Updated on 2025/06/30

写真a

 
TSUGE Mitsuru
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Special-Appointment Associate Professor
Position
Special-Appointment Associate Professor
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Research Interests

  • influenza associated encephalopathy

  • endothelial cell

  • Innate immunity

  • food allergy

  • anaphylaxis

  • influenza pneumonia

  • acute encephalopathy

  • COVID-19

  • 気管支喘息

  • アトピー性皮膚炎

  • 突発性発疹症

Research Areas

  • Life Science / Embryonic medicine and pediatrics

Professional Memberships

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Committee Memberships

  • 岡山県アレルギー疾患医療連絡協議会   委員  

    2023   

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  • 日本小児アレルギー学会   理事  

    2021.6   

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    Committee type:Academic society

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  • 日本アレルギー学会   代議員  

    2021.6   

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    Committee type:Academic society

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Papers

  • Association Between Initial Symptoms and Clinical Outcomes in COVID-19. International journal

    Eiki Ichihara, Toshiharu Mitsuhashi, Mitsuru Tsuge, Kou Hasegawa, Kenichiro Kudo, Yasushi Tanimoto, Kazuhiro Nouso, Naohiro Oda, Sho Mitsumune, Goro Kimura, Haruto Yamada, Ichiro Takata, Hideharu Hagiya, Akihiko Taniguchi, Kohei Tsukahara, Toshiyuki Aokage, Shinichi Toyooka, Hirokazu Tsukahara, Yoshinobu Maeda

    Cureus   17 ( 5 )   e84919   2025.5

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    Language:English   Publishing type:Research paper (scientific journal)  

    BACKGROUND: The clinical presentation of coronavirus disease 2019 (COVID-19) ranges from localized respiratory symptoms such as cough and sore throat to systemic symptoms such as fever and fatigue. To our knowledge, no study has assessed severe disease risk by dividing onset symptoms into localized respiratory and other symptoms. We aimed to determine whether the risk of severe COVID-19 differs depending on whether the symptoms at onset are limited to local respiratory symptoms. METHOD: This was a multicenter prospective cohort study. The patients were classified into localized respiratory or systemic symptom groups based on the symptoms at onset. Demographic data, blood biomarkers, and clinical outcomes, including mortality, intubation, admission to the intensive care unit, and time to discharge, were compared. This study included 100 adult patients diagnosed with COVID-19 between July 2020 and August 2021. RESULT: Twelve patients were classified into the localized respiratory symptom group and the remaining 88 into the systemic symptom group. No significant differences between the groups were observed in the baseline characteristics, blood biomarkers, or clinical outcomes. The mortality rates were 0.0% and 4.6%, respectively. The median durations to discharge were 11 and 10 days, respectively (p=0.512). The levels of inflammatory and oxidative stress biomarkers, including interleukin-6 and hydroperoxides, were similar between the groups. CONCLUSION: The symptom type at disease onset was not significantly associated with differences in clinical outcomes. Comprehensive assessments beyond initial symptoms are crucial for predicting disease progression and optimizing management strategies.

    DOI: 10.7759/cureus.84919

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  • A randomized controlled trial of conventional GVHD prophylaxis with or without teprenone for the prevention of severe acute GVHD. Reviewed International journal

    Wataru Kitamura, Keiko Fujii, Mitsuru Tsuge, Toshiharu Mitsuhashi, Hiroki Kobayashi, Chihiro Kamoi, Akira Yamamoto, Takumi Kondo, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Ken-Ichi Matsuoka, Nobuharu Fujii, Yoshinobu Maeda

