) resulted in sputum conversion, and single-lung transplantation was performed. ALIS therapy was continued after lung transplantation, and no M. avium disease was observed for 15 months. ALIS may cause M. avium pulmonary disease with additional indications for lung transplantation.

DOI： 10.2169/internalmedicine.3854-24

Remission of hypersensitivity pneumonitis after allogeneic hematopoietic stem cell transplantation. 査読国際誌

Yumi Inukai Motokura, Hisao Higo, Chiaki Matsumoto, Mari Uno, Kanako Fujiwara, Toshiki Terao, Satoko Makimoto, Fumiyo Higaki, Ken-Ichi Matsuoka, Fumiaki Tokioka, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory investigation 62 ( 5 ) 759 - 761 2024年7月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

A 50-year-old man was diagnosed with hypersensitivity pneumonitis caused by the environment of his bar owing to worsening symptoms, laboratory test results, and computed tomography images after an environmental inhalation challenge test. His hypersensitivity pneumonitis exacerbated despite receiving prednisolone 20 mg/day. The patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor for myelodysplastic syndrome. No exacerbation of hypersensitivity pneumonitis was observed after HSCT. An environmental inhalation challenge test involving exposure to his bar confirmed the remission of hypersensitivity pneumonitis after HSCT. This case demonstrates that hypersensitivity pneumonitis can be remitted by HSCT.

DOI： 10.1016/j.resinv.2024.06.007

Predictors of exacerbation in Japanese patients with severe asthma: Analysis of the severe asthma research program (Okayama-SARP) cohort. 査読国際誌

Hisao Higo, Akihiko Taniguchi, Satoru Senoo, Taichi Ozeki, Naoki Nakamura, Masaki Atokawa, Junko Itano, Naohiro Oda, Ryota Sunami, Yutaro Shiota, Yukako Arakawa, Yoshihiro Mori, Naomi Kunichika, Ichiro Takata, Toshimitsu Suwaki, Norihiko Nakanishi, Yasushi Tanimoto, Arihiko Kanehiro, Yoshinobu Maeda, Katsuyuki Kiura, Nobuaki Miyahara

Respiratory investigation 62 ( 4 ) 695 - 701 2024年7月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Because exacerbation of severe asthma decreases patients' quality of life, this study aimed to identify predictive factors for asthma exacerbation. METHODS: Japanese patients with severe asthma requiring treatment according to the Global Initiative for Asthma (GINA) guidelines ≥ Step 4 between January 2018 and August 2021 were prospectively enrolled and followed up for one year at facilities participating in the Okayama Respiratory Disease Study Group (Okayama Severe Asthma Research Program). RESULTS: A total of 85 patients (29 men and 56 women) were included. The median age was 64 (interquartile range [IQR], 51-72) years. Treatment according to GINA Steps 4 and 5 was required in 29 and 56 patients, respectively, and 44 patients (51.8%) were treated with biologics. The median peripheral-blood eosinophil count, fractional exhaled nitric oxide, IgE level, and percent predicted FEV1 (%FEV1) at enrollment were 204 (IQR, 49-436)/μL, 28 (IQR, 15-43) ppb, 172 (IQR, 56-473) IU/mL, and 80.0 (IQR, 61.1-96.1) %, respectively. Exacerbation during the previous year, asthma control test (ACT) score <20, %FEV1 <60%, and serum IL-10 level >6.7 pg/mL were associated with exacerbation during the observation period. CONCLUSIONS: Exacerbation during the previous year, low ACT score, and low %FEV1 were predictive factors of future exacerbation, even in a cohort with >50% of patients treated with biologics. Furthermore, high serum IL-10 levels might be a new predictive factor.

DOI： 10.1016/j.resinv.2024.05.014

Concomitant osimertinib and antituberculosis therapy in an elderly patient with EGFR-mutated lung cancer and pulmonary tuberculosis: A case report. 査読国際誌

Hiroaki Matsuura, Hisao Higo, Tadahiro Kuribayashi, Akihiko Tamaoki, Takamasa Nakasuka, Mari Uno, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Kadoaki Ohashi

Thoracic cancer 15 ( 17 ) 1390 - 1394 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

The concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well-established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89-year-old female, diagnosed with epidermal growth factor receptor (EGFR)-mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis.

DOI： 10.1111/1759-7714.15324

びまん性肺疾患トピック肺線維症急性増悪におけるS100A8/A9の役割の検討

中村尚季, 肥後寿夫, 妹尾賢, 尾関太一, 角南良太, 山元修成, 板野純子, 谷口暁彦, 田中彩加, 木下理恵, 阪口政清, 前田嘉信, 宮原信明

日本呼吸器学会誌 13 ( 増刊 ) 217 - 217 2024年3月

特発性器質化肺炎における自己免疫性疾患の特徴を伴う間質性肺炎(IPAF)の頻度および臨床像の検討

市川裕久, 肥後寿夫, 松岡克浩, 関祥子, 荒川裕佳子, 森由弘, 久山彰一, 松本千晶, 杉本啓介, 濱田昇, 洲脇俊充, 板野純子, 谷口暁彦, 犬飼優美, 有田眞知子, 槇本怜子, 児島克英, 宮原信明

日本呼吸器学会誌 13 ( 増刊 ) 365 - 365 2024年3月

The Role of Neuropeptide Y in Respiratory Disease Pathogenesis via the Airway Immune Response 招待査読国際誌

Junko Itano, Yoshinobu Maeda, Katsuyuki Kiura, Nobuaki Miyahara

Acta Medica Okayama 78 ( 2 ) 95 - 106 2024年2月

Pneumocystis jirovecii pneumonia mortality risk associated with preceding long-term steroid use for the underlying disease: A multicenter, retrospective cohort study. 査読国際誌

Kohei Miyake, Satoru Senoo, Ritsuya Shiiba, Junko Itano, Goro Kimura, Tatsuyuki Kawahara, Tomoki Tamura, Kenichiro Kudo, Tetsuji Kawamura, Yasuharu Nakahara, Hisao Higo, Daisuke Himeji, Nagio Takigawa, Nobuaki Miyahara

PloS one 19 ( 2 ) e0292507 2024年

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Long-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality. METHODS: Retrospective multicenter study to identify risk factors for PcP mortality, including average steroid dose before the first visit for PcP in non-human immunodeficiency virus (HIV)-PcP patients. We generated receiver operating characteristic (ROC) curves for 90-day all-cause mortality and the mean daily steroid dose per unit body weight in the preceding 10 to 90 days in 10-day increments. Patients were dichotomized by 90-day mortality and propensity score-based stabilized inverse probability of treatment weighting (IPTW) adjusted covariates of age, sex, and underlying disease. Multivariate analysis with logistic regression assessed whether long-term corticosteroid use affected outcome. RESULTS: Of 133 patients with non-HIV-PcP, 37 died within 90 days of initial diagnosis. The area under the ROC curve for 1-40 days was highest, and the optimal cutoff point of median adjunctive corticosteroid dosage was 0.34 mg/kg/day. Past steroid dose, underlying interstitial lung disease and emphysema, lower serum albumin and lower lymphocyte count, higher lactate dehydrogenase, use of therapeutic pentamidine and therapeutic high-dose steroids were all significantly associated with mortality. Underlying autoimmune disease, past immunosuppressant use, and a longer time from onset to start of treatment, were associated lower mortality. Logistic regression analysis after adjusting for age, sex, and underlying disease with IPTW revealed that steroid dose 1-40 days before the first visit for PcP (per 0.1 mg/kg/day increment, odds ratio 1.36 [95% confidence interval = 1.16-1.66], P<0.001), low lymphocyte counts, and high lactate dehydrogenase revel were independent mortality risk factor, while respiratory failure, early steroid, and sulfamethoxazole/trimethoprim for PcP treatment did not. CONCLUSION: A steroid dose before PcP onset was strongly associated with 90-day mortality in non-HIV-PcP patients, emphasizing the importance of appropriate prophylaxis especially in this population.

DOI： 10.1371/journal.pone.0292507

Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy. 査読国際誌

Masahiro Yamashita, Hisao Higo, Nobuharu Fujii, Chiaki Matsumoto, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory medicine case reports 51 102104 - 102104 2024年

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

A 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID-19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19.

DOI： 10.1016/j.rmcr.2024.102104

Dramatic Response to Tezepelumab as an Initial Biologic Agent for Refractory Asthma Associated with Type 2 and Non-type 2 Traits. 査読

77 ( 6 ) 671 - 674 2023年12月

Pulmonary fibrosis and type-17 immunity. 招待査読国際誌

Satoru Senoo, Hisao Higo, Akihiko Taniguchi, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory investigation 61 ( 5 ) 553 - 562 2023年9月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Fibrosis of the lung can occur in idiopathic pulmonary fibrosis, collagen vascular diseases, and hypersensitivity pneumonitis, among other diseases. Transforming growth factor (TGF)-β, vascular epithelial growth factor, fibroblast growth factor, and platelet-derived growth factor contribute to the pathophysiology of fibrosis. TGF-β and other cytokines, including interleukin (IL)-1β, IL-6, and IL-23, activate type-17 immunity, which is involved in pulmonary fibrosis. The components of type-17 immunity include type-17 helper T cells, γδT cells, IL-17A-producing CD8-positive T cells, invariant NKT cells, and group 3 innate lymphoid cells. IL-17A, the main cytokine of type-17 immunity, is able to induce the epithelial-mesenchymal transition in epithelial cells via a production of TGF-β, directly stimulate fibroblasts and fibrocytes, and inhibit autophagy, which otherwise protects against pulmonary fibrosis. IL-23 induces type-17 immunity and plays an important role in the acute exacerbation of pulmonary fibrosis. Clinical studies have also linked type-17 immunity to the pathogenesis of pulmonary fibrosis. Consequently, targeting type-17 immunity may serve as a new therapeutic strategy to prevent the development or exacerbation of pulmonary fibrosis.

DOI： 10.1016/j.resinv.2023.05.005

Switching to Dupilumab from Other Biologics without a Treatment Interval in Patients with Severe Asthma: A Multi-Center Retrospective Study. 査読国際誌

Hisao Higo, Hirohisa Ichikawa, Yukako Arakawa, Yoshihiro Mori, Junko Itano, Akihiko Taniguchi, Satoru Senoo, Goro Kimura, Yasushi Tanimoto, Kohei Miyake, Tomoya Katsuta, Mikio Kataoka, Yoshinobu Maeda, Katsuyuki Kiura, Nobuaki Miyahara, Okayama Respiratory Disease Study Group Ordsg

Journal of clinical medicine 12 ( 16 ) 2023年8月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Dupilumab is a fully humanized monoclonal antibody that blocks interleukin-4 and interleukin-13 signals. Several large clinical trials have demonstrated the efficacy of dupilumab in patients with severe asthma. However, few studies have examined a switch to dupilumab from other biologics. METHODS: This retrospective, multi-center observational study was conducted by the Okayama Respiratory Disease Study Group. Consecutive patients with severe asthma who were switched to dupilumab from other biologics without a treatment interval between May 2019 and September 2021 were enrolled. Patients with a treatment interval of more than twice the standard dosing interval for the previous biologic prior to dupilumab administration were excluded. RESULTS: The median patient age of the 27 patients enrolled in this study was 57 years (IQR, 45-68 years). Eosinophilic chronic rhinosinusitis (ECRS)/chronic rhinosinusitis with nasal polyp (CRSwNP) was confirmed in 23 patients. Previous biologics consisted of omalizumab (n = 3), mepolizumab (n = 3), and benralizumab (n = 21). Dupilumab significantly improved FEV1 (median improvement: +145 mL) and the asthma control test score (median improvement: +2). The overall response rate in patients receiving dupilumab for asthma as determined using the Global Evaluations of Treatment Effectiveness (GETE) was 77.8%. There were no significant differences in the baseline characteristics of the GETE-improved group vs. the non-GETE-improved group. ECRS/CRSwNP improved in 20 of the 23 patients (87.0%). Overall, 8 of the 27 patients (29.6%) developed transient hypereosinophilia (>1500/μL), but all were asymptomatic and able to continue dupilumab therapy. CONCLUSIONS: Dupilumab was highly effective for the treatment of severe asthma and ECRS/CRSwNP, even in patients switched from other biologics without a treatment interval.

DOI： 10.3390/jcm12165174

抗IL-4受容体抗体 GETEを用いた重症喘息におけるデュピルマブの効果予測因子の検討 iPOT4R多施設共同研究

水村賢司, 鹿野壯太郎, 正木克宜, 福永興壱, 原田紀宏, 田中明彦, 小林このみ, 長瀬洋之, 多賀谷悦子, 宮原信明, 赤松泰介, 白井敏博, 金廣有彦, 杉原徳彦, 北村登, 熊澤文雄, 寺田純子, 放生雅章, 知花和行, 權寧博

アレルギー 72 ( 6-7 ) 907 - 907 2023年8月

抗IL-4受容体抗体他の生物学的製剤からデュピルマブへ切り替えた喘息症例に関する多施設共同後ろ向き観察研究

肥後寿夫, 角南良太, 市川裕久, 荒川裕佳子, 森由弘, 板野純子, 木村五郎, 谷本安, 三宅剛平, 片岡幹男, 木浦勝行, 宮原信明

アレルギー 72 ( 6-7 ) 908 - 908 2023年8月

重症喘息におけるデュピルマブの喀痰症状への効果と呼吸機能の関連 iPOT4R多施設共同研究

鹿野壯太郎, 水村賢司, 權寧博, 正木克宜, 福永興壱, 原田紀彦, 田中明彦, 小林このみ, 長瀬洋之, 宮原信明, 赤松泰介, 白井敏博, 金廣有彦, 杉原徳彦, 北村登, 熊澤文雄, 寺田純子, 放生雅章, 知花和行, 多賀谷悦子

アレルギー 72 ( 6-7 ) 927 - 927 2023年8月

Mycobacterium shinjukuense infection successfully treated with clarithromycin, rifampicin, and ethambutol. 査読国際誌

Kayo Nakamura, Etsuko Murakami, Daizo Kishino, Shuko Mashimo, Yusuke Kurioka, Yusaku Shibata, Arihiko Taniguchi, Hisao Higo, Yasushi Hiramatsu, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory medicine case reports 45 101894 - 101894 2023年

担当区分：最終著者,　責任著者記述言語：英語

We present the case of a 59-year-old woman diagnosed with Mycobacterium shinjukuense infection using mass spectrometry of bronchioalveolar lavage fluid. We initiated treatment with clarithromycin, rifampicin, and ethambutol based on the results of drug susceptibility testing, which improved lung opacities. Most previous cases were treated with the standard regimen for Mycobacterium tuberculosis. However, our regimen may provide a therapeutic option for this rare nontuberculous Mycobacterium infection.

DOI： 10.1016/j.rmcr.2023.101894

Nationwide survey of refractory asthma with bronchiectasis by inflammatory subtypes 査読国際誌

Respiratory Research 23 ( 1 ) 365 - 365 2022年12月

Intravenous immunoglobulin for acute exacerbation of fibrotic idiopathic interstitial pneumonias: IV immunoglobulin for acute exacerbation of fibrotic IIPs 査読国際誌

Hisao Higo, Hirohisa Ichikawa, Naoki Nakamura, Masanori Fujii, Katsuhiro Matsuoka, Shoko Seki, Takamasa Wada, Noriyuki Suzaki, Takuya Nagata, Yukako Arakawa, Yoshihiro Mori, Masaomi Marukawa, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

Sarcoidosis, Vasculitis and Diffuse Lung Diseases 2022年11月

Neuropeptide Y Antagonizes Development of Pulmonary Fibrosis Through IL-1β Inhibition. 査読国際誌

Junko Itano, Akihiko Taniguchi, Satoru Senoo, Noboru Asada, Yuka Gion, Yuria Egusa, Lili Guo, Naohiro Oda, Kota Araki, Yasuharu Sato, Shinichi Toyooka, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

American journal of respiratory cell and molecular biology 67 ( 6 ) 654 - 665 2022年9月

Use of a highly sensitive lung cancer compact panel to detect KRAS G12D in the wash fluid from a lung tumor: A case report. 査読国際誌

Daisuke Minami, Nagio Takigawa, Yasuhiro Nakajima, Nobuaki Miyahara, Yasuyuki Mizumori, Mitsuhiro Ueda, Seiji Nakamura, Fumihiko Suzuki, Yoshiharu Sato, Kei Morikawa, Arihiko Kanehiro

Thoracic cancer 2022年5月

A case of Fulminant Respiratory Failure Caused by Anti-asparaginyl tRNA Synthetase (Anti-KS) Antibody Syndrome-related Interstitial Lung Disease. 査読国際誌

Naohiro Oda, Akihiko Taniguchi, Toshiyuki Aokage, Satoru Senoo, Kenta Nagashima, Reo Mitani, Ichiro Takata, Nobuaki Miyahara

2022年4月

Identification of targetable kinases in idiopathic pulmonary fibrosis. 査読国際誌

Hisao Higo, Kadoaki Ohashi, Shuta Tomida, Sachi Okawa, Hiromasa Yamamoto, Seiichiro Sugimoto, Satoru Senoo, Go Makimoto, Kiichiro Ninomiya, Takamasa Nakasuka, Kazuya Nishii, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Shinichi Toyooka, Katsuyuki Kiura

23 ( 1 ) 20 - 20 2022年2月

Protective effects of neuropeptide Y against elastase-induced pulmonary emphysema. 査読国際誌

Akihiko Taniguchi, Naohiro Oda, Daisuke Morichika, Satoru Senoo, Junko Itano, Utako Fujii, Lili Guo, Ryota Sunami, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

American journal of physiology. Lung cellular and molecular physiology 322 ( 4 ) L539-L549 2022年2月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Neuropeptide Y (NPY) is a neuropeptide widely expressed in not only the central nervous system but also immune cells and the respiratory epithelium. Patients with chronic obstructive pulmonary disease (COPD) reportedly exhibit decreased NPY expression in the airway epithelium, but the involvement of NPY in the pathophysiology of COPD has not been defined. We investigated the role of NPY in elastase-induced emphysema. NPY-deficient (NPY-/-) mice and wild-type (NPY+/+) mice received intratracheal instillation of porcine pancreas elastase (PPE). The numbers of inflammatory cells and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates were determined along with quantitative morphometry of lung sections. Intratracheal instillation of PPE induced emphysematous changes and increased NPY levels in the lungs. Compared with NPY+/+ mice, NPY-/- mice had significantly enhanced PPE-induced emphysematous changes and alveolar enlargement. Neutrophilia seen in BAL flu12id of NPY+/+ mice on day 4 after PPE instillation was also enhanced in NPY-/- mice, and the enhancement was associated with increased levels of neutrophil-related and macrophage-related chemokines and IL-17A as well as increased numbers of type 3 innate lymphoid cells in the airways. Treatment with NPY significantly reduced PPE-induced emphysematous changes. Conversely, treatment with a NPY receptor antagonist exacerbated PPE-induced emphysematous changes. These observations indicate that NPY has protective effects against elastase-induced emphysema, and suggest that targeting NPY in emphysema has potential as a therapeutic strategy for delaying disease progression.

DOI： 10.1152/ajplung.00353.2020

新規生物学的製剤抗IL-33抗体

妹尾賢, 宮原信明

呼吸器内科 41 ( 1 ) 67 - 72 2022年1月

Nonepisodic angioedema with eosinophilia during sublingual immunotherapy with house dust mite extract. 査読国際誌

Naohiro Oda, Takahisa Koyama, Yuki Nakagawa, Nobuaki Miyahara

Allergology international : official journal of the Japanese Society of Allergology 71 ( 2 ) 254 - 255 2021年12月

The effects of inhaling hydrogen gas on macrophage polarization, fibrosis, and lung function in mice with bleomycin-induced lung injury. 査読国際誌

Toshiyuki Aokage, Mizuki Seya, Takahiro Hirayama, Tsuyoshi Nojima, Masumi Iketani, Michiko Ishikawa, Yasuhiro Terasaki, Akihiko Taniguchi, Nobuaki Miyahara, Atsunori Nakao, Ikuroh Ohsawa, Hiromichi Naito

BMC pulmonary medicine 21 ( 1 ) 339 - 339 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Acute respiratory distress syndrome, which is caused by acute lung injury, is a destructive respiratory disorder caused by a systemic inflammatory response. Persistent inflammation results in irreversible alveolar fibrosis. Because hydrogen gas possesses anti-inflammatory properties, we hypothesized that daily repeated inhalation of hydrogen gas could suppress persistent lung inflammation by inducing functional changes in macrophages, and consequently inhibit lung fibrosis during late-phase lung injury. METHODS: To test this hypothesis, lung injury was induced in mice by intratracheal administration of bleomycin (1.0 mg/kg). Mice were exposed to control gas (air) or hydrogen (3.2% in air) for 6 h every day for 7 or 21 days. Respiratory physiology, tissue pathology, markers of inflammation, and macrophage phenotypes were examined. RESULTS: Mice with bleomycin-induced lung injury that received daily hydrogen therapy for 21 days (BH group) exhibited higher static compliance (0.056 mL/cmH2O, 95% CI 0.047-0.064) than mice with bleomycin-induced lung injury exposed only to air (BA group; 0.042 mL/cmH2O, 95% CI 0.031-0.053, p = 0.02) and lower static elastance (BH 18.8 cmH2O/mL, [95% CI 15.4-22.2] vs. BA 26.7 cmH2O/mL [95% CI 19.6-33.8], p = 0.02). When the mRNA levels of pro-inflammatory cytokines were examined 7 days after bleomycin administration, interleukin (IL)-6, IL-4 and IL-13 were significantly lower in the BH group than in the BA group. There were significantly fewer M2-biased macrophages in the alveolar interstitium of the BH group than in the BA group (3.1% [95% CI 1.6-4.5%] vs. 1.1% [95% CI 0.3-1.8%], p = 0.008). CONCLUSIONS: The results suggest that hydrogen inhalation inhibits the deterioration of respiratory physiological function and alveolar fibrosis in this model of lung injury.