    Annals of hematology   104 ( 3 )   1917 - 1929   2025.2

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    Therapies that effectively suppress graft-versus-host disease (GVHD) without compromising graft-versus-leukemia/lymphoma (GVL) effects is important in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematopoietic malignancies. Geranylgeranylacetone (GGA) is a main component of teprenone, a gastric mucosal protectant commonly used in clinical practice. In preclinical models, GGA suppresses proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), which are associated with GVHD as well as induces thioredoxin-1 (Trx-1), which suppresses GVHD while maintaining GVL effects. Here, we investigated whether the addition of teprenone to standard GVHD prophylaxis could reduce the cumulative incidence of severe acute GVHD (aGVHD) without attenuating GVL effects. This open-label, randomized clinical trial enrolled 40 patients (21 control and 19 teprenone group) who received allo-HSCT between May 2022 and February 2023 in our institution. Patients in the teprenone group received 50 mg of teprenone orally thrice daily for 21 days from the initiation of the conditioning regimen. The cumulative incidence of severe aGVHD by day 100 after allo-HSCT was not significantly different in the two groups (27.9 vs. 16.1%, p = 0.25). The exploratory studies revealed no obvious changes in Trx-1 levels, but the alternations from baseline in IL-1β and TNF-α levels at day 28 after allo-HSCT tended to be lower in the teprenone group. In conclusion, we could not demonstrate that teprenone significantly prevented the development of severe aGVHD. Discrepancy with preclinical model suggests that appropriate dose of teprenone may be necessary to induce the expression of antioxidant enzymes that suppress severe aGVHD. Clinical Trial Registration number:jRCTs 061210072.

    DOI: 10.1007/s00277-025-06269-2

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  • Impact of Birth Order on Paediatric Allergic Diseases: A National Birth Cohort in Japan. Reviewed International journal

    Mitsuro Kobayashi, Masanori Ikeda, Naomi Matsumoto, Mitsuru Tsuge, Masato Yashiro, Takashi Yorifuji, Hirokazu Tsukahara

    Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology   55 ( 6 )   508 - 510   2025.1

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    DOI: 10.1111/cea.14626

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  • Maternal smoking during infancy increases the risk of allergic diseases in children: a nationwide longitudinal survey in Japan. Reviewed International journal

    Kenji Shigehara, Naomi Matsumoto, Mitsuru Tsuge, Kazuhiro Uda, Yukie Saito, Masato Yashiro, Takashi Yorifuji, Masanori Ikeda, Hirokazu Tsukahara

    Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology   21 ( 1 )   4 - 4   2025.1

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    BACKGROUND: The incidence of allergic diseases has been increasing in Japan. In particular, a serious decline in the age of onset of allergic rhinitis has been observed. Passive smoking from parental smoking has a significant impact on children's health; however, it is difficult to restrict smoking in the home. While various studies have previously reported on the relationship between passive smoking and the development of allergic diseases in children. However, there have been no reports on passive smoking and allergic diseases on a national scale. METHODS: Using Japanese national longitudinal survey data (n = 38,444) for newborns born between May 10 and 24, 2010, we assessed parental smoking habits when their children were 6 months old and investigated the association with the development of allergic diseases until the age of 5.5 years. The risk ratios and 95% confidence intervals for the development of different allergic diseases were analyzed after adjusting for potential confounders using Poisson regression with a robust error variance. RESULTS: The risk ratio for developing allergic rhinitis/allergic conjunctivitis (AR/AC) in children was significantly higher in the maternal smoking groups ( ≦ 10 cigarettes/day; RR 1.15, 95% CI 1.02-1.30; ≧11 cigarettes/day; RR 1.16, 95% CI 0.93-1.44). Furthermore, associations were found between the maternal smoking group in the presence of paternal smoking and the risk of developing bronchial asthma ( ≦ 10, RR 1.33 95% CI 1.17-1.52; ≧11, RR 1.71 95% CI 1.38-2.1), food allergy ( ≦ 10, RR 1.36 95% CI 1.12-1.63; ≧11, RR 1.25 95% CI 0.84-1.86), atopic dermatitis ( ≦ 10, RR 1.42 95% CI 1.22-1.66; ≧11, RR 1.6 95% CI 1.2-2.13), and AR/AC ( ≦ 10, RR 1.21 95% CI 1.07-1.36; ≧11, RR 1.35 95% CI 1.09-1.67). CONCLUSIONS: Maternal smoking during infancy increases the risk of developing AR/AC in children. Considering paternal smoking, maternal smoking further increased the risk of developing allergic diseases in children, suggesting that reducing parental smoking at home may reduce the risk of developing allergic diseases in children.

    DOI: 10.1186/s13223-025-00952-9

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  • Changes in body mass index during early childhood on school-age asthma prevalence classified by phenotypes and sex. International journal

    Toshihiko Yabuuchi, Masanori Ikeda, Naomi Matsumoto, Mitsuru Tsuge, Takashi Yorifuji, Hirokazu Tsukahara

    Pediatrics international : official journal of the Japan Pediatric Society   67 ( 1 )   e70090   2025

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    BACKGROUND: Few studies have explored the relationship between changes in body mass index(BMI) during early childhood and asthma prevalence divided by phenotypes and sex, and the limited results are conflicting. This study assessed the impact of BMI changes during early childhood on school-age asthma, classified by phenotypes and sex, using a nationwide longitudinal survey in Japan. METHODS: From children born in 2001 (n = 47,015), we divided participants into BMI quartiles (Q1, Q2, Q3, and Q4) and the following BMI categories: Q1Q1 (i.e., Q1 at birth and Q1 at age 7), Q1Q4, Q4Q1, Q4Q4, and others. Asthma history from ages 7 to 8 was analyzed, with bronchial asthma (BA) further categorized as allergic asthma (AA) or nonallergic asthma (NA) based on the presence of other allergic diseases. Using logistic regression, we estimated the asthma odds ratio (OR) and 95% confidence intervals (CIs) for each BMI category. RESULTS: Q1Q4 showed significantly higher risks of BA, AA, and NA. In boys, BA and NA risks were significantly higher in Q1Q4 (adjusted OR: 1.47 [95% CI: 1.17-1.85], at 1.56 [95% CI: 1.16-2.1]), with no significant difference in AA risk. In girls, no increased asthma risk was observed in Q1Q4, but AA risk was significantly higher in Q4Q4 (adjusted OR: 1.78 [95% CI: 1.21-2.6]). CONCLUSION: Our results demonstrated that BMI changes during early childhood impact asthma risks, particularly that the risk of NA in boys increases with BMI changes during early childhood, and the risk of AA in girls increases with consistently high BMI.

    DOI: 10.1111/ped.70090

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MISC

  • 突発性発疹関連脳症における免疫応答に関連した宿主遺伝子発現解析

    津下 充, 濃野 優, 宇田 和宏, 茂原 研司, 塚原 宏一

    日本小児感染症学会総会・学術集会プログラム・抄録集   56回   211 - 211   2024.11

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    Language:Japanese   Publisher:(一社)日本小児感染症学会  

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  • 重症急性移植片対宿主病の発症抑制を目的としたテプレノン併用免疫抑制療法の開発

    藤井 敬子, 北村 亘, 津下 充, 三橋 利晴, 鴨井 千尋, 松原 岳大, 寺尾 俊紀, 林野 健太, 近藤 歌穂, 藤原 加奈子, 植田 裕子, 松原 千哲, 松村 彰文, 山本 晃, 小林 宏紀, 近藤 匠, 清家 圭介, 藤原 英晃, 淺田 騰, 遠西 大輔, 西森 久和, 松岡 賢市, 藤井 伸治, 前田 嘉信

    日本血液学会学術集会   86回   O2 - 6   2024.10

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    Language:English   Publisher:(一社)日本血液学会  

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  • ウパダシチニブによる皮膚炎寛解後に効果減弱を認めたアトピー性皮膚炎の一例