DOI： 10.1186/s12890-021-01712-2

Reactive Oxygen Species and Antioxidative Defense in Chronic Obstructive Pulmonary Disease. 招待査読国際誌

Akihiko Taniguchi, Mitsuru Tsuge, Nobuaki Miyahara, Hirokazu Tsukahara

Antioxidants (Basel, Switzerland) 10 ( 10 ) 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

The respiratory system is continuously exposed to endogenous and exogenous oxidants. Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways, leading to the destruction of lung parenchyma (emphysema) and declining pulmonary function. It is increasingly obvious that reactive oxygen species (ROS) and reactive nitrogen species (RNS) contribute to the progression and amplification of the inflammatory responses related to this disease. First, we described the association between cigarette smoking, the most representative exogenous oxidant, and COPD and then presented the multiple pathophysiological aspects of ROS and antioxidative defense systems in the development and progression of COPD. Second, the relationship between nitric oxide system (endothelial) dysfunction and oxidative stress has been discussed. Third, we have provided data on the use of these biomarkers in the pathogenetic mechanisms involved in COPD and its progression and presented an overview of oxidative stress biomarkers having clinical applications in respiratory medicine, including those in exhaled breath, as per recent observations. Finally, we explained the findings of recent clinical and experimental studies evaluating the efficacy of antioxidative interventions for COPD. Future breakthroughs in antioxidative therapy may provide a promising therapeutic strategy for the prevention and treatment of COPD.

DOI： 10.3390/antiox10101537

Essential role of IL-23 in the development of acute exacerbation of pulmonary fibrosis. 査読国際誌

Satoru Senoo, Akihiko Taniguchi, Junko Itano, Naohiro Oda, Daisuke Morichika, Utako Fujii, Lili Guo, Ryota Sunami, Arihiko Kanehiro, Fumiaki Tokioka, Akihiko Yoshimura, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

American journal of physiology. Lung cellular and molecular physiology 321 ( 5 ) L925-L940 2021年9月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：学位論文（博士）

Acute exacerbation of idiopathic pulmonary fibrosis has a poor prognosis associated with neutrophilic inflammation. Interleukin-23 is a proinflammatory cytokine involved in neutrophilic inflammation. However, little is known about its role in acute exacerbation of pulmonary fibrosis. This study was performed to determine the role of interleukin-23 in acute exacerbation of pulmonary fibrosis. For assessment of acute exacerbation of pulmonary fibrosis, mice were intratracheally administered bleomycin followed by lipopolysaccharide. Inflammatory cells, cytokine levels, and morphological morphometry of the lungs were analyzed. Cytokine levels were measured in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients with or without acute exacerbation. Interleukin-23, -17A, and -22 levels were increased in the airway of mice with acute exacerbation of pulmonary fibrosis. Interleukin-23p19-deficient mice with acute exacerbation of pulmonary fibrosis had markedly reduced airway inflammation and fibrosis associated with decreased levels of interleukin-17A and -22 compared with wild-type mice. Treatment with an anti-interleukin-23 antibody attenuated airway inflammation and fibrosis and reduced interleukin-17A and -22 levels in mice with acute exacerbation of pulmonary fibrosis. T helper 17 cells were the predominant source of interleukin-17A in mice with acute exacerbation of pulmonary fibrosis. Interleukin-23 levels in bronchoalveolar lavage fluid tended to be higher in idiopathic pulmonary fibrosis patients with than without acute exacerbation. The data presented here suggest that interleukin-23 is essential for the development of acute exacerbation of pulmonary fibrosis, and that blockade of interleukin-23 may be a new therapeutic strategy for acute exacerbation of pulmonary fibrosis.

DOI： 10.1152/ajplung.00582.2020

Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease. 査読国際誌

Sachi Okawa, Kammei Rai, Nobuharu Fujii, Yuka Gion, Kiichiro Ninomiya, Yuka Kato, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Nobuaki Miyahara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 60 ( 17 ) 2831 - 2837 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 68-year-old man presented with a solid mass at the left renal pelvis and ureter with multiple systemic lymphadenopathies and a mass with a cavity in the right lower lobe of the lung. While a transbronchial lung biopsy revealed no malignancy, a biopsy of the renal pelvis showed marginal zone lymphoma with polyclonal IgG4-positive cells. The serum IgG4 level and presence of a bilateral orbital mass suggested Mikulicz disease. The lesions shrank following the administration of steroids. A rebiopsy confirmed lung adenocarcinoma, and its background showed IgG4-positive cells a year later. IgG4-related diseases require careful follow-up because they can be complicated by malignancy.

DOI： 10.2169/internalmedicine.6470-20

The prevalence of comorbid respiratory disease among COVID-19 patients, and mortality during the first wave in Japan: A nationwide survey by the Japanese Respiratory Society. 国際誌

Hiroyuki Nagase, Yoshihiro Nishimura, Hisako Matsumoto, Naoya Sugimoto, Takashi Iwanaga, Akiko Sano, Satoshi Konno, Nobuyuki Hizawa, Koichiro Asano, Takahiko Horiguchi, Akihito Yokoyama

Respiratory investigation 59 ( 5 ) 679 - 682 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

There is a concern that persons with underlying respiratory disease may have increased susceptibility to COVID-19 and/or increased severity/mortality if infected. However, information regarding such patients during the first wave of the epidemic is lacking in Japan. We surveyed chest physicians nationwide, and collected anonymous data concerning 1444 patients. Among COVID-19 patients, the prevalence of asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases (ILD) was 3.4%, 4.8%, and 1.5%, respectively. Among COVID-19 patients with these 3 comorbidities, exacerbation of the comorbidity occurred in 12.2%, 18.8%, and 36.4%, respectively, and mortality (6.2% overall) was 4.1%, 13.0%, and 31.8%, respectively. The prevalence of asthma among COVID-19 patients was not higher than that for the general population, and mortality in COVID-19 patients with asthma was not higher than mortality in COVID-19 patients without underlying respiratory disease. COVID-19 patients having COPD or ILD had relatively high mortality, especially for ILD.

DOI： 10.1016/j.resinv.2021.06.008

Pulmonary Aspergilloma and Allergic Bronchopulmonary Aspergillosis Following the 2018 Heavy Rain Event in Western Japan: A Case Report. 査読国際誌

Eri Ando, Takamasa Nakasuka, Toshio Kubo, Akihiko Taniguchi, Kiichiro Ninomiya, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masaomi Yamane, Nobuaki Miyahara, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 61 ( 3 ) 379 - 383 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 16-year-old boy with asthma participated in recovery volunteer work following the 2018 heavy rains in Japan. One month later, he experienced chest pain and dyspnea. Chest computed tomography revealed a cavity with a fungal ball, and Aspergillus fumigatus was detected in his bronchoalveolar lavage fluid. He was treated with voriconazole, but new consolidations appeared rapidly. He also experienced allergic bronchopulmonary aspergillosis. After prednisolone prescription, the consolidations improved; however, his asthma worsened. He underwent partial lung resection to avoid allergens, and his symptoms improved. We must recognize cases of infection after a disaster, especially in patients with chronic respiratory diseases.

DOI： 10.2169/internalmedicine.7124-21

Exacerbation of pulmonary cryptococcosis associated with enhancement of Th2 response in the postpartum period. 査読国際誌

Shota Miyoshi, Naohiro Oda, Yuka Gion, Takahiro Taki, Reo Mitani, Ichiro Takata, Akihiko Taniguchi, Yasuharu Sato, Nobuaki Miyahara

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 27 ( 8 ) 1248 - 1250 2021年8月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

Cryptococcosis is an invasive mycosis that has become increasingly prevalent in immunocompromised patients. Pregnant women are also one of the risk populations for cryptococcosis. Reversal of Th2 to Th1 response following resolution of immunosuppression during the postpartum period can lead to overt clinical manifestations of a previously silent infection, resembling an immune reconstitution inflammatory syndrome. Here, we report a case of a 30-year-old woman who had an exacerbation of pulmonary cryptococcosis in the postpartum period mimicking an immune reconstitution inflammatory syndrome. In the present case, chest computed tomography showed multiple small nodules on the day of the delivery; however, pulmonary cryptococcosis, which was subclinical during pregnancy, rapidly worsened to mass-like consolidation at one month after the delivery. Pathohistological examination of the lung specimen showed lung parenchyma infiltration with histiocytes and numerous lymphocytes without granulomatous formations, and a small number of yeast-like organisms consistent with Cryptococcus without capillary involvement. Immunohistochemical staining showed predominance of CD3+ cells and CD4+ cells over CD8+ cells. In addition, GATA3+ cells dominated over T-bet + cells. These data suggested exacerbation of pulmonary cryptococcosis associated with enhancement of Th2 response in the postpartum period.

DOI： 10.1016/j.jiac.2021.03.025

経食道的気管支鏡下穿刺吸引生検法(EUS-B-FNA)後に縦隔血腫を来した1例査読

南大輔, 柴田祐作, 中村香葉, 村上悦子, 宮原信明, 岸野大蔵, 瀧川奈義夫, 吉川真生, 田尾裕之, 水谷尚雄, 堀田真智子, 山岡正和, 廣岡空良, 石崎秀美

姫路赤十字病院誌 45 15 - 18 2021年7月

Loss of IL-33 enhances elastase-induced and cigarette smoke extract-induced emphysema in mice. 査読国際誌

Daisuke Morichika, Akihiko Taniguchi, Naohiro Oda, Utako Fujii, Satoru Senoo, Junko Itano, Arihiko Kanehiro, Yoshiaki Kitaguchi, Masanori Yasuo, Masayuki Hanaoka, Takashi Satoh, Shizuo Akira, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory research 22 ( 1 ) 150 - 150 2021年5月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: IL-33, which is known to induce type 2 immune responses via group 2 innate lymphoid cells, has been reported to contribute to neutrophilic airway inflammation in chronic obstructive pulmonary disease. However, its role in the pathogenesis of emphysema remains unclear. METHODS: We determined the role of interleukin (IL)-33 in the development of emphysema using porcine pancreas elastase (PPE) and cigarette smoke extract (CSE) in mice. First, IL-33-/- mice and wild-type (WT) mice were given PPE intratracheally. The numbers of inflammatory cells, and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates, were analyzed; quantitative morphometry of lung sections was also performed. Second, mice received CSE by intratracheal instillation. Quantitative morphometry of lung sections was then performed again. RESULTS: Intratracheal instillation of PPE induced emphysematous changes and increased IL-33 levels in the lungs. Compared to WT mice, IL-33-/- mice showed significantly greater PPE-induced emphysematous changes. No differences were observed between IL-33-/- and WT mice in the numbers of macrophages or neutrophils in BAL fluid. The levels of hepatocyte growth factor were lower in the BAL fluid of PPE-treated IL-33-/- mice than WT mice. IL-33-/- mice also showed significantly greater emphysematous changes in the lungs, compared to WT mice, following intratracheal instillation of CSE. CONCLUSION: These observations suggest that loss of IL-33 promotes the development of emphysema and may be potentially harmful to patients with COPD.

DOI： 10.1186/s12931-021-01705-z

Interstitial Pneumonia Secondary to Hermansky-Pudlak Syndrome Type 4 Treated with Different Antifibrotic Agents. 査読国際誌

Junko Itano, Yasushi Tanimoto, Goro Kimura, Noboru Hamada, Hisaaki Tanaka, Shinsuke Ninomiya, Kenjiro Kosaki, Nobuaki Miyahara, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 60 ( 5 ) 783 - 788 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive hereditary disease that may be complicated by progressive and potentially fatal interstitial pneumonia. We herein report a 64-year-old woman with interstitial pneumonia associated with HPS type 4 whom we treated with nintedanib after pirfenidone proved ineffective. To our knowledge, there have been no previous reports of nintedanib being used to treat a patient with HPS type 4. There is a need for clinical trials of antifibrotic agents, including nintedanib, pirfenidone, and new therapeutic agents with different mechanisms of action in these patients.

DOI： 10.2169/internalmedicine.5493-20

Pulmonary epithelioid haemangioendothelioma mimicking lung cancer. 査読国際誌

Naohiro Oda, Yoshinobu Maeda, Kastuyuki Kiura, Nobuaki Miyahara

BMJ case reports 14 ( 2 ) 2021年2月

The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. 査読国際誌

Kota Araki, Rie Kinoshita, Nahoko Tomonobu, Yuma Gohara, Shuta Tomida, Yuta Takahashi, Satoru Senoo, Akihiko Taniguchi, Junko Itano, Ken-Ichi Yamamoto, Hitoshi Murata, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kouichi Ichimura, Masahiro Nishibori, Nobuaki Miyahara, Shinichi Toyooka, Masakiyo Sakaguchi

Journal of molecular medicine (Berlin, Germany) 99 ( 1 ) 131 - 145 2021年1月

記述言語：英語掲載種別：学位論文（博士）

In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

DOI： 10.1007/s00109-020-02001-x

A Case of Lung Cancer That Showed an Abscopal Effect after Irradiation of Simultaneous Oropharyngeal Cancer

Kayo Nakamura, Eiki Ichihara, Yusaku Shibata, Etsuko Murakami, Nobuaki Miyahara, Daizo Kishino

Japanese Journal of Lung Cancer 91 ( 2 ) 109 - 112 2021年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japan Lung Cancer Society

Background. The abscopal effect is a phenomenon in which tumor shrinkage occurs outside the radiation field. It usually occurs between the primary tumor and metastatic lesions of the same cancer or between metastatic lesions, and there have been no reports on the abscopal effect occurring after irradiation of other cancer types. Case. A woman in her 50s was diagnosed with double primary cancer of lung and oropharyngeal cancer. After the administration of nivolumab as second-line treatment for lung cancer, the lung cancer did not show any increase in size for six months (stable disease). However, the pharyngeal cancer showed progression, so irradiation was started for it. After radiotherapy, shrinkage of the primary lung cancer (outside the irradiation field) was observed. Conclusion. We experienced a case in which primary lung cancer shrank after irradiation for primary pharyngeal cancer. This case suggests that abscopal-like effects may occur between different cancer types.

DOI： 10.2482/HAIGAN.61.109

Deterioration of high-resolution computed tomography findings predicts disease progression after initial decline in forced vital capacity in idiopathic pulmonary fibrosis patients treated with pirfenidone. 査読国際誌

Hisao Higo, Nobuaki Miyahara, Akihiko Taniguchi, Satoru Senoo, Junko Itano, Hiromi Watanabe, Naohiro Oda, Hiroe Kayatani, Hirohisa Ichikawa, Takuo Shibayama, Kazuhiro Kajimoto, Yasushi Tanimoto, Arihiko Kanehiro, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory investigation 58 ( 3 ) 185 - 189 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Pirfenidone suppresses the decline of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF). However, IPF progresses in some patients despite treatment. We analyzed patients with meaningful FVC declines during pirfenidone treatment and explored the factors predictive of disease progression after FVC decline. METHODS: This study was a retrospective, multicenter, observational study conducted by the Okayama Respiratory Disease Study Group. We defined initial decline in %FVC as 5% or greater per 6-month period during pirfenidone treatment. IPF patients who were treated with pirfenidone and experienced an initial decline from December 2008 to September 2017 were enrolled. RESULTS: We analyzed 21 patients with IPF. After the initial decline, 4 (19.0%) patients showed improvement in disease, 11 (52.4%) showed stable disease, and 6 (28.6%) showed progressive disease. There was no significant correlation between %FVC reduction on initial decline and subsequent %FVC change (p = 0.475). Deterioration of high-resolution computed tomography (HRCT) findings on initial decline was observed significantly more often in the progressive versus improved/stable disease groups (100% vs 20.0%, p = 0.009). CONCLUSIONS: We revealed that deterioration of HRCT findings may predict disease progression after the initial decline in %FVC in IPF patients treated with pirfenidone.

DOI： 10.1016/j.resinv.2019.12.007

Nintedanib can be used safely and effectively for idiopathic pulmonary fibrosis with predicted forced vital capacity ≤ 50%: A multi-center retrospective analysis. 査読国際誌

Satoru Senoo, Nobuaki Miyahara, Akihiko Taniguchi, Naohiro Oda, Junko Itano, Hisao Higo, Naofumi Hara, Hiromi Watanabe, Hirohisa Kano, Toshimitsu Suwaki, Yasuko Fuchimoto, Kazuhiro Kajimoto, Hirohisa Ichikawa, Kenichiro Kudo, Takuo Shibayama, Yasushi Tanimoto, Shoichi Kuyama, Arihiko Kanehiro, Yoshinobu Maeda, Katsuyuki Kiura

PloS one 15 ( 8 ) e0236935 2020年

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Nintedanib is a multi-kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF); however, its efficacy and safety for patients with IPF and restricted pulmonary function remain unclear. Therefore, the objective of this study was to determine the efficacy and safety of nintedanib for patients with IPF and forced vital capacity (FVC) ≤ 50%. METHODS: This was a multi-center retrospective study performed by the Okayama Respiratory Disease Study Group. Patients were allocated into FVC ≤ 50% and FVC > 50% groups based on their predicted FVC. The primary endpoints were FVC changes from baseline after 6 and 12 months. RESULTS: 45 patients were eligible for the study. 18 patients had FVC ≤ 50%, and 27 patients had FVC > 50%. Overall, 31 and 19 patients underwent pulmonary function tests at 6 and 12 months after initiating nintedanib, respectively. FVC changes from baseline at 6 and 12 months after initiating nintedanib were comparable between the two groups. Adverse events were seen in all patients, and the rates of patients who discontinued nintedanib were also comparable (38.9% vs. 37.0%, p = 1.000). Multiple regression analysis showed that age and forced expiratory volume in 1 second (FEV1)/FVC were negatively correlated with changes in FVC at 6 months after initiating nintedanib. CONCLUSIONS: Our data suggest that nintedanib can be a useful agent for IPF patients, including those with a low FVC, and that age and FEV1/FVC are predictive markers for changes in FVC following nintedanib treatment.

DOI： 10.1371/journal.pone.0236935

[The role of neuropeptide Y for the development of allergic airway responses]. 招待査読

Nobuaki Miyahara

Nihon yakurigaku zasshi. Folia pharmacologica Japonica 155 ( 6 ) 360 - 363 2020年

担当区分：筆頭著者,　最終著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）

Neuropeptide Y (NPY) is a neurotransmitter that is widely expressed in the brain and peripheral nervous system. Various immune cells express the receptor for NPY, Y1 receptor. NPY modulates these cells via its Y1 receptor, and involvement of NPY in the pathophysiology of bronchial asthma, has been reported. Increased plasma levels of NPY in asthmatic patients have been reported. NPY polymorphisms are associated with an increased risk for asthma in overweight subjects and young adults. We and other researchers have reported that using murine models of allergic airway responses, NPY and Y1 receptor play critical roles for the development of allergic airway inflammation and airway hyperresponsiveness. Therefore, manipulating NPY-Y1 pathway represents a novel therapeutic target to control allergic airway responses, and might be beneficial for treatment of bronchial asthma.

DOI： 10.1254/fpj.20036

Solitary pulmonary nodules caused by Mycobacterium avium complex. 査読国際誌

Marukawa M, Taniguchi A, Kimura G, Kunichika N, Kuyama S, Maeda Y, Kiura K, Miyahara N, OKAYAMA Respiratory, Disease Study Group, ORDSG

Respiratory investigation 57 ( 6 ) 566 - 573 2019年11月

Successful Re-administration of Osimertinib in Osimertinib-induced Interstitial Lung Disease with an Organizing Pneumonia Pattern: A Case Report and Literature Review. 査読

Itano J, Higo H, Ohashi K, Makimoto G, Nishii K, Hotta K, Miyahara N, Maeda Y, Kiura K

Internal medicine (Tokyo, Japan) 59 ( 6 ) 823 - 828 2019年11月

Managing Lung Cancer with Comorbid Interstitial Pneumonia. 査読

Ichihara E, Miyahara N, Maeda Y, Kiura K

Internal medicine (Tokyo, Japan) 59 ( 2 ) 163 - 167 2019年9月

Cause of pleuroparenchymal fibroelastosis following allogeneic hematopoietic stem cell transplantation. 査読国際誌

Higo H, Miyahara N, Taniguchi A, Maeda Y, Kiura K

Respiratory investigation 57 ( 4 ) 321 - 324 2019年7月

Requirement for neuropeptide Y in the development of type 2 responses and allergen-induced airway hyperresponsiveness and inflammation. 査読国際誌

Oda N, Miyahara N, Taniguchi A, Morichika D, Senoo S, Fujii U, Itano J, Gion Y, Kiura K, Kanehiro A, Maeda Y

American journal of physiology. Lung cellular and molecular physiology 316 ( 3 ) L407 - L417 2019年3月

A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation. 査読国際誌

Daisuke Morichika, Nobuaki Miyahara, Utako Fujii, Akihiko Taniguchi, Naohiro Oda, Satoru Senoo, Mikio Kataoka, Mitsune Tanimoto, Hiroki Kakuta, Katsuyuki Kiura, Yoshinobu Maeda, Arihiko Kanehiro

Respiratory research 20 ( 1 ) 2 - 2 2019年1月

記述言語：英語掲載種別：学位論文（博士）

BACKGROUND: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined. METHODS: We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction. RESULTS: Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice. CONCLUSION: These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.

DOI： 10.1186/s12931-018-0963-0

Long-term spontaneous remission with active surveillance in IgG4-related pleuritis: A case report and literature review. 査読国際誌

Makimoto G, Ohashi K, Taniguchi K, Soh J, Taniguchi A, Miyahara N, Toyooka S, Yoshino T, Maeda Y, Kiura K

Respiratory medicine case reports 28 100938 - 100938 2019年

A case of axillary lymphadenitis caused by Mycobacterium intracellulare in an immunocompetent patient. 査読国際誌

Itano J, Ohashi K, Senoo S, Oda N, Nishii K, Taniguchi A, Miyahara N, Maeda Y, Kiura K

Respiratory medicine case reports 28 100947 - 100947 2019年

Severe asthma concomitant with allergic bronchopulmonary aspergillosis successfully treated with mepolizumab. 査読国際誌

Oda N, Miyahara N, Senoo S, Itano J, Taniguchi A, Morichika D, Fujii U, Maeda Y, Kiura K, Kanehiro A

Allergology international : official journal of the Japanese Society of Allergology 67 ( 4 ) 521 - 523 2018年10月

Lavender Essential Oil and Its Main Constituents Inhibit the Expression of TNF-α-induced Cell Adhesion Molecules in Endothelial Cells. 査読

Aoe M, Ueno-Iio T, Shibakura M, Shinohata R, Usui S, Arao Y, Ikeda S, Miyahara N, Tanimoto M, Kataoka M

Acta medica Okayama 71 ( 6 ) 493 - 503 2017年12月

Protective Effects of Bisoprolol against Acute Exacerbation in Moderate-to-Severe Chronic Obstructive Pulmonary Disease 査読

Akihiko Taniguchi, Nobuaki Miyahara, Naohiro Oda, Daisuke Morichika, Eiki Ichihara, Isao Oze, Yasushi Tanimoto, Hirohisa Ichikawa, Utako Fujii, Mitsune Tanimoto, Arihiko Kanehiro, Katsuyuki Kiura

ACTA MEDICA OKAYAMA 71 ( 5 ) 453 - 457 2017年10月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

Although recent retrospective studies suggested that the use of beta-blockers appears to help improve the mortality rate and decrease the rate of exacerbation in chronic obstructive pulmonary disease (COPD) patients with heart failure, the effects of beta-blockers on COPD patients without heart failure have not been established. Based on previous reports, we have launched a multicenter, prospective, single-arm phase II study to evaluate the preventive effect of the cardioselective beta-blocker bisoprolol in COPD exacerbation, in Japanese individuals with moderate-to-severe COPD who do not have heart failure but do have hypertension requiring the use of medication. The primary endpoint is the rate of mild-to-severe COPD exacerbation. The results of this study will clarify whether bisoprolol can prevent exacerbation in COPD patients without heart failure.

DOI： 10.18926/AMO/55446

Clinical characteristics of Japanese candidates for lung transplant for interstitial lung disease and risk factors for early death while on the waiting list. 査読国際誌

Hisao Higo, Takeshi Kurosaki, Eiki Ichihara, Toshio Kubo, Kentaroh Miyoshi, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Nobuaki Miyahara, Katsuyuki Kiura, Shinichiro Miyoshi, Takahiro Oto

Respiratory investigation 55 ( 4 ) 264 - 269 2017年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Lung transplants have produced very favorable outcomes for patients with interstitial lung disease (ILD) in Japan. However, because of the severe donor lung shortage, patients must wait approximately 2.5 years before they can undergo transplantation and many candidates die before allocation. We reveal the clinical characteristics of Japanese patients with ILD who are candidates for lung transplants and the risk factors for early death while on the waiting list. METHODS: We retrospectively reviewed the clinical data of patients registered in the Japan Organ Transplant Network from Okayama University Hospital who are candidates for cadaveric lung transplants for ILD between 1999 and 2015. RESULTS: Fifty-three patients with ILD were included (24 patients with idiopathic pulmonary fibrosis and 29 others). They had severe pulmonary dysfunction and low exercise tolerability. The median waiting time for transplantation was 462 days, and 22 patients died before allocation. Patients who died before 462 days without undergoing transplantation had more severe dyspnea, shorter 6-minute walk distance (6MWD), and lower performance status than those who waited ≥462 days. CONCLUSIONS: Japanese candidates for cadaveric lung transplants for ILD have severe pulmonary dysfunction. Severe dyspnea, short 6MWD, and low performance status are risk factors for early death while on the waiting list.

DOI： 10.1016/j.resinv.2017.03.002

Long-term effects of beta-blocker use on lung function in japanese patients with chronic obstructive pulmonary disease 査読

Naohiro Oda, Nobuaki Miyahara, Hirohisa Ichikawa, Yasushi Tanimoto, Kazuhiro Kajimoto, Makoto Sakugawa, Haruyuki Kawai, Akihiko Taniguchi, Daisuke Morichika, Mitsune Tanimoto, Arihiko Kanehiro, Katsuyuki Kiura

International Journal of COPD 12 1119 - 1124 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Dove Medical Press Ltd.

Background: Some recent studies have suggested that beta-blocker use in patients with chronic obstructive pulmonary disease (COPD) is associated with a reduction in the frequency of acute exacerbations. However, the long-term effects of beta-blocker use on lung function of COPD patients have hardly been evaluated. Patients and methods: We retrospectively reviewed 31 Japanese COPD patients taking beta-blockers for &gt
1 year and 72 patients not taking them. The association between beta-blocker use and the annual change in forced expiratory volume in 1 second (FEV1) was assessed. Results: At baseline, patient demographic characteristics were as follows: 97 males (mean age 67.0±8.2 years)
32 current smokers
and Global Initiative for Chronic Obstructive Lung disease (GOLD) stages I: n=26, II: n=52, III: n=19, and IV: n=6. Patients taking beta-blockers exhibited a significantly lower forced vital capacity (FVC), FEV1, and %FVC, and a more advanced GOLD stage. The mean duration of beta-blocker administration was 2.8±1.7 years. There were no differences in the annual change in FEV1 between patients who did and did not use beta-blockers (-7.6±93.5 mL/year vs -4.7±118.9 mL/year, P=0.671). After controlling for relevant confounders in multivariate analyses, it was found that beta-blocker use was not significantly associated with the annual decline in FEV1 (β=-0.019
95% confidence interval: -0.073 to 0.036
P=0.503). Conclusion: Long-term beta-blocker use in Japanese COPD patients might not affect the FEV1, one of the most important parameters of lung function in COPD patients.

DOI： 10.2147/COPD.S133071

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma 査読

Utako Fujii, Nobuaki Miyahara, Akihiko Taniguchi, Naohiro Oda, Daisuke Morichika, Etsuko Murakami, Hikari Nakayama, Koichi Waseda, Mikio Kataoka, Hiroki Kakuta, Mitsune Tanimoto, Arihiko Kanehiro

Respiratory Research 18 ( 1 ) 23 2017年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BioMed Central Ltd.

Background: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners-e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induced airway responses is not well defined. The goal of this study is to elucidate the role of RXRs in asthma pathogenesis and the potency of RXR partial agonist in the treatment of allergic airway inflammation and airway hyperresponsiveness using a murine model of asthma. Methods: We investigated the effect of a novel RXR partial agonist (NEt-4IB) on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in a murine model of asthma. Balb/c mice were sensitized (days 0 and 14) and challenged (days 28-30) with ovalbumin (OVA), and airway inflammation and airway responses were monitored 48 h after the last OVA challenge. NEt-4IB was administered orally on days 25 to 32. Results: Oral administration of NEt-4IB significantly suppressed AHR and inflammatory cell accumulation in the airways and attenuated the levels of TNF-α in the lung and IL-5, IL-13 and NO levels in bronchoalveolar lavage (BAL) fluid and the number of periodic acid Schiff (PAS)-positive goblet cells in lung tissue. Treatment with NEt-4IB also significantly suppressed NF-ΚB expression. Conclusion: These data suggest that RXRs may be of crucial importance in the mechanism of allergic asthma and that the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of allergic airway inflammation and airway hyperresponsiveness in a model of allergic asthma.

DOI： 10.1186/s12931-017-0507-z

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma 査読

Utako Fujii, Nobuaki Miyahara, Akihiko Taniguchi, Naohiro Oda, Daisuke Morichika, Etsuko Murakami, Hikari Nakayama, Koichi Waseda, Mikio Kataoka, Hiroki Kakuta, Mitsune Tanimoto, Arihiko Kanehiro

RESPIRATORY RESEARCH 18 2017年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

Background: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners-e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induced airway responses is not well defined. The goal of this study is to elucidate the role of RXRs in asthma pathogenesis and the potency of RXR partial agonist in the treatment of allergic airway inflammation and airway hyperresponsiveness using a murine model of asthma.
Methods: We investigated the effect of a novel RXR partial agonist (NEt-4IB) on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in a murine model of asthma. Balb/c mice were sensitized (days 0 and 14) and challenged (days 28-30) with ovalbumin (OVA), and airway inflammation and airway responses were monitored 48 h after the last OVA challenge. NEt-4IB was administered orally on days 25 to 32.
Results: Oral administration of NEt-4IB significantly suppressed AHR and inflammatory cell accumulation in the airways and attenuated the levels of TNF-a in the lung and IL-5, IL-13 and NO levels in bronchoalveolar lavage (BAL) fluid and the number of periodic acid Schiff (PAS)-positive goblet cells in lung tissue. Treatment with NEt-4IB also significantly suppressed NF-.B expression.
Conclusion: These data suggest that RXRs may be of crucial importance in the mechanism of allergic asthma and that the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of allergic airway inflammation and airway hyperresponsiveness in a model of allergic asthma.

DOI： 10.1186/s12931-017-0507-z

Pneumocystis Pneumonia Concomitant with Ectopic ACTH Syndrome Caused by a Large Cell Neuroendocrine Carcinoma of the Thymus 査読

Naohiro Oda, Nobuaki Miyahara, Masahiro Tabata, Daisuke Minami, Kiichiro Ninomiya, Arihiko Kanehiro, Motoshi Komatsubara, Kenichi Inagaki, Mitsune Tanimoto, Katsuyuki Kiura

INTERNAL MEDICINE 56 ( 5 ) 551 - 555 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

We herein report the case of a 44-year-old man who was diagnosed with pneumocystis pneumonia (PCP) concomitant with ectopic adrenocorticotropic hormone (ACTH) syndrome, which had been caused by a large cell neuroendocrine carcinoma of the thymus. Chest computed tomography revealed ground-glass opacities in the lungs. PCP was diagnosed by a polymerase chain reaction with bronchoalveolar lavage. The levels of cortisol were slowly corrected with an adrenal enzyme inhibitor, and the exacerbation of PCP was successfully avoided. Our case indicates that in addition to prophylaxis, the early diagnosis of PCP and the slow correction of hypercortisolemia should be considered in order to prevent an exacerbation due to the reconstitution of the immune function in patients with ectopic ACTH syndrome.

DOI： 10.2169/internalmedicine.56.7655

Long-term effects of beta-blocker use on lung function in Japanese patients with chronic obstructive pulmonary disease 査読

Naohiro Oda, Nobuaki Miyahara, Hirohisa Ichikawa, Yasushi Tanimoto, Kazuhiro Kajimoto, Makoto Sakugawa, Haruyuki Kawai, Akihiko Taniguchi, Daisuke Morichika, Mitsune Tanimoto, Arihiko Kanehiro, Katsuyuki Kiura

INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE 12 1119 - 1124 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：DOVE MEDICAL PRESS LTD

Background: Some recent studies have suggested that beta-blocker use in patients with chronic obstructive pulmonary disease (COPD) is associated with a reduction in the frequency of acute exacerbations. However, the long-term effects of beta-blocker use on lung function of COPD patients have hardly been evaluated.
Patients and methods: We retrospectively reviewed 31 Japanese COPD patients taking beta-blockers for >1 year and 72 patients not taking them. The association between beta-blocker use and the annual change in forced expiratory volume in 1 second (FEV1) was assessed.
Results: At baseline, patient demographic characteristics were as follows: 97 males (mean age 67.0 +/- 8.2 years); 32 current smokers; and Global Initiative for Chronic Obstructive Lung disease (GOLD) stages I: n=26, II: n=52, III: n=19, and IV: n=6. Patients taking beta-blockers exhibited a significantly lower forced vital capacity (FVC), FEV1, and %FVC, and a more advanced GOLD stage. The mean duration of beta-blocker administration was 2.8 +/- 1.7 years. There were no differences in the annual change in FEV1 between patients who did and did not use beta-blockers (-7.6 +/- 93.5 mL/year vs -4.7 +/- 118.9 mL/year, P=0.671). After controlling for relevant confounders in multivariate analyses, it was found that beta-blocker use was not significantly associated with the annual decline in FEV1 (beta=-0.019; 95% confidence interval: -0.073 to 0.036; P=0.503).
Conclusion: Long-term beta-blocker use in Japanese COPD patients might not affect the FEV1, one of the most important parameters of lung function in COPD patients.

DOI： 10.2147/COPD.S133071

Safety And Discomfort During Bronchoscopy Performed Under Sedation With Fentanyl And Midazolam: A Prospective Study 査読

D. Minami, N. Takigawa, T. Ninomiya, T. Kubo, E. Ichihara, K. Ohashi, A. Sato, K. Hotta, T. Shibayama, N. Miyahara, M. Tabata, A. Kanehiro, K. Kiura

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 195 ( 9 ) 871 - 874 2017年

IL-23 Is Essential for the Development of Elastase-Induced Pulmonary Inflammation and Emphysema 査読

Utako Fujii, Nobuaki Miyahara, Akihiko Taniguchi, Koichi Waseda, Daisuke Morichika, Etsuko Kurimoto, Hikari Koga, Mikio Kataoka, Erwin W. Gelfand, Daniel J. Cua, Akihiko Yoshimura, Mitsune Tanimoto, Arihiko Kanehiro

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 55 ( 5 ) 697 - 707 2016年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

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 type 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. Intratracheal instillation of PPE induced emphysematous changes in the lungs and was associated with increased levels of IL-23 in lung homogenates. Compared with WT mice, IL-23(-/-) mice developed significantly lower static compliance values and markedly reduced emphysematous changes on histological analyses after 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 fluid ofWTmice was attenuated in IL-23(-/-) mice, and the reduction was associated with decreased levels of keratinocyte-derived cytokine and macrophage inflammatory protein-2 in bronchoalveolar lavage 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.

DOI： 10.1165/rcmb.2016-0015OC

Heerfordt's Syndrome Associated with a High Fever and Elevation of TNF-α. 査読

Makimoto G, Miyahara N, Yoshikawa M, Taniguchi A, Kanehiro A, Tanimoto M, Kiura K

Acta medica Okayama 70 ( 4 ) 273 - 277 2016年8月

Increased Serum KL-6 Levels Induced by Pulmonary Mycobacterium Avium Complex Infection in a Patient with RA-associated Lung Disease 査読

Koichi Waseda, Kazuki Ocho, Kou Hasegawa, Kosuke Kimura, Masaya Iwamuro, Yoshihisa Hanayama, Eisei Kondo, Nobuaki Miyahara, Fumio Otsuka

ACTA MEDICA OKAYAMA 70 ( 3 ) 217 - 221 2016年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/54422

Immunomodulatory Effects of Ambroxol on Airway Hyperresponsiveness and Inflammation 査読

Katsuyuki Takeda, Nobuaki Miyahara, Shigeki Matsubara, Christian Taube, Kenichi Kitamura, Astushi Hirano, Mitsune Tanimoto, Erwin W. Gelfand

IMMUNE NETWORK 16 ( 3 ) 165 - 175 2016年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：KOREA ASSOC IMMUNOLOGISTS

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-gamma, 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.

DOI： 10.4110/in.2016.16.3.165

成人気管支喘息における好酸球性中耳炎合併の実態についての検討

谷本安, 板野純子, 石賀充典, 難波史代, 田中寿明, 小野勝一郎, 高橋秀治, 濱田昇, 河田典子, 木村五郎, 宮原信明, 木浦勝行, 谷本光音, 宗田良

日本呼吸器学会誌 5 ( 増刊 ) 251 - 251 2016年3月

A case of acquired hemophilia a diagnosed in conjunction with oral bleeding 査読

Eriko Yanagi, Toshiyuki Kishi, Takao Matsumura, Yoshinori Tani, Nobuaki Miyahara

Journal of Otolaryngology of Japan 119 ( 8 ) 1133 - 1136 2016年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Oto-Rhino-Laryngological Society of Japan Inc.

Acquired hemophilia A is a rare disease in which autoantibodies to factor VIII are present. It is often manifested as a sudden onset of a critical bleeding episode, and its incidence is reported to be 1.48 cases per million persons per year. We report herein on a case of acquired hemophilia A associated with a submucosal hematoma of the oral floor, pharynx, and larynx. A 78-year-old male presented with fresh bleeding from his mouth, associated with hematoma of the oral floor, pharynx, and larynx. Laboratory test showed that the activated partial thromboplastin time was prolonged, and the platelet count and prothrombin time were normal. Coagulation tests revealed decreased factor VIII levels, and the presence of factor VIII inhibitor. A diagnosis of acquired hemophilia A was made, and immunotherapy with corticosteroids was initiated. After treatment, the bleeding tendency was controlled. On hospital day 29, the symptoms disappeared. Although acquired hemophilia A is a rare coagulopathic condition, it should be considered as one of the differential diagnoses in a case of sudden onset of severe hemorrhagic tendency of unknown origin.

DOI： 10.3950/jibiinkoka.119.1133

Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness 査読

Akihiko Taniguchi, Nobuaki Miyahara, Koichi Waseda, Etsuko Kurimoto, Utako Fujii, Yasushi Tanimoto, Mikio Kataoka, Yasuhiko Yamamoto, Erwin W. Gelfand, Hiroshi Yamamoto, Mitsune Tanimoto, Arihiko Kanehiro

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY 309 ( 8 ) L789 - L800 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER PHYSIOLOGICAL SOC

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.

DOI： 10.1152/ajplung.00087.2015

Emphysema Requires the Receptor for Advanced Glycation End-Products Triggering on Structural Cells 査読

Koichi Waseda, Nobuaki Miyahara, Akihiko Taniguchi, Etsuko Kurimoto, Genyo Ikeda, Hikari Koga, Utako Fujii, Yasuhiko Yamamoto, Erwin W. Gelfand, Hiroshi Yamamoto, Mitsune Tanimoto, Arihiko Kanehiro

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 52 ( 4 ) 482 - 491 2015年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The receptor for advanced glycation end-products (RAGE) is a multiligand 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 lung compliance, lung histology, and the levels of neutrophil-related chemokine and proinflammatory cytokines in bronchoalveolar lavage fluid were determined on Days 4 and 21. Neutrophilia in bronchoalveolar lavage fluid, seen in elastase-treated RAGE(+/+) mice, was reduced in elastase-treated RAGE(-/-) mice on Day 4, and was associated with decreased levels of keratinocyte chemoattractant, macrophage inflammatory protein-2, and IL-1 beta. Static lung compliance values and emphysematous changes in the lung tissue were decreased in RAGE(-/-) mice compared with 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.

DOI： 10.1165/rcmb.2014-0027OC

肺腺癌に合併し診断に苦慮した続発性クリプトコッカス症の2例

森近大介, 南大輔, 二宮貴一郎, 入江真大, 葉山牧夫, 山本寛斎, 堀田勝幸, 宮原信明, 田端雅弘, 三好新一郎, 谷本光音, 木浦勝行

気管支学 36 ( 2 ) 210 - 210 2014年3月

Effect of a Cysteinyl Leukotriene Receptor Antagonist on Experimental Emphysema and Asthma Combined with Emphysema 査読

Genyo Ikeda, Nobuaki Miyahara, Hikari Koga, Yasuko Fuchimoto, Koichi Waseda, Etsuko Kurimoto, Akihiko Taniguchi, Yasushi Tanimoto, Mikio Kataoka, Mitsune Tanimoto, Arihiko Kanehiro

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 50 ( 1 ) 18 - 29 2014年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

The incidence of overlapping bronchial asthma and chronic obstructive pulmonary disease has increased in recent years. Cysteinyl leukotrienes (CysLTs) play an important role in asthma, and the type 1 CysLT receptor (CysLT(1)R) is expressed by many inflammatory cells. We evaluated the effect of montelukast, a CysLT(1)R antagonist, on mouse models of asthma, porcine pancreatic elastase (PPE)-induced emphysema, and asthma combined with emphysema. 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, LTs, and perforin in the bronchoalveolar lavage fluid, and the quantitative morphometry of lung sections were analyzed on Day 32. 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. Our data suggest that CysLT(1)R antagonists may be effective in ameliorating the consequences of PPE-induced lung damage and the changes that follow allergen sensitization and challenges.

DOI： 10.1165/rcmb.2012-0418OC

Invasive Mucinous Adenocarcinoma Mimicking Organizing Pneumonia Associated with Mycobacterium fortuitum Infection 査読

Daisuke Morichika, Nobuaki Miyahara, Katsuyuki Hotta, Yoshiko Okamoto, Daisuke Minami, Masahiro Irie, Yasushi Tanimoto, Arihiko Kanehiro, Mitsune Tanimoto, Katsuyuki Kiura

INTERNAL MEDICINE 53 ( 24 ) 2795 - 2799 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

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.

DOI： 10.2169/internalmedicine.53.2783

Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: Neutrophil elastase inhibition attenuates allergic airway responses 査読

Hikari Koga, Nobuaki Miyahara, Yasuko Fuchimoto, Genyo Ikeda, Koichi Waseda, Katsuichiro Ono, Yasushi Tanimoto, Mikio Kataoka, Erwin W. Gelfand, Mitsune Tanimoto, Arihiko Kanehiro

Respiratory Research 14 ( 1 ) 8 2013年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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. © 2013 Koga et al.
licensee BioMed Central Ltd.

DOI： 10.1186/1465-9921-14-8

IL-17A is essential to the development of elastase-induced pulmonary inflammation and emphysema in mice 査読

Etsuko Kurimoto, Nobuaki Miyahara, Arihiko Kanehiro, Koichi Waseda, Akihiko Taniguchi, Genyo Ikeda, Hikari Koga, Hisakazu Nishimori, Yasushi Tanimoto, Mikio Kataoka, Yoichiro Iwakura, Erwin W. Gelfand, Mitsune Tanimoto

Respiratory Research 14 ( 1 ) 5 2013年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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. © 2013 Kurimoto et al.
licensee BioMed Central Ltd.

DOI： 10.1186/1465-9921-14-5

Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses 査読

Hikari Koga, Nobuaki Miyahara, Yasuko Fuchimoto, Genyo Ikeda, Koichi Waseda, Katsuichiro Ono, Yasushi Tanimoto, Mikio Kataoka, Erwin W. Gelfand, Mitsune Tanimoto, Arihiko Kanehiro

RESPIRATORY RESEARCH 14 2013年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

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-beta 1 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.

DOI： 10.1186/1465-9921-14-8

A Definite Case of L-carbocisteine-induced Pneumonia with CATCH22 Syndrome 査読

Kenichiro Kudo, Eiki Ichihara, Akiko Hisamoto, Katsuyuki Hotta, Nobuaki Miyahara, Yasushi Tanimoto, Sadaharu Akagi, Katsuya Kato, Mitsune Tanimoto, Katsuyuki Kiura

INTERNAL MEDICINE 52 ( 1 ) 97 - 100 2013年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

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.

DOI： 10.2169/internalmedicine.52.7882

[Bronchial asthma and allergic diseases]. 査読

Miyahara N, Kiura K

Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 8 545 - 549 2012年11月

Requirement for Chemokine Receptor 5 in the Development of Allergen-Induced Airway Hyperresponsiveness and Inflammation 査読

Yasuko Fuchimoto, Arihiko Kanehiro, Nobuaki Miyahara, Hikari Koga, Genyo Ikeda, Koichi Waseda, Yasushi Tanimoto, Satoshi Ueha, Mikio Kataoka, Erwin W. Gelfand, Mitsune Tanimoto

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 45 ( 6 ) 1248 - 1255 2011年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

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.

DOI： 10.1165/rcmb.2010-0465OC

Successful Extracorporeal Life Support for Life-threatening Hypercapnia with Bronchiolitis Obliterans after Allogeneic Hematopoietic Stem Cell Transplantation 査読

Koichi Waseda, Yasushi Tanimoto, Shingo Ichiba, Nobuaki Miyahara, Toshi Murakami, Nobuaki Ochi, Michihisa Terado, Osamu Nagano, Yoshinobu Maeda, Arihiko Kanehiro, Yoshihito Ujike, Mitsune Tanimoto

ACTA MEDICA OKAYAMA 65 ( 6 ) 403 - 406 2011年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/47266

Blocking the Leukotriene B4 Receptor 1 Inhibits Late-Phase Airway Responses in Established Disease 査読

Koichi Waseda, Nobuaki Miyahara, Arihiko Kanehiro, Genyo Ikeda, Hikari Koga, Yasuko Fuchimoto, Etsuko Kurimoto, Yasushi Tanimoto, Mikio Kataoka, Mitsune Tanimoto, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 45 ( 4 ) 851 - 857 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

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.

DOI： 10.1165/rcmb.2010-0455OC

Churg-Strauss Syndrome with Necrosis of Toe Tips 査読

Koichi Waseda, Yasushi Tanimoto, Kenjiro Hasegawa, Nobuaki Miyahara, Daisuke Nojima, Genyo Ikeda, Arihiko Kanehiro, Chiharu Okada, Yoshihiro Kimata, Mitsune Tanimoto

ACTA MEDICA OKAYAMA 65 ( 3 ) 215 - 218 2011年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/46635

Measurement of early-phase, late-phase, and nonspecific nasal responses in allergic rhinitis mouse by whole body plethysmography. 査読

Miyahara S, Miyahara N, Matsubara S

Nihon yakurigaku zasshi. Folia pharmacologica Japonica 137 ( 3 ) 141 - 145 2011年3月

The relationships between the peak inspiratory flow and the characteristics factors in the asthmatics with inhaled corticosteroid - A multicenter study in Chugoku Shikoku area 査読

Yasushi Obase, Arihiko Kanehiro, Yasushi Tanimoto, Nobuaki Miyahara, Mikio Oka, Ryosuke Eda, Tetsuya Kubota, Akihito Yokoyama, Kiryo Wakabayashi, Hiroyasu Takeyama, Chiharu Okada, Goro Kimura, Ryo Soda, Kiyoshi Takahashi, Mitsune Tanimoto

Japanese Journal of Allergology 60 ( 12 ) 1621 - 1629 2011年

記述言語：日本語掲載種別：研究論文（学術雑誌）

Background: 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. Methods: 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. Results: 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&lt
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 %FEV 10. Conclusion: 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. ©2011 Japanese Society of Allergology.

Plasticity of Invariant NKT Cell Regulation of Allergic Airway Disease Is Dependent on IFN-gamma Production 査読

Hiroyuki Matsuda, Katsuyuki Takeda, Toshiyuki Koya, Masakazu Okamoto, Yoshiki Shiraishi, Nobuaki Miyahara, Azzeddine Dakhama, Jennifer L. Matsuda, Laurent Gapin, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 185 ( 1 ) 253 - 262 2010年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

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/alpha GalCer)-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/alpha GalCer BMDCs failed to do so. In contrast, transfer of these same OVA/alpha GalCer 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, J alpha 18deficient 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/alpha GalCer BMDCs failed to do so. Transfer of iNKT cells from IFN-gamma(-/-) mice restored the development of these responses in J alpha 18-deficient recipients following OVA-BMDC transfer; the responses were enhanced following OVA/alpha GalCer 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, 2010, 185: 253-262.

DOI： 10.4049/jimmunol.0902301

Effects of combination therapy with montelukast and carbocysteine in allergen-induced airway hyperresponsiveness and airway inflammation 査読

Takeda K, Shiraishi Y, Matsubara S, Miyahara N, Matsuda H, Okamoto M, Joetham A, Gelfand E.W

British Journal of Pharmacology 160 ( 6 ) 1399 - 1407 2010年7月

Experimental Pulmonary Granuloma Mimicking Sarcoidosis Induced by Propionibacterium acnes in Mice 査読

Kouji Iio, Tomoe Ueno Iio, Yuhei Okui, Hirohisa Ichikawa, Yasushi Tanimoto, Nobuaki Miyahara, Arihiko Kanehiro, Mitsune Tanimoto, Yasunari Nakata, Mikio Kataoka

ACTA MEDICA OKAYAMA 64 ( 2 ) 75 - 83 2010年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

Propionibacterium acnes has been implicated as an etiologic agent of sarcoidosis since the isolation of this bacterium from sarcoid lesions. We experimentally produced a murine pulmonary granuloma model using P. acnes with several features that simulate sarcoidosis. Mice were sensitized with heat-killed P. acnes and complete Freund's adjuvant and were subsequently challenged with heat-killed P. acnes at 2-week intervals. P. acnes-challenged mice developed epitheloid cell granulomas in the lungs. These mice showed a pulmonary immune response characterized by an increased number of T-lymphocytes, especially CD4+ cells, and the ratio of CD4+/CD8+ in bronchoalveolar lavage (BAL) fluid also increased. Furthermore, significant elevations in both angiotensin-converting enzyme (ACE) serum levels and antibody titers against P. acnes were observed. Mice sensitized with P. acnes without complete Freund's adjuvant were capable of forming pulmonary granulomas, which appeared to be caused by indigenous P. acnes. The genome of P. acnes was found in the lungs, BAL cells, hilar lymph nodes, liver, and spleen in non-sensitized mice, which were thought to be germ-free. These results suggest that the immune response against indigenous P. acnes may play an important role in the pathogenesis of granuloma formation in a murine model.

DOI： 10.18926/AMO/32852

Diffuse alveolar hemorrhage with chronic thyroiditis in an advanced-age adult 査読

Masanori Fujii, Nobuaki Miyahara, Yasushi Tanimoto, Nagio Takigawa, Masahiro Tabata, Arihiko Kanehiro, Katsuyuki Kiura, Mitsune Tanimoto

Respiratory Medicine CME 3 ( 2 ) 90 - 92 2010年

記述言語：英語掲載種別：研究論文（学術雑誌）

Idiopathic pulmonary hemosiderosis (IPH) is one of the rare causes of diffuse alveolar hemorrhage (DAH), and usually occurs in children. The mechanism underlying this disease development has not been defined. During the acute phase, death due to massive alveolar hemorrhage and subsequent severe respiratory failure with multiple organ failure often occurs. We report a case of IPH which occurred in an advanced-aged adult during following thyroidectomy for chronic thyroiditis. Following surgery this 83-year-old male developed acute onset dyspnea and pulmonary hemorrhage. In a search for underlying causes, no disorders were found and the only finding was the presence of anti-thyroid antibody. Systemic corticosteroid therapy was effective and he fully recovered. To our knowledge, this is the second documentation of IPH in association with chronic thyroiditis. © 2009 Elsevier Ltd.

DOI： 10.1016/j.rmedc.2009.04.006

P8-8 血性の気管支肺胞洗浄液所見のために診断が遅れた肺胞蛋白症の1例(感染・びまん性肺疾患,ポスター8,第33回日本呼吸器内視鏡学会学術集会)

谷口暁彦, 谷本安, 能島大輔, 小崎佐恵子, 南大輔, 田中寿明, 高田三郎, 堀田勝幸, 宮原信明, 瀧川奈義夫, 金廣有彦, 田端雅弘, 木浦勝行, 片岡幹男, 谷本光音

気管支学 32 S200 2010年

OR5-2 超音波気管支鏡ガイド下針生検(EBUS-TBNA)有用症例の検討(EBUS-TBNA1,一般口演5,第33回日本呼吸器内視鏡学会学術集会)

南大輔, 瀧川奈義夫, 村上斗司, 谷口暁彦, 小崎佐恵子, 田中寿明, 高田三郎, 市原英基, 堀田勝幸, 宮原信明, 谷本安, 田端雅弘, 金廣有彦, 木浦勝行, 谷本光音

気管支学 32 S137 2010年

P3-2-5 ステロイド薬の減量中に再燃を繰り返す慢性好酸球性肺炎にシクロフォスファミドの併用が有効であった1例(P3-2好酸球性肺炎・過敏性肺炎,一般演題,第22回日本アレルギー学会春季臨床大会)

能島大輔, 谷本安, 栗本悦子, 早稲田公一, 池田元洋, 古賀光, 宮原信明, 金廣有彦, 片岡幹男, 谷本光音

アレルギー 59 ( 3 ) 413 - 413 2010年

27.超音波気管支鏡ガイド下針生検(EBUS-TBNA)により診断に至ったLambert-Eaton症候群合併肺小細胞癌の1例(第18回日本呼吸器内視鏡学会中国四国支部会)

谷口暁彦, 瀧川奈義夫, 木浦勝行, 村上斗司, 栗本悦子, 高田三郎, 小崎佐恵子, 南大輔, 田中寿明, 市原英基, 堀田勝幸, 田端雅弘, 宮原信明, 谷本安, 金廣有彦, 谷本光音

気管支学 32 ( 2 ) 201 - 202 2010年

29.超音波気管支鏡ガイド下針生検(EBUS-TBNA)で診断したEGFR遺伝子変異陽性の高齢者肺癌(第18回日本呼吸器内視鏡学会中国四国支部会)

南大輔, 堀田勝幸, 瀧川奈義夫, 村上斗司, 谷口暁彦, 小崎佐恵子, 田中寿明, 高田三郎, 市原英基, 宮原信明, 谷本安, 田端雅弘, 金廣有彦, 木浦勝行, 谷本光音

気管支学 32 ( 2 ) 202 - 202 2010年

MW8-6 アレルギー性気道反応における経口免疫寛容の効果(MW8 動物モデルを用いた喘息病態と治療法開発,ミニワークショップ,第60回日本アレルギー学会秋季学術大会)

宮原信明, 武田勝行, 宮原聡子, 早稲田公一, 栗本悦子, 池田元洋, 古賀光, 谷口暁彦, 能島大輔, 渕本康子, 谷本安, 金廣有彦, 片岡幹男, Erwin Gelfand, 谷本光音

アレルギー 59 ( 9 ) 1353 - 1353 2010年

MW15-5 ヒト好塩基球の抗原提示能に関する検討 : IL-3で活性化された好塩基球はHLA-DRを発現する(MW15 マスト細胞/好塩基球,ミニワークショップ,第60回日本アレルギー学会秋季学術大会)

能島大輔, 谷本安, 栗本悦子, 早稲田公一, 宮原信明, 金廣有彦, 岸本卓巳, 片岡幹男, 高橋清, 谷本光音

アレルギー 59 ( 9 ) 1363 - 1363 2010年

Differential Effects of Dendritic Cell Transfer on Airway Hyperresponsiveness and Inflammation 査読

Toshiyuki Koya, Hiroyuki Matsuda, Shigeki Matsubara, Nobuaki Miyahara, Azzeddine Dakhama, Katsuyuki Takeda, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 41 ( 3 ) 271 - 280 2009年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Dendritic cells (DCs) are considered to be the most efficient antigen-presenting cells. Intratracheal administration of allergen-pulsed bone marrow-derived dendritic cells (BMDCs) before allergen challenge induces airway hyperresponsiveness (AHR) and inflammation. Ovalbumin (OVA)-pulsed BMDCs from wild-type (WT) mice were transferred into naive WT, CD4(-/-), CD8(-/-), or IL-13(-/-) mice. Two days (short protocol) or 10 days (long protocol) after BMDC transfer, mice were challenged with 1% OVA for 3 days and assayed 2 days later. Transfer of OVA-primed BMDCs into BALB/c or C57BL/6 mice elicited AHR in both protocols. Airway eosinophilia, Th2 cytokines, or goblet cell metaplasia were increased in the long but not short protocol. Lung T cells from both protocols produced Th2 cytokines in response to OVA in vitro. Carboxyfluorescein diacetate succinimidylester-labeled BMDCs were observed in bronchoalveolar lavage (BAL) fluid and lung parenchyma at early time points, and were detected in draining lymph nodes 48 hours after transfer. CD8(-/-) mice developed AHR comparable to WT mice in the short protocol, but decreased levels of AHR, airway eosinophilia, Th2 cytokines in BAL fluid, and goblet cell metaplasia compared with WT mice in the long protocol. CD4(-/-) or IL-13(-/-) mice did not develop AHR or airway inflammation in either protocol. These data suggest that allergen-pulsed BMDCs initiate development of AHR that is dependent initially on CD4(+) T cells, and at later time periods on CD8+ T cells and IL-13. Thus, the timing of allergen challenge after transfer of allergen-pulsed BMDC affects the development of AHR and airway inflammation.

DOI： 10.1165/rcmb.2008-0256OC

気管支喘息動物モデル肥満細胞およびロイコトリエンB4の気道過敏性における役割の検討査読

宮原信明, 大西広志, 金廣有彦, 早稲田公一, 池田元洋, 古賀光, 渕本康子, 栗本悦子, 能島大輔, 谷本安, 片岡幹男, Gelfand Erwin, 谷本光音

アレルギー 58 ( 8-9 ) 1247 - 1247 2009年9月

アレルギー疾患と脂質メディエーター最近の知見ロイコトリエンB4 査読

宮原信明, 大西広志, 武田勝行, 宮原聡子, 早稲田公一, 池田元洋, 古賀光, 渊本康子, 栗本悦子, 金廣有彦, Gelfand Erwin, 谷本光音

アレルギー 58 ( 8-9 ) 1154 - 1154 2009年9月

Vaccine-Induced CD8(+) T Cell-Dependent Suppression of Airway Hyperresponsiveness and Inflammation 査読

Katsuyuki Takeda, Steven W. Dow, Nobuaki Miyahara, Taku Kodama, Toshiyuki Koya, Christian Taube, Anthony Joetham, Jung-Won Park, Azzeddine Dakhama, Ross M. Kedl, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 183 ( 1 ) 181 - 190 2009年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Suppressing the abnormalities associated with asthma has been difficult to accomplish using immunotherapy or vaccination once the disease is established. The effector cells necessary for effective immunization/vaccination and immunotherapy of asthma are also not well understood. Therefore, we vaccinated allergen (OVA)-sensitized mice to determine whether therapeutic immunization could suppress airway hyperresponsiveness (AHR) and inflammation and to identify key immune effector cells and cytokines. Mice were immunized with a vaccine comprised of Ag and cationic liposome-DNA complexes (CLDC), a vaccine which has previously been shown to elicit strong CD4(+) and CD8(+) T cell responses and activation of Th1 immunity. We showed that immunization with the OVA-CLDC vaccine significantly suppressed AHR, eosinophilia, goblet cell metaplasia, and Th2 cytokine production. In contrast, immunization with CLDC alone suppressed eosinophilia and Th2 cytokine production, but failed to suppress AHR and goblet cell changes. Using adoptive transfer experiments, we found that suppression of AHR was mediated by Ag-specific CD8(+) T cells and was dependent on IFN-gamma production by the transferred T cells. Thus, we conclude that generation of strong, allergen-specific CD8(+) T cell responses by immunization may be capable of suppressing AHR and allergic airway inflammation, even in previously sensitized and challenged mice. The Journal of Immunology, 2009, 183: 181-190.

DOI： 10.4049/jimmunol.0803967

Leukotriene B4 Release from Mast Cells in IgE-Mediated Airway Hyperresponsiveness and Inflammation 査読

Nobuaki Miyahara, Hiroshi Ohnishi, Satoko Miyahara, Katsuyuki Takeda, Shigeki Matsubara, Hiroyuki Matsuda, Masakazu Okamoto, Joan E. Loader, Anthony Joetham, Mitsune Tanimoto, Azzeddine Dakhama, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 40 ( 6 ) 672 - 682 2009年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Previous studies have shown that leukotriene B4 (LTB4), a proinflammatory lipid mediator, is linked to the development of airway hyperresponsiveness through the accumulation of IL-13-producing CD8+ T cells, which express a high affinity receptor for LTB4, BLT1 (Miyahara et al., Am J Respir Crit Care Med 2005;172:161-167; J Immunol 2005;174:4979-4984). By using leukotriene A4 hydrolase-deficient (LTA4H-/-) mice, which fail to synthesize LTB4, we determined the role of this lipid mediator in allergen-induced airway responses. Two approaches were used. In the first, LTA4H-/- mice and wild-type (LTA4H+/+) mice were systemically sensitized and challenged via the airways to ovalbumin. In the second, mice were passively sensitized with anti-ovalbumin IgE and exposed to ovalbumin via the airways. Mast cells were generated from bone marrow of LTA4H+/+ mice or LTA4H-/- mice. After active sensitization and challenge, LTA4H-/- mice showed significantly lower airway hyperresponsiveness compared with LTA4H+/+ mice, and eosinophil numbers and IL-13 levels in the bronchoalveoloar lavage, of LTA4H-/- mice were also significantly lower. LTA4H-/- mice also showed decreased airway reactivity after passive sensitization and challenge. After LTA4H+/+ mast cell transfer, LTA4H-/- mice showed increased airway reactivity after passive sensitization and challenge, but not after systemic sensitization and challenge. These data confirm the important role for LTB4 in the development of altered airway responses and suggest that LTB4 secretion from mast cells is critical to eliciting increased airway reactivity after passive sensitization with allergen-specific IgE.

DOI： 10.1165/rcmb.2008-0095OC

慢性閉塞性肺疾患(COPD)を合併した進行肺非小細胞癌(NSCLC)の予後

原田大二郎, 瀧川奈義夫, 木浦勝行, 谷本安, 堀田勝幸, 平木章夫, 宮原信明, 田端雅弘, 金廣有彦, 谷本光音

日本呼吸器学会雑誌 47 ( 増刊 ) 300 - 300 2009年5月

乳癌に対する放射線照射後に発症したBOOP症候群の臨床的検討

谷本安, 久山彰一, 高尾和志, 岸俊行, 堀田勝幸, 瀧川奈義夫, 宮原信明, 金廣有彦, 田端雅弘, 木浦勝行, 片岡幹男, 谷本光音

日本呼吸器学会雑誌 47 ( 増刊 ) 325 - 325 2009年5月

Allergic Airway Hyperresponsiveness-Enhancing gamma delta T Cells Develop in Normal Untreated Mice and Fail to Produce IL-4/13, Unlike Th2 and NKT Cells 査読

Niyun Jin, Christina L. Roark, Nobuaki Miyahara, Christian Taube, M. Kemal Aydintug, J. M. Wands, Yafei Huang, Youn-Soo Hahn, Erwin W. Gelfand, Rebecca L. O'Brien, Willi K. Born

JOURNAL OF IMMUNOLOGY 182 ( 4 ) 2002 - 2010 2009年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Allergic airway hyperresponsiveness (AHR) in OVA-sensitized and challenged mice, mediated by allergen-specific Th2 cells and Th2-like invariant NKT (iNKT) cells, develops under the influence of enhancing and inhibitory gamma delta T cells. The AHR-enhancing cells belong to the V gamma 1(+) gamma delta T cell subset, cells that are capable of increasing IL-5 and IL-13 levels in the airways in a manner like Th2 cells. They also synergize with iNKT cells in mediating AHR. However, unlike Th2 cells, the AHR enhancers arise in untreated mice, and we show here that they exhibit their functional bias already as thymocytes, at an HSA(high) maturational stage. In further contrast to Th2 cells and also unlike iNKT cells, they could not be stimulated to produce IL-4 and IL-13, consistent with their synergistic dependence on iNKT cells in mediating AHR. Mice deficient in IFN-gamma, TNFRp75, or IL-4 did not produce these AHR-enhancing gamma delta T cells, but in the absence of IFN-gamma, spontaneous development of these cells was restored by adoptive transfer of IFN-gamma-competent dendritic cells from untreated donors. The i.p. injection of OVA/aluminum hydroxide restored development of the AHR enhancers in all of the mutant strains, indicating that the enhancers still can be induced when they fail to develop spontaneously, and that they themselves need not express TNFRp75, IFN-gamma, or IL-4 to exert their function. We conclude that both the development and the cytokine potential of the AHR-enhancing gamma delta T cells differs critically from that of Th2 cells and NKT cells, despite similar influences of these cell populations on AHR. The Journal of Immunology, 2009, 182: 2002-2010.

DOI： 10.4049/jimmunol.0803280

Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8(+) T cell-mediated airway hyperresponsiveness and inflammation 査読

Hiroshi Ohnishi, Katsuyuki Takeda, Joanne Domenico, Joseph J. Lucas, Nobuaki Miyahara, Christina H. Swasey, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 123 ( 1 ) 249 - 257 2009年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY-ELSEVIER

Background: Ligation of the leukotriene B-4 (LTB4) receptor I on effector memory CD8(+) T cells by LTB4 is important for the recruitment of CD8(+) T cells into the airways, which appears central to the induction of airway hyperresponsiveness (AHR) and allergic inflammation. Phosphorylation of extracellular signal-regulated kinase (ERK) is important in activation and cytokine production from many cell types.
Objective: The roles of ERKs in effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR were determined.
Methods: Effector CD8(+) T cells were generated from OVA(257.264) (SIINFEKL) peptide-primed mononuclear cells from OT-1 mice. The effects of U0126, an ERK inhibitor, on effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR and allergic inflammation were examined.
Results: Pretreatment of effector CD8(+) T cells with U0126 suppressed anti-CD3/anti-CD28-induced ERK1/2 phosphorylation and cytokine production, but did not affect LTB4-induced Ca2+ mobilization or chemotaxis. Adoptive transfer of U0126-treated CD8(+) T cells into sensitized mice before secondary allergen challenge resulted in significant decreases in AHR, eosinophilic inflammation, goblet cell metaplasia, and IL-5 and IL-13 levels in bronchoalveolar lavage fluid of recipient mice. The number of transferred CD8(+) T cells accumulating in bronchoalveolar lavage fluid or lungs was unaffected by treatment.
Conclusion: ERK1/2-dependent pathways are essential for the effector functions of CD8(+) T cells, including T(H)2 cytokine production, allergic inflammation, and development of AHR. Inhibition of ERK1/2 signaling has potential therapeutic benefit in preventing CD8(+) T cell-mediated AHR. (J Allergy Clin Immunol 2009;123:249-57.)

DOI： 10.1016/j.jaci.2008.10.054

PO8-3 血液悪性腫瘍の治療中に出現した胸部異常影に対する気管支鏡検査(びまん性疾患,ポスター8,第32回日本呼吸器内視鏡学会学術集会)

村上斗司, 瀧川奈義夫, 谷本安, 二宮崇, 栗本悦子, 能島大輔, 本多宣裕, 堀田勝幸, 宮原信明, 田端雅弘, 金廣有彦, 木浦勝行, 谷本光音

気管支学 31 S157 2009年

PO11-1 非乾酪性類上皮細胞肉芽腫病変を伴ったために診断に苦慮したホジキンリンパ腫の1例(リンパ腫・胸腺・胸膜腫瘍,ポスター11,第32回日本呼吸器内視鏡学会学術集会)

栗本悦子, 谷本安, 瀧川奈義夫, 二宮崇, 能島大輔, 村上斗司, 本多宣裕, 堀田勝幸, 宮原信明, 田端雅弘, 金廣有彦, 木浦勝行, 谷本光音, 片岡幹男

気管支学 31 S165 2009年

41.気管支鏡下生検で診断された19年後の再発乳癌の1例(第17回日本呼吸器内視鏡学会中国四国支部会)

村上斗司, 木浦勝行, 瀧川奈義夫, 能島大輔, 本多宣裕, 二宮崇, 栗本悦子, 堀田勝幸, 宮原信明, 谷本安, 田端雅弘, 金廣有彦, 谷本光音

気管支学 31 ( 3 ) 178 - 178 2009年

MS40-7 乳癌に対する放射線照射後に発症したBOOP症候群の治療・管理に関する検討(食物アレルギー・薬物アレルギー-病態生理と治療5-薬物アレルギー-,第59回日本アレルギー学会秋季学術大会)

谷本安, 高尾和志, 能島大輔, 早稲田公一, 宮原信明, 金廣有彦, 片岡幹男, 中田安成, 谷本光音

アレルギー 58 ( 8 ) 1328 - 1328 2009年

MS17-#2 STAT6欠損慢性喘息モデルにおける気道過敏性,気道炎症,気道リモデリング形成についての検討(気管支喘息-動物モデル2,第59回日本アレルギー学会秋季学術大会)

小野勝一郎, 金廣有彦, 宮原信明, 平野淳, 池田元洋, 古賀光, 渕本康子, 早稲田公一, 能島大輔, 栗本悦子, 谷本安, 片岡幹男, 伊藤亘, 谷本光音

アレルギー 58 ( 8 ) 1250 - 1250 2009年

MS16-12 既にアレルギー性気道炎症を発症したマウスモデルにおけるロイコトリエンB4の役割(気管支喘息-動物モデル1,第59回日本アレルギー学会秋季学術大会)

早稲田公一, 宮原信明, 金廣有彦, 池田元洋, 古賀光, 渕本康子, 栗本悦子, 能島大輔, 谷本安, 片岡幹男, Gelfand Erwin, 谷本光音

アレルギー 58 ( 8 ) 1250 - 1250 2009年

Leukotriene B(4) receptor 1 expression on dendritic cells is required for the development of Th2 responses and allergen-induced airway hyperresponsiveness 査読

Nobuaki Miyahara, Hiroshi Ohnishi, Hiroyuki Matsuda, Satoko Miyahara, Katsuyuki Takeda, Toshiyuki Koya, Shigeki Matsubara, Masakazu Okamoto, Azzeddine Dakhama, Bodduluri Haribabu, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 181 ( 2 ) 1170 - 1178 2008年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B(4) (LTB(4)), interacting with its high-affinity receptor, LTB4 receptor 1 (BLT1), is known to attract and activate leukocytes during inflammation. We have previously shown that BLT1 expression on Ag-primed T cells is required for the development of airway hyperresponsiveness (AHR; Miyahara et al. 2005. Am. J. Respir. Crit. Care Med. 172: 161-167). However, the role for the LTB(4)-BLT1 pathway in DC function in allergen-induced airway responses has not been defined. Bone marrow-derived DCs (BMDC) were generated. Naive BALB/c mice received OVA-pulsed BLT1-deficient (BLTI(-/-)) BMDCs or wild-type BMDCs intratracheally and were then challenged with OVA for 3 days. Airway responses were monitored 48 h after the last allergen challenge. BLTI(-/-) BMDCs showed normal maturation judged from surface expression of CD markers. Compared with recipients of wild-type BMDCs, mice that received BLT1(-/-) BMDCs developed significantly lower AHR to inhaled methacholine, lower goblet cell metaplasia, and eosinophilic infiltration in the airways and decreased levels of Th2 type cytokines in the bronchoalveolar lavage fluid. Migration of BLTI(-/-) BMDCs into peribronchial lymph nodes was significantly impaired compared with BLTI(+/+) BMDCs after intratracheal instillation. These data suggest that BLTI expression on DCs is required for migration of DCs to regional lymph nodes as well as in the development of AHR and airway inflammation.

DOI： 10.4049/jimmunol.181.2.1170

Evidence that CD8(+) dendritic cells enable the development of gamma delta T cells that modulate airway hyperresponsiveness 査読

Laura Cook, Nobuaki Miyahara, Niyun Jin, J. M. Wands, Christian Taube, Christina L. Roark, Terry A. Potter, Erwin W. Gelfand, Rebecca L. O'Brien, Willi K. Born

JOURNAL OF IMMUNOLOGY 181 ( 1 ) 309 - 319 2008年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Airway hyperresponsiveness (AHR), a hallmark of asthma and several other diseases, can be modulated by gamma delta T cells. In mice sensitized and challenged with OVA, AHR depends on allergen-specific alpha beta T cells; but V gamma 1(+) gamma delta T cells spontaneously enhance AHR, whereas V gamma 4(+) gamma delta T cells, after being induced by airway challenge, suppress AHR. The activity of these gamma delta T cell modulators is allergen nonspecific, and how they develop is unclear. We now show that CD8 is essential for the development of both the AHR suppressor and enhancer gamma delta T cells, although neither type needs to express CD8 itself. Both cell types encounter CD8-expressing non-T cells in the spleen, and their functional development in an otherwise CD8-negative environment can be restored with transferred spleen cell preparations containing CD8(+) dendritic cells (DCs), but not CD8(+) T cells or CD8-DCs. Our findings suggest that CD8(+) DCs in the lymphoid tissues enable an early step in the development of gamma delta T cells through direct cell contact. DC-expressed CD8 might take part in this interaction.

DOI： 10.4049/jimmunol.181.1.309

Plasticity of regulatory T cells: Subversion of suppressive function and conversion to enhancement of lung allergic responses 査読

Anthony Joetham, Shigeki Matsubara, Masakazu Okamoto, Katsuyuki Takeda, Nobuaki Miyahara, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 180 ( 11 ) 7117 - 7124 2008年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Activation of CD4(+)CD25(+)Foxp3(+) naturally occurring regulatory T cells (nTregs) resulting in suppression of lung allergic responses requires interaction of MHC class I on nTregs and CD8. In the absence of CD8 (CD8(-/-) recipients), transferred nTregs restored airway hyperresponsiveness, eosinophilic inflammation, and IL-13 levels following allergen exposure. Enhancement of lung allergic responses was accompanied by reduced expression of Foxp3 and increased expression of IL-13 in the transferred nTregs. In CD8(-/-) recipients pretreated with glucocorticoid-induced TNFR-related protein-ligand Ab, the transferred nTregs maintained high levels of Foxp3 and did not result in altered lung responses. Thus, the regulatory function of nTregs can be subverted by reducing the expression of Foxp3 and following signaling through glucocorticoid-induced TNFR-related protein are converted nTregs into IL-13-producing CD4(+) T cells mediating lung allergic responses.

DOI： 10.4049/jimmunol.180.11.7117

Estrogen determines sex differences in airway responsiveness after allergen exposure 査読

Shigeki Matsubara, Christina H. Swasey, Loan E. Loader, Azzeddine Dakhama, Anthony Joetham, Hiroshi Ohnishi, Annette Balhorn, Nobuaki Miyahara, Katsuyuki Takeda, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 38 ( 5 ) 501 - 508 2008年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

The female hormone estrogen is an important factor in the regulation of airway function and inflammation, and sex differences in the prevalence of asthma are well described. Using an animal model, we determined how sex differences may underlie the development of altered airway function in response to allergen exposure. We compared sex differences in the development of airway hyperresponsiveness (AHR) after allergen exposure exclusively via the airways. Ovalbumin (OVA) was administered by nebulization on 10 consecutive days in BALB/c mice. After methacholine challenge, significant AHR developed in male mice but not in female mice. Ovariectomized female mice showed significant AHR after 10-day OVA inhalation. IC11182,780, an estrogen antagonist, similarly enhanced airway responsiveness even when administered 1 hour before assay. In contrast, 17 beta-estradiol dose-dependently suppressed AHR in male mice. In all cases, airway responsiveness was inhibited by the administration of a neurokinin I receptor antagonist. These results demonstrate that sex differences in 10-day OVA-induced AHR are due to endogenous estrogen, which negatively regulates airway responsiveness in female mice. Cumulatively, the results suggest that endogenous estrogen may regulate the neurokinin 1-dependent prejunctional activation of airway smooth muscle in allergen-exposed mice.

DOI： 10.1165/rcmb.2007-0298OC

ゲフィチニブ単剤療法が施行された肺非小細胞癌における予後因子としての血清KL-6

藤原義朗, 木浦勝行, 瀧川奈義夫, 豊岡伸一, 堀田勝幸, 宗淳一, 宮原信明, 谷本安, 金廣有彦, 田端雅弘, 加藤勝也, 伊達洋至, 谷本光音

日本呼吸器学会雑誌 46 ( 増刊 ) 131 - 131 2008年5月

Corticosteroids enhance CD8(+) T cell-mediated airway hyperresponsiveness and allergic inflammation by upregulating leukotriene B-4 receptor 1 査読

Hiroshi Ohnishi, Nobuaki Miyahara, Azzeddine Dakhama, Katsuyuki Takeda, Steven Mathis, Bodduluri Haribabu, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 121 ( 4 ) 864 - 871 2008年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY-ELSEVIER

Background: Leukotriene B-4 (LTB4) is a potent inflammatory lipid mediator that binds to LTB4 receptor 1 (BLT1). Ligation of BLT1 by LTB4 plays an important role in the recruitment of effector memory CD8(+) T cells into the airways of sensitized and challenged mice.
Objectives: The effects of the corticosteroid dexamethasone (DEX) on BLT1-expressing effector memory CD8(+) T cells and effector memory CD8(+) T cell-mediated airway hyperresponsiveness (AHR) and allergic inflammation were determined.
Methods: Effector memory CD8(+) T cells were generated from ovalbumin(257-264)-primed mononuclear cells from OT-1 mice in the presence of IL-2. In some cultures DEX was added. The effects of DEX on BLT1 expression, LTB4-induced Ca2+ influx, phosphorylation of extracellular signal-regulated kinase 1/2, chemotaxis, and effector memory CD8(+) T cell-mediated AHR were examined.
Results: DEX-treated effector memory CD8(+) T cells showed significant increases in surface expression of BLT1, LTB4-induced intracellular Ca2+ influx, phosphorylation of extracellular signal-regulated kinase 1/2, and chemotaxis. Upregulation of BLT1 by DEX was accompanied by increased IL-2 receptor expression. Adoptive transfer of DEX-treated effector memory CD8(+) T cells into ovalbumin-sensitized and ovalbumin-challenged CD8(-/-) mice resulted in significant increases in AHR, allergic inflammation, goblet cell metaplasia, and numbers of both CD8(+) and CD4(+) T cells in the bronchoalveolar lavage fluid and lungs.
Conclusions: Corticosteroids upregulate BLT1 on effector memory CD8(+) T cells and related signaling pathways and potentiate allergic airway inflammation and AHR induced by these cells.

DOI： 10.1016/j.jaci.2008.01.035

Contribution of allergen-specific and nonspecific nasal responses to early-phase and late-phase nasal responses 査読

Satoko Miyahara, Nobuaki Miyahara, Joseph J. Lucas, Anthony Joetham, Shikegi Matsubara, Hiroshi Ohnishi, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 121 ( 3 ) 718 - 724 2008年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY-ELSEVIER

Background: The relative contributions of the allergen-specific early-phase nasal response and nonspecific nasal response and mast cells to the pathophysiology of allergic rhinitis are not well defined.
Objectives: To determine the contributions of specific reactivity, nonspecific reactivity, and mast cells to the development of early-phase and late-phase responses using a mouse model of allergic rhinitis.
Methods: Sensitized wild-type and Fc epsilon RI-deficient (FC epsilon RI(-/-)) mice were exposed to allergen for 3, 5, or 12 days. As indicators of nasal reactivity, respiratory frequency and nasal resistance were monitored.
Results: Sensitized mice exposed to 3 days of nasal allergen challenge showed a nonspecific early-phase response. As the number of allergen exposures increased, there was progressive diminution in nonspecific responses with increased allergen-specific early-phase responses and a late-phase response. Sensitized Fc epsilon RI(-/-) mice did not develop nonspecific nasal responses or late-phase responses, but transfer of in vitro-differentiated wild-type mast cells into Fc epsilon RI(-/-) mice restored nonspecific early-phase nasal responses but not the late-phase response.
Conclusion: These data identify the nonspecific nasal response as a major contributor to the early-phase response, especially during initial allergen exposure, and is dependent on mast cells. Increasing allergen exposure results in increasing allergen-specific responses, converting the nonspecific early-phase response to a late-phase response that is allergen-specific and mast cell-independent.

DOI： 10.1016/j.jaci.2007.11.002

IFN-gamma production during initial infection determines the outcome of reinfection with respiratory syncytial virus 査読

Young-Mok Lee, Nobuaki Miyahara, Katsuyuki Takeda, John Prpich, Anita Oh, Annette Balhorn, Anthony Joetham, Erwin W. Gelfand, Azzeddine Dakhama

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 177 ( 2 ) 208 - 218 2008年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Rationale. Severe respiratory syncytial virus (RSV) bronchiolitis has been associated with deficient IFN-gamma production in humans, but the role of this cytokine in determining the outcome of reinfection is unknown.
Objectives: To define the role of IFN-gamma in the development of RSV-mediated airway hype rresponsiveness (AHR) and lung histopathology in mice.
Methods: Wild-type (WT) and IFN-gamma knockout mice were infected with RSV in the newborn or weaning stages and reinfected 5 weeks later. Airway responses were assessed on Day 6 after the primary or secondary infection.
Measurements and Main Results: Both WT and IFN-gamma knockout mice developed similar levels of AHR and airway inflammation after primary infection. After reinfection, IFN-gamma knockout mice, but not WT mice, developed AHR, airway eosinophilia, and mucus hyperproduction. Intranasal administration of IFN-gamma during primary infection but not during reinfection prevented the development of these altered airway responses on reinfection in IFN-gamma knockout mice. Adoptive transfer of WT T cells into IFN-gamma knockout mice before primary infection restored IFN-gamma production in the lungs and prevented the development of altered airway responses on reinfection. Treatment of mice with IFN-gamma during primary neonatal infection prevented the enhancement of AHR and the development of airway eosinophilia and mucus hyperproduction on reinfection.
Conclusions: IFN-gamma production during primary RSV infection is critical to the development of protection against AHR and lung histopathology on reinfection. Provision of IFN-gamma during primary infection in infancy may be a potential therapeutic approach to alter the course of RSV-mediated long-term sequelae.

DOI： 10.1164/rccm.200612-1890OC

The role of leukotriene B4 in allergic diseases 査読

Hiroshi Ohnishi, Nobuaki Miyahara, Erwin W. Gelfand

Allergology International 57 ( 4 ) 291 - 298 2008年

記述言語：英語出版者・発行元：Japanese Society of Allergology

Leukotriene B4 (LTB4) is a lipid mediator with potent chemoattractant properties and that is rapidly generated from activated innate immune cells such as neutrophils, macrophages, and mast cells. Elevated levels of LTB4 have been reported in various allergic diseases and these levels have been related to disease activity and response to treatment. Recent studies using LTB4 receptor-1 (BLT1) antagonists or BLT1-deficient mice have revealed that ligation of BLT1 by LTB4 is important for the activation and recruitment of inflammatory cells including neutrophils, eosinophils, imonocytes/macrophages, mast cells, dendritic cells, and more recently, effector T cells to inflamed tissues in various inflammatory diseases. The LTB4/BLT1 pathway appears to play an important role in the pathogenesis of severe persistent asthma, aspirin- and exercise-induced asthma, allergic rhinitis, and atopic dermatitis together with other mediators including cysteinyl leukotrienes, cytokines, and chemokines. LTB4 production is in general resistant to corticosteroid treatment. In fact, corticosteroids can upregulate BLT1 expression on corticosteroid-resistant inflammatory cells such as neutrophils, monocytes, and effector memory CD8+ T cells. As a result, this corticosteroid-resistant LTB4/BLT1 pathway may contribute to the development of inflammation in allergic diseases that do not respond to the introduction of corticosteroids. Inhibition of this pathway has potential therapeutic benefit in various allergic diseases that have involvement of corticosteroid-insensitivity. © 2008 Japanese Society of Allergology.

DOI： 10.2332/allergolint.08-RAI-0019

46 COPDおよびCOPD合併喘息モデルに対するロイコトリエン受容体拮抗薬の効果について(動物モデル3,第58回日本アレルギー学会秋季学術大会)

池田元洋, 金廣有彦, 宮原信明, 早稲田公一, 古賀光, 渊本康子, 近藤稔人, 小野勝一郎, 平野淳, 谷本安, 片岡幹男, 谷本光音

アレルギー 57 ( 9 ) 1458 - 1458 2008年

MS17-10 肺サルコイドーシス治療におけるメソトレキサート(MTX)の有用性に関する検討(膠原病と類縁疾患,第58回日本アレルギー学会秋季学術大会)

谷本安, 中田安成, 片岡幹男, 早稲田公一, 池田元洋, 渊本康子, 古賀光, 市川裕久, 宮原信明, 金廣有彦, 森由弘, 谷本光音

アレルギー 57 ( 9 ) 1436 - 1436 2008年

MS9-7 アレルギー性気道炎症におけるCCR5の役割について(基礎-サイトカイン/ケモカイン,第58回日本アレルギー学会秋季学術大会)

渊本康子, 金廣有彦, 宮原信明, 古賀光, 池田元洋, 早稲田公一, 谷本安, 片岡幹男, 谷本光音, 松島綱治

アレルギー 57 ( 9 ) 1413 - 1413 2008年

MS2-2 高齢者喘息の管理における喘息コントロールテスト(ACT)の有用性に関する検討(気管支喘息コントロールの評価,第20回日本アレルギー学会春季臨床大会)

谷本安, 渊本康子, 尾形佳子, 早稲田公一, 金澤聰, 宮原信明, 金廣有彦, 片岡幹男, 高橋清, 谷本光音

アレルギー 57 ( 3 ) 358 - 358 2008年

P236 喘息患者指導における医師,薬剤師の連携に関する調査研究(気管支喘息治療3,第20回日本アレルギー学会春季臨床大会)

岡田千春, 平野淳, 木村五郎, 谷本安, 金廣有彦, 宮原信明, 宗田良, 高橋清

アレルギー 57 ( 3 ) 439 - 439 2008年

P108 モンテルカストが有効であった高齢者好酸球性胃腸炎の1例(好酸球1,第20回日本アレルギー学会春季臨床大会)

平野淳, 岡田千春, 木村五郎, 谷本安, 金廣有彦, 宮原信明, 片岡幹男, 宗田良, 高橋清

アレルギー 57 ( 3 ) 407 - 407 2008年

[Coinfection with Mycoplasma pneumoniae and Chlamydophila pneumoniae in a middle-aged adult]. 査読

Kubo T, Takigawa N, Tanimoto Y, Ichihara E, Tabata M, Miyahara N, Kanehiro A, Kiura K, Tanimoto M

Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 45 ( 10 ) 808 - 811 2007年10月

CD8(+) T cell-mediated airway hyperresponsiveness and inflammation is dependent on CD4(+)IL-4(+) T cells 査読

Toshiyuki Koya, Nobuaki Miyahara, Katsuyuki Takeda, Shigeki Matsubara, Hiroyuki Matsuda, Christina Swasey, Annette Balhorn, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 179 ( 5 ) 2787 - 2796 2007年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

CD4(+) T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. However, the requirements for interactions between CD4+ and CD8(+) T cells in airway allergic inflammation have not been delineated. Sensitized and challenged OT-1 mice in which CD8(+) T cells expressing the transgene for the OVA(257-264) peptide (SIINFEKL) failed to develop airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine elevation, or goblet cell metaplasia. OT-1 mice that received naive CD4(+)IL-4(+) T cells but not CD4(+)IL-4(-) T cells before sensitization developed all of these responses to the same degree as wild-type mice. Moreover, recipients of CD4(+)IL-4(+) T cells developed significant increases in the number of CD8(+)IL-13(+) T cells in the lung, whereas sensitized OT-1 mice that received primed CD4(+) T cells just before challenge failed to develop these responses. Sensitized CD8-deficient mice that received CD8(+) T cells from OT-1 mice that received naive CD4(+) T cells before sensitization increased AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged with allergen. In contrast, sensitized CD8-deficient mice receiving CD8(+) T cells from OT-1 mice without CD4(+) T cells developed reduced AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged. These data suggest that interactions between CD4(+) and CD8(+) T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8(+)IL-13(+) T cell-dependent AHR and airway allergic inflammation.

DOI： 10.4049/jimmunol.179.5.2787

Activation of naturally occurring lung CD4(+) CD25(+) regulatory T cells requires CD8 and MHC I interaction 査読

Anthony Joetham, Katsuyuki Takeda, Nobuaki Miyahara, Shigeki Matsubara, Hiroshi Ohnishi, Toshiyuki Koya, Azzeddine Dakhama, Erwin W. Gelfand

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 104 ( 38 ) 15057 - 15062 2007年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATL ACAD SCIENCES

Naturally occurring Foxp3(+)CD4(+)CD25(+) T cells (nTregs) isolated from lungs of naive mice regulate allergic airway hyperresponsiveness (AHR) and inflammation. Here, we demonstrate the critical requirement for engagement of MHC class I on CD4(+)CD25(+) T cells by CD8 for the functional activation of these nTregs. Suppression of allergen-induced AHR and inflammation by nTregs was abolished in mice treated with anti-CD8. Correspondingly, decreased levels of IL-10 and TGF-beta and increased levels of Th2 cytokines in bronchoalveolar lavage were detected in these treated mice. Similarly, nTregs isolated from beta 2m(-/-) mice or from mice treated with anti-MHC I antibody in vitro before intratracheal transfer failed to modulate AHR or inflammation. Coculture of nTregs with CD8(+) T cells increased IL-10 and TGF-beta. Addition of anti-MHC I or anti-CD8 reduced IL-10 and TGF-beta. These results demonstrate that functional activation of nTregs requires the interaction between MHC I on CD4(+)CD25(+) T cells and CD8.

DOI： 10.1073/pnas.0706765104

Airway hyperresponsiveness through synergy of gamma delta T cells and NKT cells 査読

Niyun Jin, Nobuaki Miyahara, Christina L. Roark, Jena D. French, M. Kemal Aydintug, Jennifer L. Matsuda, Laurent Gapin, Rebecca L. O'Brien, Erwin W. Gelfand, Willi K. Born

JOURNAL OF IMMUNOLOGY 179 ( 5 ) 2961 - 2968 2007年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred gamma(delta) T cells and invariant NKT cells, whereas either cell type alone was not effective. Only V gamma 1(+)V delta 5(+) gamma delta T cells enhanced AHR. Surprisingly, OVA-specific alpha beta T cells were not required, revealing a pathway of AHR development mediated entirely by innate T cells. The data suggest that lymphocytic synergism, which is key to the Ag-specific adaptive immune response, is also intrinsic to T cell-dependent innate responses.

DOI： 10.4049/jimmunol.179.5.2961

Arhgef1 is required by T cells for the development of airway hyperreactivity and inflammation 査読

Jeanette P. Brown, Christian Taube, Nobuaki Miyahara, Toshiyuki Koya, Roberta Pelanda, Erwin W. Gelfand, Raul M. Torres

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 176 ( 1 ) 10 - 19 2007年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Rationale: Arhgef1 is an intracellular protein, expressed by hematopoietic cells, that regulates signaling by both G protein-coupled receptors and RhoA, and, consequently, is required for appropriate migration and adhesion of diverse leukocyte populations. Objectives: To evaluate a possible contribution for Arhgef1 in the development of airway inflammation and airway hyperreactivity. Methods: Arhgef1-deficient (Arhgef1(-/-)) and wild-type (WT) mice were sensitized and airway challenged, followed by measurement of airway responsiveness to inhaled methacholine. Inflammation was assessed by several parameters that included flow cytometric analysis and histology. Arhgef1-deficient recipients were reconstituted with WT T lymphocytes before sensitization and challenge, and again measured for airway responsiveness and inflammation. Cytokine production in response to specific antigen was measured in cultures of isolated leukocytes from lung and spleen and compared with the levels generated in lung and spleen explant cultures. Measurements and Main Results: Arhgef1(-/-) mice display significantly reduced airway hyperreactivity, Th2 cytokine production, and lung inflammation, despite intact systemic immunity. After airway challenge of Arhgef1(-/-) mice, antigen-specific T cells were present in mutant lungs, but were found to interact with CD11c(+) cells at a significantly reduced frequency. Adoptive transfer of WTTcells into Arhgef1(-/-) mice restored airway hyperreactivity and inflammation. Conclusions: These data demonstrate that T cells depend on Arhgef1 to promote lung inflammation. Moreover, a deficiency in Arhgef1 results in reduced T cell-CD11c(+) antigen-presenting cell interaction, and likely underscores the inability of Arhgef1(-/-) mice to mount an adaptive immune response to airway challenge.

DOI： 10.1164/rccm.200702-270OC

IL-10-treated dendritic cells decrease airway hyperresponsiveness and airway inflammation in mice 査読

Toshiyuki Koya, Hiroyuki Matsuda, Katsuyuki Takeda, Shigeki Matsubara, Nobuaki Miyahara, Annette Balhorn, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 119 ( 5 ) 1241 - 1250 2007年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY-ELSEVIER

Background: IL-10 affects dendritic cell (DC) function, but the effects on airway hyperresponsiveness (AHR) and inflammation are not defined.
Objective: We sought to determine the importance of IL-10 in regulating DC function in allergen-induced AHR and airway inflammation.
Methods: DCs were generated from bone marrow in the presence or absence of IL-10. In vivo IL-10-treated DCs from IL-10(+/+) and IL-10(-/-) donors pulsed with ovalbumin (OVA) were transferred to naive or sensitized mice before challenge. In recipient mice AHR, cytokine levels, cell composition of bronchoalveolar lavage (BAL) fluid, and lung histology were monitored.
Results: In vitro, IL-10-treated DCs expressed lower levels of CD11c, CD80, and CD86; expressed lower levels of IL-12; and suppressed T(H)2 cytokine production. In vivo, after transfer of OVA-pulsed IL-10-treated DCs, naive mice did not have AHR, airway eosinophilia, T(H)2 cytokine increase in BAL fluid, or goblet cell metaplasia when challenged, and in sensitized and challenged mice IL-10-treated I)Cs suppressed these responses. Levels of IL-10 in BAL fluid and numbers of lung CD4(+)IL-10(+) T cells were increased in mice that received OVA-pulsed IL-10-treated DCs. Transfer of IL-10-treated DCs from IL-10-deficient mice were ineffective in suppressing the responses in sensitized and challenged mice.
Conclusions: These data demonstrate that IL-10-treated DCs are potent suppressors of the development of AHR, inflammation, and T(H)2 cytokine production; these regulatory functions are at least in part through the induction of endogenous (DQ production of IL-10. Clinical implications: Modification of DC function by IL-10 can attenuate lung allergic responses, including the development of AHR.

DOI： 10.1016/j.jaci.2007.01.039

IL-2 and IL-18 attenuation of airway hyperresponsiveness requires STAT4, IFN-gamma, and natural killer cells 査読

Shigeki Matsubara, Katsuyuki Takeda, Taku Kodama, Anthony Joetham, Nobuaki Miyahara, Toshiyuki Koya, Christina H. Swasey, Masakazu Okamoto, Azzeddine Dakhama, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 36 ( 3 ) 324 - 332 2007年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

IL-18 is known to induce IFN-gamma production, which is enhanced when combined with IL-2. In the present study, we investigated whether the combination of exogenous IL-2 and IL-18 alters airway hyperresponsiveness (AHR) and airway inflammation. Sensitized mice exposed to ovalbumin (OVA) challenge developed AHR, inflammatory cells in the bronchoalveolar lavage (BAL) fluid, and increases in levels of Th2 cytokines and goblet cell numbers. The combination of IL-2 and IL-18, but neither alone, prevented these changes while increasing levels of IL-12 and IFN-gamma. The combination of IL-2 and IL-18 was ineffective in IFN-gamma-deficient and signal transducer and activator of transcription (STAT)4-deficient mice. Flow cytometry analysis showed significant increases in numbers of IFN-gamma-positive natural killer (NK) cells in the lung after treatment with the combination therapy, and transfer of lung NK cells isolated from sensitized and challenged mice treated with the combination significantly suppressed AHR and BAL eosinophilia. These data demonstrate that the combination of IL-2 and IL-18 prevents AHR and airway inflammation, likely through IL-12-mediated induction of IFN-gamma production in NK cells.

DOI： 10.1165/rcmb.2006-0231OC

Naturally occurring lung CD4(+) CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta 査読

Anthony Joetham, Katsuyuki Takada, Christian Taube, Nobuaki Miyahara, Satoko Matsubara, Toshiyuki Koya, Yeong-Ho Rha, Azzeddine Dakhama, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 178 ( 3 ) 1433 - 1442 2007年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Peripheral tolerance to allergens is mediated in large part by the naturally occurring lung CD4(+)CD25(+) T cells, but their effects on allergen-induced airway responsiveness have not been well defined. Intratracheal, but not i.v., administration of naive lung CD4(+)CD25(+) T cells before allergen challenge of sensitized mice, similar to the administration of the combination of rIL-10 and rTGF-beta, resulted in reduced airway hyperresponsiveness (AHR) and inflammation, lower levels of Th2 cytokines, higher levels of IL-10 and TGF-beta, and less severe lung histopathology. Significantly, CD4(+)CD25(+) T cells isolated from IL-10(-/-) mice had no effect on AHR and inflammation, but when incubated with rIL-10 before transfer, suppressed AHR, and inflammation, and was associated with elevated levels of bronchoalveolar lavage TGF-beta levels. By analogy, anti-TGF-beta treatment reduced regulatory T cell activity. These data identify naturally occurring lung CD4(+)CD25(+) T cells as capable of regulating lung allergic responses in an IL-10- and TGF-beta-dependent manner.

DOI： 10.4049/jimmunol.178.3.1433

Critical role of the Fc receptor gamma-chain on APCs in the development of allergen-induced airway hyperresponsiveness and inflammation 査読

Kenichi Kitamura, Katsuyuki Takeda, Toshiyuki Koya, Nobuaki Miyahara, Taku Kodama, Azzeddine Dakhama, Toshiyuki Takai, Atsushi Hirano, Mitsune Tanimoto, Mine Harada, Erwin W. Gelfand

JOURNAL OF IMMUNOLOGY 178 ( 1 ) 480 - 488 2007年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

The FeR common y-chain (FcRy) is an essential component of the receptors Fe epsilon RI, Fc gamma RI, and Fc gamma RIII, which are expressed on many inflammatory cell types. The role of these receptors in the initiation or maintenance of allergic inflammation has not been well defined. FcR gamma-deficient (FcRy(-/-)) and control (wild-type (WT)), mice were sensitized and subsequently challenged with OVA. Following sensitization and challenge to OVA, FeRy-deficient (FcRy(-/-)) mice developed comparable levels of IgE and IgG1 as WT mice. However, numbers of eosinophils, levels of IL-5, IL-13, and eotaxin in bronchoalveolar lavage fluid, and mononuclear cell (MNC) proliferative responses to OVA were significantly reduced, as was airway hyperresponsiveness (AHR) to inhaled methacholine. Reconstitution of FeRy(-/-) mice with whole spleen MNC from WT mice before sensitization restored development of AHR and the numbers of eosinophils in bronchoalveolar lavage fluid; reconstitution after sensitization but before OVA challenge only partially restored these responses. These responses were also restored when FcRy(-/-) mice received T cell-depleted MNC, T and B cell-depleted MNC, or bone marrow-derived dendritic cells before sensitization from FcR(+/+) or Fe gamma RIII-deficient but not FcRy(-/-) mice. The expression levels of Fc gamma RIV on bone marrow-derived dendritic cells from FcR(+/+) mice were found to be low. These results demonstrate that expression of FcR gamma, most likely Fc gamma RI, on APCs is important during the sensitization phase for the development of allergic airway inflammation and AHR.

DOI： 10.4049/jimmunol.178.1.480

IL-13 is essential to the late-phase response in allergic rhinitis 査読

Satoko Miyahara, Nobuaki Miyahara, Shigeki Matsubara, Katsuyuki Takeda, Toshiyuki Koya, Erwin W. Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 118 ( 5 ) 1110 - 1116 2006年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY-ELSEVIER

Background: The pathophysiology of the early- and late-phase nasal response to allergen challenge is not completely defined. Recent technical advances enable direct monitoring of these responses in mice.
Objective: IL-13 is detected in the nasal membranes of both human beings and mice with allergic rhinitis, but its role in disease pathogenesis is unclear. We measured early and late nasal allergic responses after treatment with soluble IL-13R alpha 2-IgG fusion protein (sIL-13R alpha 2-Fc), and in IL-13-deficient mice (IL-13(-/-)).
Methods: IL-13(-/-) mice (BALB/c background) and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged intranasally with ovalbumin without sedation. The sIL-13R alpha 2-Fc or control human IgG was administered by intraperitoneal (i.p.) injection 24 hours and 1 hour before each ovalbumin challenge. Early nasal responses after the 4th ovalbumin challenge and late nasal responses 24 hours after the 6th ovalbumin challenge were assessed. Results: Sensitized/challenged wild-type mice treated with sIL-13R alpha 2-Fc or IL-13(-/-) mice demonstrated significantly reduced late nasal responses in face of persistent nasal tissue eosinophilia; the early nasal response was little affected by targeting IL-13. Goblet cell hyperplasia was not detected in nasal membranes.
Conclusion: The data indicate that IL-13 is a major contributor to the development of a late nasal response with little influence on the early response, and without affecting nasal eosinophilic inflammation. Inhibition of IL-13 may have an important therapeutic application in preventing the persistent nasal blockage in allergic rhinitis.
Clinical implications: Current therapies for allergic rhinitis may not take into account the important differences in the pathophysiology of the early and late responses and the important role of IL-13 in sustaining chronic nasal congestion and obstruction.

DOI： 10.1016/j.jaci.2006.06.014

RANTES (CCL5) regulates airway responsiveness after repeated allergen challenge 査読

Toshiyuki Koya, Katsuyuki Takeda, Taku Kodama, Nobuaki Miyahara, Shigeki Matsubara, Annette Balhorn, Anthony Joetham, Azzedine Dakhama, Erwin W. Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 35 ( 2 ) 147 - 154 2006年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

RANTES (CC chemokine ligand 5) contributes to airway inflammation through accumulation of eosinophils, but the exact role of RANTES (CCL5) is not defined. C57BL/6 mice, sensitized by injection of ovalbumin (OVA) on Days I and 14, were challenged with OVA on Days 28, 29, and 30 (3 challenges, short-term-challenge model) or on Days 28, 29, 30, 36, 40, 44, and 48 (7 challenges, repeated-challenge model) and evaluated 48 h later. Anti-mouse RANTES was given intravenously, and recombinant mouse RANTES or PBS was given intratracheally. These reagents were given on Days 28, 29, and 30 in the short-term-challenge study and on Days 44 and 48 in the repeated-challenge study. After short-term challenge, there were no effects after administration of anti-RANTES or RANTES. In the repeated-challenge study, although control mice showed a decrease in airway hyperresponsiveness, administration of anti-RANTES sustained and enhanced airway hyperresponsiveness and increased goblet cell numbers. In contrast, administration of RANTES normalized airway function but reduced goblet cell numbers. IL-12 and IFN-gamma levels in BAL decreased in the anti-RANTES group and increased in the RANTES group. IFN-gamma-producing CD4 T cells in lung, and IFN-gamma production from lung T cells in response to OVA in the anti-RANTES group, were significantly decreased but were increased in the RANTES group. Anti-IFN-gamma administered with RANTES, decreased the effects of RANTES on AHR after repeated challenge. These data indicate that RANTES plays a role in the regulation of airway function after repeated allergen challenge, in part through modulation of levels of IFN-gamma and IL-12.

DOI： 10.1165/rcmb.2005-0394OC

Role of the LTB4/BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation. 査読

Miyahara N, Miyahara S, Takeda K, Gelfand EW

Allergology international : official journal of the Japanese Society of Allergology 55 ( 2 ) 91 - 97 2006年6月

記述言語：英語出版者・発行元：一般社団法人日本アレルギー学会

LTB4, a proinflammatory lipid mediator generated from arachidonic acid through the action of 5-lipoxygenase, has been known for over two decades and is implicated in a wide variety of inflammatory disorders. BLT1, a G-protein-coupled receptor, has recently been identified as a high affinity receptor specific for LTB4. Recent studies in allergen-induced airway hyperresponsiveness and inflammation using mice lacking BLT1 have shown crucial new roles for leukotriene B4 and BLT1 in Th2 cytokine IL-13 production from lung T cells and recruitment of antigen-specific effector CD8+ T cells, suggesting novel mechanisms for their actions. The leukotriene B4-BLT1 pathway is an important target for the treatment of bronchial asthma.<br>

DOI： 10.2332/allergolint.55.91

Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation 査読

C Taube, JM Thurman, K Takeda, A Joetham, N Miyahara, MC Carroll, A Dakhama, PC Giclas, VM Holers, EW Gelfand

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 103 ( 21 ) 8084 - 8089 2006年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATL ACAD SCIENCES

Exposure to inhaled allergens leads to increases in airway hyper-responsiveness (AHR) and inflammation, associated with increased levels of biologically active fragments derived from the complement C3 and C5 family of proteins. Further, complement activation during allergen challenge in sensitized animals is necessary for the development of AHR and airway inflammation. To define the complement pathway involved, we studied mice deficient in complement factor 4 (C4-/-), a critical component of the classical pathway, or factor B (fB-/-), an essential protein in the alternative complement pathway. WT, C4-/-, and fB-/- mice were sensitized to ovalbumin and subsequently exposed to nebulized ovalbumin (1% in saline) on 3 consecutive days. After allergen sensitization and challenge, fB-/- mice demonstrated significantly lower airway responsiveness to methacholine and less airway inflammation. In contrast, C4-/- mice showed no reduction in AHR and airway inflammation compared with WT mice. Tissue inflammation, goblet cell hyperplasia, and IL-4, IL-5, and IL-13 levels in BAL fluid were significantly reduced in fB-/- mice compared with C4-/- and WT mice. The development of AHR and airway inflammation in sensitized fB-/- mice could be restored after intranasal administration of purified factor B before the airway challenge. In addition, administration of a neutralizing anti-factor B mAb to sensitized mice before airway challenge reduced the development of AHR and airway inflammation. These results demonstrate that in sensitized hosts complement activation through the alternative pathway after allergen exposure is critical to the development of AHR and airway inflammation.

DOI： 10.1073/pnas.0602357103

Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation 査読

S Matsubara, T Koya, K Takeda, A Joetham, N Miyahara, P Pine, ES Masuda, CH Swasey, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 34 ( 4 ) 426 - 433 2006年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

We evaluated the role of Syk, using an inhibitor, on allergen-induced airway hyperresponsiveness (AHR) and airway inflammation in a system shown to be B cell- and mast cell-independent. Sensitization of BALB/c mice with ovalbumin (OVA) and alum after three consecutive OVA challenges resulted in AHR to inhaled methacholine and airway inflammation. The Syk inhibitor R406 (30 mg/kg, administered orally, twice daily) prevented the development of AHR, increases in eosinophils and lymphocytes and IL-13 levels in bronchoalveolar lavage (BAL) fluid, and goblet cell metaplasia when administered after sensitization and before challenge with OVA. Levels of IL-4, IL-5, and IFN-gamma in BAL fluid and allergen-specific antibody levels in serum were not affected by treatment. Because many of these responses may be influenced by dendritic cell function, we investigated the effect of R406 on bone marrow-derived dendritic cell (BMDC) function. Co-culture of BMDC with immune complexes of OVA and IgG anti-OVA together with OVA-sensitized spleen mononuclear cells resulted in increases in IL-13 production. IL-13 production was inhibited if the BMDCs were pretreated with the Syk inhibitor. Intratracheal transfer of immune complex-pulsed BMDCs (but not nonpulsed BMDCs) to naive mice before airway allergen challenge induced the development of AHR and increases in BAL eosinophils and lymphocytes. All of these responses were inhibited if the transferred BMDCs were pretreated with R406. These results demonstrate that Syk inhibition prevents allergen-induced AHR and airway inflammation after systemic sensitization and challenge, at least in part through alteration of DC function.

DOI： 10.1165/rcmb.2005-0298OC

The leukotriene B4 receptor (BLT1) is required for effector CD8(+) T cell-mediated, mast cell-dependent airway hyperresponsiveness 査読

C Taube, N Miyahara, Ott, V, B Swanson, K Takeda, J Loader, LD Shultz, AM Tager, AD Luster, A Dakhama, EW Gelfand

JOURNAL OF IMMUNOLOGY 176 ( 5 ) 3157 - 3164 2006年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Studies in both humans and rodents have suggested that CD8(+) T cells contribute to the development of airway hyperresponsiveness (AHR) and that leukotriene B4 (LTB4) is involved in the chemotaxis of effector CD8(+) T cells (T-EFF) to the lung by virtue of their expression of BLT1, the receptor for LTB4. In the present study, we used a mast cell-CD8-dependent model of AHR to further define the role of BLT1 in CD8(+) T cell-mediated AHR. C57BL/6(+/+) and CD8-deficient (CD8(-/-)) mice were passively sensitized with anti-OVA IgE and exposed to OVA via the airways. Following passive sensitization and allergen exposure, C57BL/6(+/+) mice developed altered airway function, whereas passively sensitized and allergen-exposed CD8(-/-) mice failed to do so. CD8(-/-) mice reconstituted with CD8(+) T-EFF developed AHR in response to challenge. In contrast, CD8(-/-) mice reconstituted with BLT1-deficient effector CD8(+) T cells did not develop AHR. The induction of increased airway responsiveness following transfer of CD8(+) TEFF or in wild-type mice could be blocked by administration of an LTB4 receptor antagonist confirming the role of BLT1 in CD8(+) T cell-mediated AHR. Together, these data define the important role for mast cells and the LTB4-BLT1 pathway in the development of CD8(+) T cell-mediated allergic responses in the lung.

DOI： 10.4049/jimmunol.176.5.3157

Importance of myeloid dendritic cells in persistent airway disease after repeated allergen exposure 査読

T Koya, T Kodama, K Takeda, N Miyahara, ES Yang, C Taube, A Joetham, JW Park, A Dakhama, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 173 ( 1 ) 42 - 55 2006年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Rationale: There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice.
Methods: Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or I I occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow-derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors.
Results: Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta(1), eotaxin-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and OVA-specific IgG1 and IgE; and resulted in AHR. After seven airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5. and IL-13. Levels of IL-10 in both strains and the level of IL-12 in BALB/c mice increased. After 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profiles continued to change. At this time point, the number of myeloid dendritic cells and expression of CD80 and CD86 in lungs were decreased compared with three challenges. After 11 challenges, intratracheal instillation of bone marrow-derived dendritic cells restored AHR and airway eosinophilia.
Conclusions: These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.

DOI： 10.1164/rccm.200505-783OC

Inhibition of spleen tyrosine kinase prevents mast cell activation and airway hyperresponsiveness 査読

S Matsubara, GM Li, K Takeda, JE Loader, P Pine, ES Masuda, N Miyahara, S Miyahara, JJ Lucas, A Dakhama, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 173 ( 1 ) 56 - 63 2006年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Rationale: Spleen tyrosine kinase (Syk) is important for Fc and B-cell receptor-mediated signaling.
Objective: To determine the activity of a specific Syk inhibitor (11406) on mast cell activation in vitro and on the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in vivo.
Methods: AHR and inflammation were induced after 10 d of allergen (ovalbumin [OVA]) exposure exclusively via the airways and in the absence of adjuvant. This approach was previously established to be IgE, Fc epsilon RI, and mast cell dependent. Alternatively, mice were passively sensitized with OVA-specific IgE, followed by limited airway challenge. In vitro, the inhibitor was added to cultures of IgE-sensitized bone marrow-derived mast cells (BMMCs) before crosslinking with allergen.
Results: The inhibitor prevented OVA-induced degranulation of passively IgE-sensitized murine IBMMCs and inhibited the production of interieukin (IL)-13, tumor necrosis factor a, IL-2, and IL-6 in these sensitized BMMCs. When administered in vivo, R406 inhibited AHR, which developed in BALB/c mice exposed to aerosolized 1% OVA for 10 consecutive d (20 min/d), as well as pulmonary eosinophilia and goblet cell metaplasia. A similar inhibition of AHR was demonstrated in mice passively sensitized with OVA-specific IgE and exposed to limited airway challenge.
Conclusion: This study delineates a functional role for Syk in the development of mast cell- and IgE-mediated AHR and airway inflammation, and these results indicate that inhibition of Syk may be a target in the treatment of allergic asthma.

DOI： 10.1164/rccm.200503-361OC

Physiologic assessment of allergic rhinitis in mice: Role of the high-affinity IgE receptor (Fc epsilon RI) 査読

S Miyahara, N Miyahara, K Takeda, A Joetham, EW Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 116 ( 5 ) 1020 - 1027 2005年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY, INC

Background: There have been few reports using animal models to study the development of allergic rhinitis. Characterization of such a model in mice would be advantageous given the availability of reagents and gene-manipulated strains.
Objective: We sought to develop a murine model of allergic rhinitis in the absence of lower airway changes.
Methods: After sensitization and challenge, both wild-type and Fe epsilon RI-deficient mice were studied for their ability to develop early- and late-phase nasal responses. In the invasive approach, direct measurements of nasal airway resistance (R-NA) were obtained; in the noninvasive approach using whole-body plethysmography, respiratory frequency and expiratory and inspiratory times were monitored. In both approaches, nasal responses were determined either acutely after challenge (early phase) or 24 hours after challenge (late phase).
Results: After challenge of sensitized mice, R-NA significantly increased. In parallel, respiratory frequency significantly decreased and was highly correlated with the increases in R-NA-Sensitized wild-type mice had an early-phase nasal response and persistent nasal blockage (late-phase response) after allergen challenge. In contrast, sensitized and challenged Fc epsilon RI alpha-chain-deficient mice did not have an early-phase nasal reaction and exhibited reduced nasal blockage and lower IL-13 levels in nasal tissue homogenates.
Conclusions: These data indicate that Fc epsilon RI is essential to development of an early-phase nasal response and contributes to the development of the late-phase nasal response. These invasive and noninvasive approaches provide new opportunities to evaluate the mechanisms underlying the development of nasal responses to allergen and to assess various therapeutic interventions.

DOI： 10.1016/j.jaci.2005.08.020

S-carboxymethylcysteine normalises airway responsiveness in sensitised and challenged mice 査読

K Takeda, N Miyahara, T Kodama, C Taube, A Balhorn, A Dakhama, K Kitamura, A Hirano, M Tanimoto, EW Gelfand

EUROPEAN RESPIRATORY JOURNAL 26 ( 4 ) 577 - 585 2005年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD

S-carboxymethylcysteine (S-CMC) has been used as a mucoregulator in respiratory diseases. However, the mechanism of action of S-CMC on allergic airway inflammation has not yet been defined.
In the present study, BALB/c mice were initially sensitised and challenged to ovalbumin (OVA) and, weeks later, re-challenged with OVA (secondary challenge). S-CMC (5-100 mg.kg(-1)) was administered from 2 days before the secondary challenge through to the day of assay.
Mice developed airway hyperresponsiveness (AHR) 6 h after the secondary challenge and increased numbers of neutrophils were present in the bronchoalveolar lavage (BAL) fluid. At 72 h after secondary challenge, mice again developed AHR, but the BAL fluid contained large numbers of eosinophils. S-CMC treatment was found to reduce AHR and neutrophilia at 6 h, as well as eosinophilia and AHR at 72 h. These effects appeared to be dose dependent. Goblet cell hyperplasia, observed at 72 h, was reduced by S-CMC. In BAL fluid, increased levels of interferon-gamma, interleukin (IL)-12 and IL-10 and decreased levels of IL-5 and IL-13 were detected.
In conclusion, the data indicate that S-carboxymethylcysteine is effective in reducing airway hyperresponsiveness and airway inflammation at two distinct phases of the response to the secondary allergen challenge in sensitised mice.

DOI： 10.1183/09031936.05.00090304

The enhancement or prevention of airway hyperresponsiveness during reinfection with respiratory syncytial virus is critically dependent on the age at first infection and IL-13 production 査読

A Dakhama, JW Park, C Taube, A Joetham, A Balhorn, N Miyahara, K Takeda, EW Gelfand

JOURNAL OF IMMUNOLOGY 175 ( 3 ) 1876 - 1883 2005年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Respiratory syncytial virus (RSV) infection in early life is suspected to play a role in the development of postbronchiolitis wheezing and asthma. Reinfection is common at all ages, but factors that determine the development of altered airway function after reinfection are not well understood. This study was conducted in a mouse model to define the role of age in determining the consequences on airway function after reinfection. Mice were infected shortly after birth or at weaning and were reinfected 5 wk later, followed by assessment of airway function, airway inflammation, and lung histopathology. Infection of mice at weaning elicited a protective airway response upon reinfection. In this age group, reinfection resulted in increased airway inflammation, but without development of airway hyperresponsiveness (AHR) or eosinophilia and decreased IL-13 levels. By contrast, neonatal infection failed to protect the airways and resulted in enhanced AHR after reinfection. This secondary response was associated with the development of airway eosinophilia, increased IL-13 levels, and mucus hyperproduction. Both CD4- and CD8-positive T cells were a source of IL-13 in the lung, and inhibition of IL-13 abolished AHR and mucus production in these mice. Inoculation of UV-inactivated virus failed to elicit these divergent responses to reinfection, emphasizing the requirement for active lung infection during initial exposure. Thus, neonatal RSV infection predisposes to the development of airway eosinophilia and enhanced AHR via an IL-13-dependent mechanism during reinfection, whereas infection at a later age protects against the development of these altered airway responses after reinfection.

DOI： 10.4049/jimmunol.175.3.1876

Airway hyperresponsiveness in the absence of CD4+T cells after primary but not secondary challenge 査読

A Joetham, K Takeda, C Taube, N Miyahara, A Kanehiro, A Dakhama, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 33 ( 1 ) 89 - 96 2005年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

CD4+ T cells have been shown to play a role in the development of airway hyperresponsivness (AHR) and airway eosinophilia in mice using ablation as well as adoptive transfer experiments. However, as other T cell subsets (CD8, NKT) may play a role in these models, we examined the responses of sensitized CD4-deficient mice after either primary or secondary airway allergen challenge. After sensitization, CD4-deficiency in mice was not associated with airway eosinophilia, allergen-specific IgE, or elevated levels of interleukin (IL)-4 or IL-13. Increases in lung CD8 T cells and IL-5 were observed and shown to be essential for AHR as demonstrated after CD8 T cell depletion or anti-IL-5 treatment. In contrast to the response of sensitized CD4-deficient mice to primary allergen challenge, they failed to develop AHR after secondary allergen challenge. Although the importance of this CD4+ T cell-independent pathway in normal mice is unclear at this time, these studies identify the diversity of the cellular pathway, which may contribute to the development of AHR after primary allergen exposure of sensitized mice.

DOI： 10.1165/rcmb.2004-0414OC

Requirement for leukotriene B-4 receptor 1 in allergen-induced airway hyperresponsiveness 査読

N Miyahara, K Takeda, S Miyahara, S Matsubara, T Koya, A Joetham, E Krishnan, A Dakhama, B Haribabu, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 172 ( 2 ) 161 - 167 2005年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Rationale: Leukotriene B-4 (LTB4) is a rapidly synthesized, early leukocyte chemoattractant that signals via its cell surface receptor, leukotriene B4 receptor 1 (BLT1), to attract and activate leukocytes during inflammation. A role for the LTB4-BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation is not well defined. Objectives: To define the role of the LTB4 receptor (BLT1) in the development of airway inflammation and altered airway function. Methods: BLT1-deficient (BLT1(-/-)) mice and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged with ovalbumin via the airways. Airway responsiveness to inhaled methacholine, bronchoalveolar lavage fluid cell composition and cytokine levels, and lung inflammation and goblet cell hyperplasia were assessed. Results: Compared with wild-type mice, BLT1(-/-) mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased interleukin (IL)-13 production both in vivo, in the bronchoalveolar lavage fluid, and in vitro, after antigen stimulation of lung cells in culture. Intracellular cytokine staining of lung cells revealed that bronchoalveolar lavage IL-1 3 levels and numbers of IL-13(+)/CD4(+) and IL-13(+)/CD8(+) T cells were also reduced in BLT1 (-/-) mice. Reconstitution of sensitized and challenged BLT1(-/-) mice with allergen-sensitized BLT1(+/+) T cells fully restored the development of airway hyperresponsiveness. In contrast, transfer of naive T cells failed to do so. Conclusion: These data suggest that BLT1 expression on primed T cells is required for the full development of airway hyperresponsiveness, which appears to be associated with IL-13 production in these cells.

DOI： 10.1164/rccm.200502-205OC

Leukotriene B4 receptor-1 is essential for allergen-mediated recruitment of CD8(+) T cells and airway hyperresponsiveness 査読

N Miyahara, K Takeda, S Miyahara, C Taube, A Joetham, T Koya, S Matsubara, A Dakhama, AM Tager, AD Luster, EW Gelfand

JOURNAL OF IMMUNOLOGY 174 ( 8 ) 4979 - 4984 2005年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Recent studies in both human and rodents have indicated that in addition to CD4(+) T cells, CD8(+) T cells play an important role in allergic inflammation. We previously demonstrated that allergen-sensitized and -challenged CD8-deficient (CD8(-/-)) mice develop significantly lower airway hyperresponsiveness (AHR), eosinophilic inflammation, and IL-13 levels in bronchoalveolar lavage fluid compared with wild-type mice, and that all these responses were restored by adoptive transfer of in vivo-primed CD8(+) T cells or in vitro-generated effector CD8(+) T cells (T-EFF). Recently, leukotriene B4 and its high affinity receptor, BLT1, have been shown to mediate in vitro-generated T-EEF recruitment into inflamed tissues. In this study we investigated whether BLT1 is essential for the development of CD8(+) T cell-mediated allergic AHR and inflammation. Adoptive trans fer of in vivo-primed BLT1(+/+), but not BLTI-/-, CD8(+) T cells into sensitized and challenged CD8(-/-) mice restored AHR, eosinophilic inflammation, and IL-13 levels. Moreover, when adoptively transferred into sensitized CD8(-/-) mice, in vitro-generated BLTI+/+, but not BLT1(-/-), T-EFF accumulated in the lung and mediated these altered airway responses to allergen challenge. These data are the first to show both a functional and an essential role for BLT1 in allergen-mediated CD8(+) T-EFF recruitment into the lung and development of AHR and airway inflammation.

DOI： 10.4049/jimmunol.174.8.4979

Alteration of airway neuropeptide expression and development of airway hyperresponsiveness following respiratory syncytial virus infection 査読

A Dakhama, JW Park, C Taube, M El Gazzar, T Kodama, N Miyahara, K Takeda, A Kanehiro, A Balhorn, A Joetham, JE Loader, GL Larsen, EW Gelfand

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY 288 ( 4 ) L761 - L770 2005年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER PHYSIOLOGICAL SOC

The mechanisms by which respiratory syncytial virus (RSV) infection causes airway hyperresponsiveness (AHR) are not fully established. We hypothesized that RSV infection may alter the expression of airway sensory neuropeptides, thereby contributing to the development of altered airway function. BALB/c mice were infected with RSV followed by assessment of airway function, inflammation, and sensory neuropeptide expression. After RSV infection, mice developed significant airway inflammation associated with increased airway resistance to inhaled methacholine and increased tracheal smooth muscle responsiveness to electrical field stimulation. In these animals, substance P expression was markedly increased, whereas calcitonin gene-related peptide ( CGRP) expression was decreased in airway tissue. Prophylactic treatment with Sendide, a highly selective antagonist of the neurokinin-1 receptor, or CGRP, but not the CGRP antagonist CGRP( 8 - 37), inhibited the development of airway inflammation and AHR in RSV-infected animals. Therapeutic treatment with CGRP, but not CGRP( 8 - 37) or Sendide, abolished AHR in RSV-infected animals despite increased substance P levels and previously established airway inflammation. These data suggest that RSV-induced airway dysfunction is, at least in part, due to an imbalance in sensory neuropeptide expression in the airways. Restoration of this balance may be beneficial for the treatment of RSV-mediated airway dysfunction.

DOI： 10.1152/ajplung.00143.2004

The role of virus-specific immunoglobulin E in airway hyperresponsiveness 査読

A Dakhama, JW Park, C Taube, K Chayama, A Balhorn, A Joetham, XD Wei, RH Fan, C Swasey, N Miyahara, T Kodama, A Alvarez, K Takeda, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 170 ( 9 ) 952 - 959 2004年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis during infancy and is associated with subsequent wheezing and asthma, but the nature of this association is not fully understood. We investigated the role of RSV-specific IgE antibodies in the pathophysiology of virus-induced airway dysfunction in a mouse model. Lung infection with RSV resulted in significant increases in mRNA expression for IgE and both of its high- and low-affinity receptors. In serum, virus-specific IgE antibodies reached peak levels by Day 21 after infection. Data from in vitro experiments show that RSV can induce mast cell degranulation, but only if these cells are sensitized with specific IgE. When passively sensitized in vivo with virus-specific IgE, mice developed exaggerated airway responsiveness to methacholine on airway infection, an effect that required the high-affinity receptor of IgE. These data suggest that RSV-specific IgE may contribute to the pathophysiology of airway dysfunction in children who develop this class of specific antibody.

DOI： 10.1164/rccm.200311-1610oc

Effector CD8(+) T cells mediate inflammation and airway hyper-responsiveness 査読

N Miyahara, BJ Swanson, K Takeda, C Taube, S Miyahara, T Kodama, A Dakhama, VL Ott, EW Gelfand

NATURE MEDICINE 10 ( 8 ) 865 - 869 2004年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyperresponsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8(+) T cells(1). Previously, two distinct populations of antigen-experienced CD8(+) T cells, termed effector (T-EFF) and central memory (T-CM) cells, have been described(2-5). After adoptive transfer into CD8-deficient mice, T-EFF, but not T-CM, cells restored AHR, eosinophilic inflammation and IL-13 levels. T-EFF, but not T-CM, cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred T-EFF cells were a source of IL-13. These data suggest an important role for effector CD8(+) T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.

DOI： 10.1038/nm1081

Interleukin-1 receptor antagonist attenuates airway hyperresponsiveness following exposure to ozone 査読

JW Park, C Taube, C Swasey, T Kodama, A Joetham, A Balhorn, K Takeda, N Miyahara, CB Allen, A Dakhama, SH Kim, CA Dinarello, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 30 ( 6 ) 830 - 836 2004年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

The role of an interleukin (IL)-1 receptor antagonist (IL-1Ra) on the development of airway hyperresponsiveness (AHR) and airway inflammation following acute O-3 exposure in mice was investigated. Exposure of C57/BL6 mice to O-3 at a concentration of 2.0 ppm or filtered air for 3 h resulted in increases in airway responsiveness to inhaled methacholine (MCh) 8 and 16 h after the exposure, and an increase in neutrophils in the bronchoalveolar lavage (BAL) fluid. IL-1beta expression, assessed by gene microarray, was increased 2-fold 4 h after O-3 exposure, and returned to baseline levels by 24 h. Levels of IL-1beta in lung homogenates were also increased 8 h after O-3 exposure. Administration of (human) IL-1Ra before, and after O-3 exposure prevented development of AHR and decreased BAL fluid neutrophilia. Increases in chemokine levels in lung homogenates, tumor necrosis factor-alpha, MIP-2, and keratinocyte chemoattractant following O-3 exposure were prevented by IL-1Ra. Inhalation of dexamethasone, an inhibitor of IL-1 production, blocked the development of AHR, BAL fluid neutrophilia, and decreased levels of IL-1 following O-3 exposure. In summary, acute exposure to O-3 induces AHR, neutrophilic inflammation, epithelial damage, and IL-1. An IL-1Ra effectively prevents the development of altered airway function, inflammation, and structural damage.

DOI： 10.1165/rcmb.2003.0373OC

Mast cells, Fc epsilon RI, and IL-13 are required for development of airway hyperresponsiveness after aerosolized allergen exposure in the absence of adjuvant 査読

C Taube, XD Wei, CH Swasey, A Joetham, S Zarini, T Lively, K Takeda, J Loader, N Miyahara, T Kodama, LD Shultz, DD Donaldson, EH Hamelmann, A Dakhama, EW Gelfand

JOURNAL OF IMMUNOLOGY 172 ( 10 ) 6398 - 6406 2004年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

In certain models of allergic airway disease, mast cells facilitate the development of inflammation and airway hyper-responsiveness (AHR). To define the role of the high affinity IgE receptor (Fcis an element ofRI) in the development of AHR, mice with a disruption of the a subunit of the high affinity IgE receptor (Fcis an element ofRI(-/-)) were exposed on 10 consecutive days to nebulized OVA. Forty-eight hours after the last nebulization, airway responsiveness was monitored by the contractile response of tracheal smooth muscle to electrical field. stimulation (EFS). After the 10-day OVA challenge protocol, wild-type mice demonstrated increased responsiveness to EFS, whereas similarly challenged Fcis an element ofRI(-/-) mice showed a low response to EFS, similar to nonexposed animals. Further, allergen-challenged Fcis an element ofRI(-/-) mice showed less airway inflammation, goblet cell hyperplasia, and lower levels of IL-13 in lung homogenates compared with the controls. IL-13-deficient mice failed to develop an increased response to EFS or goblet cell hyperplasia after the 10-day OVA challenge. We transferred bone marrow-derived mast cells from wild-type mice to Fcis an element ofRI(-/-) mice 1 day before initiating the challenge protocol. After the 10-day OVA challenge, recipient Fcis an element ofRI(-/-) mice demonstrated EFS-induced responses similar to those of challenged wild-type mice. Transferred mast cells could be detected in tracheal preparations. These results show that Fcis an element ofRI is important for the development of AHR after an aerosolized allergen sensitization protocol and that this effect is mediated through Fcis an element ofRI on mast cells and production of IL-13 in the lung.

DOI： 10.4049/jimmunol.172.10.6398

Contribution of antigen-primed CD8(+) T cells to the development of airway hyperresponsiveness and inflammation is associated with IL-13 査読

N Miyahara, K Takeda, T Kodama, A Joetham, C Taube, JW Park, S Miyahara, A Balhorn, A Dakhama, EW Gelfand

JOURNAL OF IMMUNOLOGY 172 ( 4 ) 2549 - 2558 2004年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

The role of Th2/CD4 T cells, which secrete IL-4, IL-5, and IL-13, in allergic disease is well established; however, the role of CD8(+) T cells (allergen-induced airway hyperresponsiveness (AHR) and inflammation) is less clear. This study was conducted to define the role of Ag-primed CD8(+) T cells in the development of these allergen-induced responses. CD8-deficient (CD8(-/-)) mice and wild-type mice were sensitized to OVA by i.p. injection and then challenged with OVA via the airways. Compared with wild-type. mice, CD8(-/-) mice developed significantly lower airway responsiveness to inhaled methacholine and lung eosinophilia, and exhibited decreased IL-13 production both in vivo, in the bronchoalveolar lavage (BAL) fluid, and in vitro, following Ag stimulation of peribronchial lymph node (PBLN) cells in culture. Reconstitution of sensitized and challenged CD8(-/-) mice with allergen-sensitized CD8(+) T cells fully restored the development of AHR, BAL cosinophilia, and IL-13 levels in BAL and in culture supernatants from PBLN cells. In contrast, transfer of naive CD8(+) T cells or allergen-sensitized CD8(+) T cells from IL-13-deficient donor mice failed to do so. Intracellular cytokine staining of lung as well as PBLN T cells revealed that CD8(+) T cells were a source of IL-13. These data suggest that Ag-primed CD8(+) T cells are required for the full development of AHR and airway inflammation, which appears to be associated with IL-13 production from these primed T cells. The Journal of Immunology, 2004, 172: 2549-2558.

DOI： 10.4049/jimmunol.172.4.2549

Respiratory syncytial virus-induced airway hyperresponsiveness is independent of IL-13 compared with that induced by allergen 査読

JW Park, C Taube, ES Yang, A Joetham, A Balhorn, K Takeda, N Miyahara, A Dakhama, DD Donaldson, EW Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 112 ( 6 ) 1078 - 1087 2003年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY, INC

Background: IL-13 is a central mediator of allergen-induced airway hyperresponsiveness, (AHR), but its role in respiratory syncytial virus (RSV)-induced AHR is not defined. The combination of allergen exposure and RSV infection is known to increase AHR and lung inflammation, but whether IL-13 regulates this increase is similarly not known.
Objective: Our objective was to determine the role of RSV infection and IL-13 on airway responsiveness and lung inflammation on sensitized and challenged mice.
Methods: Using a murine model of RSV infection and allergen exposure, we examined the role of IL-13 in the development of AHR and lung inflammation in IL-13 knockout mice, as well as using a potent IL-13 inhibitor (IL-13i). Mice were sensitized and challenged to allergen, and 6 days after the last challenge, they were infected with RSV. IL-13 was inhibited using an IL-13 receptor alpha(2)-human IgG fusion protein. AHR to inhaled methacholine was measured 6 days after infection, as was bronchoalveolar lavage fluid and lung inflammatory and cytokine responses.
Results: RSV-induced AHR was unaffected by the IL-13i, despite prevention of goblet cell hyperplasia. Similar results were seen in IL-13-deficient mice. In sensitized and challenged mice, RSV infection significantly increased AHR, and after IL-13i treatment, AHR was significantly reduced, but to the levels seen in RSV-infected mice alone.
Conclusions: These results indicate that despite some similarities, the mechanisms leading to AHR induced by RSV are different from those that follow allergen sensitization and challenge. Because IL-13 inhibition is effective in preventing the increases in AHR and mucus production in sensitized and challenged mice infected with RSV, IL-13i could play an important role in preventing the consequences of viral infection in patients with allergic asthma.

DOI： 10.1016/j.jaci.2003.08.046

Surfactant protein D regulates airway function and allergic inflammation through modulation of macrophage function 査読

K Takeda, N Miyahara, YH Rha, C Taube, ES Yang, A Joetham, T Kodama, AM Balhorn, A Dakhama, C Duez, AJ Evans, DR Voelker, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 168 ( 7 ) 783 - 789 2003年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

The lung collectin surfactant protein D (SP-D) is an important component of the innate immune response but is also believed to play a role in other regulatory aspects of immune and inflammatory responses within the lung. The role of SP-D in the development of allergen-induced airway inflammation and hyperresponsiveness (AHR) is not well defined. SP-D levels progressively increased up to 48 hours after allergen challenge of sensitized mice and then subsequently decreased. The levels of SP-D paralleled the development of airway eosinophilia and AHR. To determine if this association was functionally relevant, mice were administered rat SP-D (rSP-D) intratracheally. When given to sensitized mice before challenge, AHR and eosinophilia were reduced by rSP-D in a dose-dependent manner but not by mutant rSP-D. rSP-D administration resulted in increased levels of interleukin (IL)-10, IL-12, and IFN-gamma in bronchoalveolar lavage fluid and reduced goblet cell hyperplasia. Culture of alveolar macrophages together with SP-D and allergen resulted in increased production of IL-10, IL-12, and IFN-gamma. These results indicate that SP-D can (negatively) regulate the development of AHR and airway inflammation after airway challenge of sensitized mice, at least in part, by modulating the function of alveolar macrophages.

DOI： 10.1164/rccm.200304-548OC

Pneumonitis induced by rifampicin 査読国際誌

N Kunichika, N Miyahara, K Kotani, H Takeyama, M Harada, M Tanimoto

THORAX 57 ( 11 ) 1000 - 1001 2002年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BRITISH MED JOURNAL PUBL GROUP

An 81 year old man was admitted to hospital with pulmonary Mycobocterium tuberculosis infection and was treated with rifampicin (UP), isoniazid (INH), and ethambutol (EB). On day 9 he developed fever and dyspnoea. Chest radiographs showed new infiltration shadows in the right lung. Bronchoalveolar lavage (BAL) was performed and increased numbers of lymphocytes were recovered. Drug induced pneumonitis was suspected so the antituberculous regimen was discontinued and methylprednisolone was administered. The symptoms and infiltration shadows improved. INH and EB were reintroduced without any recurrence of the abnormal shadows. T cell subsets in the BAL fluid and a positive lymphocyte stimulation test for RFP suggest that RFP induced pneumonitis may be related to a complex immunological response.

Respiratory variation in superior vena cava flow in patients with chronic obstructive pulmonary disease: Estimation of pulmonary hypertension using Doppler flow index 査読国際誌

N Kunichika, N Miyahara, M Harada, M Tanimoto

JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY 15 ( 10 ) 1165 - 1169 2002年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY, INC

Patients with chronic obstructive pulmonary disease (COPD) are difficult to assess by conventional transthoracic echocardiography (TTE) because of emphysematous lungs or mediastinal deviation. We hypothesized that superior vena cava (SVC) flow is related to pulmonary circulation and may be useful for the detection of pulmonary hypertension (PH) in patients with COPD that cannot been assessed by direct evaluation using the tricuspid regurgitant Doppler velocity. SVC Doppler flow velocities were examined in 46 patients with COPD and the pressure gradient between the right ventricular and right atrial. pressure (RV-RADeltaP) was calculated by tricuspid regurgitant Doppler velocities. The patients were divided into 2 groups: 11 patients with PH (RV-RADeltaP > 25 min Hg) were compared with 35 without PH. There was no significant difference in the maximal SVC peak systolic forward flow velocity during inspiration (INS) between these 2 groups. However, the minimal SVC peak systolic forward flow velocity during expiration (EXP) in the group with PH was significantly higher than that in the group without PH (37.4 +/- 20.0 cm/s vs 26.4 +/- 8.5 cm/s, P = .01). Linear regression analysis revealed a significant correlation between RV-RADeltaP and the EXP/INS ratio (r = 0.61, P < .001). in COPD patients with PH, the increased expiratory SVC systolic flow supplemented the preload for the impaired right ventricular filling flow caused by PH, thereby maintaining the transtricuspid driving pressure. Our observation suggests that respiratory variation in SVC systolic forward flow may be a sensitive Doppler flow index for evaluating severity of PH in patients with COPD that cannot been assessed by conventional TTE.

DOI： 10.1067/mje.2002.122355

[Case of pulmonary Langerhans-cell histiocytosis]. 査読

Sakugawa M, Tanimoto Y, Miyahara N, Kanehiro A, Kataoka M, Tanimoto M, Date H, Shimizu N, Yamadori I, Shibayama T

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 91 ( 9 ) 2765 - 2767 2002年9月

記述言語：日本語出版者・発行元：The Japanese Society of Internal Medicine

症例は19歳,男性. 17歳時より1日20本の喫煙歴あり.検診にて胸部異常陰影を指摘され,胸部CTでは両側上肺野に多発性嚢胞性病変を認めた.気管支肺胞洗浄液(BALF)の塗抹標本にてCDla陽性細胞およびS-100陽性細胞の増加を認め,胸腔鏡下肺生検により肺Langerhans細胞性組織球症(肺LCH)の診断が得られた.肺LCHは喫煙の関与が指摘されている稀な疾患であり,文献的考察を加えて報告する.

DOI： 10.2169/naika.91.2765

その他リンク： https://jlc.jst.go.jp/DN/JALC/00159941087?from=CiNii

[Orchiectomy for tuberculous epididymitis: a report of two cases with intractable to antituberculosis treatment].

N Kunichika, K Murakami, K Makihata, K Takao, K Chikamori, K Aoe, N Miyahara, T Maeda, R Eda, H Takeyama

Kekkaku : [Tuberculosis] 76 ( 10 ) 673 - 6 2001年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）

This paper describes two cases with tuberculous epididymitis. The first case was a 69-year-old man who was admitted to our hospital because of ulceration or right scrotum. Physical examination revealed a hard, rounded, a little bigger than egg-sized mass in the right scrotum. The second case was a 40-year-old man who was admitted to our hospital because of cough, fever and body weight loss. He was treated for pulmonary tuberculosis with isoniazid, rifampicin, streptomycin and pyrazinamide. Six months after admission, he complained of a painless swelling of the right scrotum. Physical examination revealed a hard, rounded, more than egg-sized mass in the right scrotum. Right orchiectomy was performed in these two cases, and they were cured.

Pulmonary lymphoma of large B-cell type mimicking Wegener's granulomatosis 査読

N Miyahara, R Eda, Y Umemori, T Murakami, N Kunichika, K Makihata, K Aoe, K Murakami, H Takeyama, M Harada

INTERNAL MEDICINE 40 ( 8 ) 786 - 790 2001年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

A 27-year-old man with a primary pulmonary lymphoma of large B-cell type is described. Symptoms involved both the upper and lower respiratory tract. A chest roentgenogram showed a dense mass with cavitation. Transbronchial biopsy specimens revealed no atypical cells, rather they demonstrated granulomatous infiltration and vasculitis consistent with but not conclusively diagnostic of Wegener's granulomatosis. The pulmonary mass became smaller after sulfamethoxazole-trimethoprim therapy. These features suggested Wegener's granulomatosis. However, an open biopsy specimen was diagnostic for diffuse lymphoma of large B-cell type. High-grade pulmonary lymphoma should be considered in the differential diagnosis of patients with clinical and pathologic features suggesting Wegener's granulomatosis.

Compound heterozygosity for alpha-1-antitrypsin (S(iiyama) and QO(clayton)) in an Oriental patient.

N Miyahara, K Seyama, T Sato, Y Fukuchi, R Eda, H Takeyama, M Harada

Internal medicine (Tokyo, Japan) 40 ( 4 ) 336 - 40 2001年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Alpha-1-antitrypsin (alpha1AT) deficiency is extremely rare among Orientals. We treated a 37-year-old man with severe pulmonary emphysema associated with a low serum concentration of alpha1AT. Mutation analysis of the alpha1AT gene was performed using a reverse transcription-polymerase chain reaction followed by sequencing. The patient proved to be a compound heterozygote carrying a S(iiyama) deficient allele and a QO(clayton) null allele. This is the first Japanese case of alpha1AT deficiency to arise from such compound heterozygosity in a family with no apparent consanguineous marriage, suggesting that the gene frequency for deficient alleles might be somewhat higher than previously estimated.

Effects of short-term pulmonary rehabilitation on exercise capacity and quality of life in patients with chronic obstructive pulmonary disease.

N Miyahara, R Eda, H Takeyama, N Kunichika, M Moriyama, K Aoe, H Kohara, K Chikamori, T Maeda, M Harada

Acta medica Okayama 54 ( 4 ) 179 - 84 2000年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although the rehabilitation of patients with chronic obstructive pulmonary disease (COPD) improves both exercise capacity and quality of life, a standard protocol for COPD patients has not been established. To clarify whether physiologic and quality-of-life improvements can be achieved by an inpatient pulmonary rehabilitation program 5 days per week for 3 weeks, 18 patients with COPD were enrolled in a rehabilitation program. The physical exercise training regimen consisted of respiratory muscle stretch gymnastics and cycle ergometer exercise training. Pulmonary function tests, an incremental ergometer exercise test, a 6-min walking test, and a quality of life assessment by the Chronic Respiratory Questionnaire were administered before and after the program. The peak VO2, an indicator of maximal exercise capacity, did not increase, although the 6-min walking distance, an indicator of functional exercise capacity, increased significantly after rehabilitation. There was a significant improvement in the quality of life in terms of dyspnea, fatigue, and emotional state. These findings suggest that even a 3-week program may be beneficial for COPD patients. Increases in functional exercise capacity, even without an increase in maximal exercise capacity, are helpful for reducing dyspnea and improving quality of life parameters in patients with COPD.

Cardiorespiratory responses during cycle ergometer exercise with different ramp slope increments in patients with chronic obstructive pulmonary disease.

N Miyahara, R Eda, H Takeyama, T Maeda, K Aoe, N Kunichika, H Kohara, M Harada

Internal medicine (Tokyo, Japan) 39 ( 1 ) 15 - 9 2000年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: The ramp exercise test has been widely used to evaluate cardiopulmonary responses to an incremental exercise load. This study was performed to clarify whether different slopes of the ramp exercise test influence exercise tolerance, exercise limiting factors, and respiratory pattern in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: We applied three different slopes (5 W/min, 10 W/min and 20 W/min) of the ramp exercise test in 9 patients with COPD and evaluated cardiopulmonary responses. RESULTS: There were no significant differences in peak oxygen uptake, anaerobic threshold (AT), minute ventilation, heart rate, arterial oxygen saturation, expired tidal volume, or respiratory rate at the maximal load among the three different ramp exercises tested. AT could be determined in six of nine patients (67%) at the slope of 5 W/min, in 8/9 (89%) at the slope of 10 W/min, and in 9/9 (100%) at the slope of 20 W/min. CONCLUSION: The findings suggest that the ramp slope does not affect exercise tolerance, exercise limiting factors, or respiratory patterns and each of these ramp slopes is useful for the evaluation of COPD. Ramp slopes of 10 W/ min or 20 W/min should be appropriate for the determination of AT.

1. 高齢者誤嚥性肺炎によるARDSの1例(一般演題)(第8回日本気管支学会中国四国支部会)

巻幡清, 江田良輔, 宮原信明, 森山道彦, 日山篤人, 村上一生, 近森研一, 小原弘之, 国近尚美, 青江啓介, 前田忠士, 竹山博泰, 内田亨, 遠藤定紀

気管支学 22 ( 4 ) 306 - 306 2000年

16. Rifampicinによる薬剤性肺炎の1例(一般演題)(第8回日本気管支学会中国四国支部会)

國近尚美, 宮原信明, 江田良輔, 森山道彦, 巻幡清, 近森研一, 小原弘之, 青江啓介, 前田忠士, 竹山博泰

気管支学 22 ( 4 ) 308 - 308 2000年

Bronchial atresia with transient spontaneous disappearance of a mucocele.

N Miyahara, R Eda, S Makihara, T Maeda, K Aoe, N Kunichika, H Kohara, H Takeyama, M Harada

Internal medicine (Tokyo, Japan) 38 ( 12 ) 974 - 8 1999年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

We report the transient spontaneous disappearance of a mucocele due to bronchial atresia. Two years before presentation, a chest radiograph showed a hyperlucent right upper lung and a mucocele near the right hilum. A chest radiograph taken 1 year later showed that the mucocele had disappeared leaving an ovoid outline of a dilated bronchus. A chest radiograph obtained 3 months before presentation showed that the mucocele was present again. Atresia of the B3b bronchus of the right upper lobe was noted on thoracotomy. The "disappearance" of the mucocele probably was due to the clearance of mucoid material through collateral airways.

39. Isoniazid によると考えられた薬剤性間質性肺炎の 1 例(第 7 回日本気管支学会中国四国支部会)

石川優子, 宮原信明, 江田良輔, 國近尚美, 青江啓介, 森山道彦, 近森研一, 前田忠士, 河村武郎, 竹山博泰

気管支学 21 ( 2 ) 128 - 128 1999年

36. 喫煙開始 2 週間後に発症した急性好酸球性肺炎の 1 例(第 7 回日本気管支学会中国四国支部会)

江田良輔, 宮原信明, 国近尚美, 森山道彦, 石川優子, 河村武郎, 青江啓介, 小原弘之, 近森研一, 前田忠士, 石田浩一, 竹山博泰

気管支学 21 ( 2 ) 127 - 127 1999年

3. 肺癌検診にて発見された肺動脈原発と考えられた肺平滑筋肉腫の 1 例(第 5 回日本気管支学会中国・四国支部会)

前田忠士, 竹山博泰, 江田良輔, 宮原信明, 正吉豊久, 森本尚美, 北村賢一, 牧原重喜

気管支学 19 ( 3 ) 261 - 261 1997年

418 慢性喘息患者の長期管理におけるピークフロー (PEF) モニタリングの有用性と限界に関する検討

江田良輔, 宮原信明, 竹山博泰

アレルギー 46 ( 8 ) 921 - 921 1997年

333 気管支喘息患者における末梢血単核球(PBMC)のサイトカイン産生能の検討

堀場昌英, 藤井誠, 武田明子, 玉置明彦, 鳥越弘幸, 宮原信明, 木村五郎, 金廣有彦, 片岡幹男, 多田慎也, 原田実根, 高橋清

アレルギー 44 ( 8 ) 982 - 982 1995年

241 蚊アレルギーの1例

金廣有彦, 堀場昌英, 洲脇俊充, 宮原信明, 石川泰浩, 木村和陽, 木村五郎, 多田慎也, 木村郁郎, 宗田良, 高橋清

アレルギー 43 ( 2 ) 379 - 379 1994年

60 難治性喘息におけるCiclosporinの作用機序についての検討

岡野智治, 石川泰浩, 宮原信明, 後藤基子, 河田典子, 木村五郎, 金廣有彦, 多田慎也, 木村郁郎, 宗田良, 高橋清

アレルギー 43 ( 2 ) 333 - 333 1994年

4 気管支喘息病態におけるCandida albicansの関与 : 気道局在との関連について

玉置明彦, 鳥越弘幸, 宮原信明, 木村和陽, 木村五郎, 金廣有彦, 多田慎也, 原田実根, 木村郁郎, 岡田千春, 宗田良, 高橋清

アレルギー 43 ( 8 ) 957 - 957 1994年

80 ステロイド依存性難治性喘息におけるリンパ球機能に及ぼすステロイド剤の影響

古藤直紀, 石川泰浩, 宮原信明, 木村和陽, 金廣有彦, 多田慎也, 木村郁郎, 宗田良, 高橋清

アレルギー 42 ( 3 ) 428 - 428 1993年

6 喘息病態に基づく新病型分類法の試み : HD・miteとCandida抗原によるIgE及びリンパ球の反応性を中心に

木村和陽, 宮原信明, 谷本安, 猪木篤弘, 木村五郎, 磯嶋浩二, 難波一弘, 宗田良, 多田慎也, 高橋清, 木村郁郎

アレルギー 41 ( 8 ) 1065 - 1065 1992年

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