    津下 充, 濃野 優, 茂原 研司, 宇田 和宏, 塚原 宏一

    日本小児アレルギー学会誌   38 ( 4 )   402 - 402   2024.9

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  • 後頭部可逆性白質脳症を合併した肢端紅痛症の1例

    武川 真也, 鈴木 健吾, 宇田 和宏, 茂原 研司, 荒川 恭佑, 齋藤 有希惠, 宮原 宏幸, 長谷川 高誠, 小原 隆史, 塚原 紘平, 八代 将登, 津下 充, 塚原 宏一

    日本小児科学会雑誌   128 ( 7 )   1004 - 1005   2024.7

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    Language:Japanese   Publisher:(公社)日本小児科学会  

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  • 肥満症に対する効果的な治療戦略と健康障害の改善に資する減量数値目標を見出すための介入研究(SLIM-TARGET)耐糖能障害

    越坂 理也, 横尾 英孝, 長島 健悟, 佐藤 泰憲, 前田 祐香里, 武田 健治, 石川 耕, 小野 啓, 齋木 厚人, 龍野 一郎, 津下 一代, 高原 充佳, 下村 伊一郎, 笹子 敬洋, 門脇 孝, 横手 幸太郎

    糖尿病   67 ( Suppl.1 )   S - 215   2024.4

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    Language:Japanese   Publisher:(一社)日本糖尿病学会  

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Research Projects

  • IL-1受容体・トール様受容体シグナルを制御するインフルエンザ脳症の新規治療探索

    Grant number:22K07935  2022.04 - 2025.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    津下 充

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

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  • Elucidation of pathogenesis and preventive measures for complications in pediatric COVID-19

    Grant number:22K07820  2022.04 - 2025.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    塚原 宏一, 津下 充

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    Grant amount:\3900000 ( Direct expense: \3000000 、 Indirect expense:\900000 )

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  • Search for new treatments for influenza associated encephalopathy targeting innate immune mediators

    Grant number:19K08278  2019.04 - 2022.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    TSUGE MITSURU

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    We investigated whether high mobility group box-1 (HMGB-1) monoclonal antibody could suppress the increase in vascular permeability of human primary cerebral vascular endothelial cells by tumor necrosis factor (TNF-α). After TNF-α stimulation, vascular permeability was significantly enhanced, and cell spindle-like deformation, increased intercellular space, increased F-actin formation, and decreased amount of VE-cadherin protein, which is a tight junction molecule, were observed. In the presence of anti-HMGB-1 antibody, vascular hyperpermeability was significantly suppressed, and the increase in intercellular space and the decrease in VE-cadherin protein were significantly suppressed. The concentrations of IL-6 and IP-10, which are inflammatory cytokines in the supernatant, increased by TNF-α stimulation were significantly suppressed in the presence of anti-HMGB-1 antibody.

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  • Study of the therapeutic agent for the treatment of highly pathogenic influenza

    Grant number:25670465  2013.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    MORISHIMA Tsuneo, FUJI Yousuke, TSUGE Mitsuru

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    Grant amount:\3770000 ( Direct expense: \2900000 、 Indirect expense:\870000 )

    The discovery of a novel anti-influenza therapeutic approach would increase the effectiveness of traditional virus-based strategies. This study was undertaken to evaluate the therapeutic effects of anti-high mobility group box-1 (HMGB1) monoclonal antibody (mAb) treatment for influenza A virus (H1N1)-induced pneumonia in mice.Anti-HMGB1 mAb significantly improved the survival rate of H1N1-inoculated mice. The treatment also significantly attenuated histological changes and neutrophil infiltration in the lung of H1N1-inoculated mice; which was associated with inhibition of HMGB1 and suppression of inflammatory cytokine/chemokine expression and oxidative stress enhancement, which were observed in H1N1-inoculated mice. Anti-HMGB1 mAb may provide a novel and effective pharmacological strategy for severe influenza virus infection in humans by reducing the inflammatory responses induced by HMGB1.

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  • 痙攣重積型インフルエンザ脳症の病態解析と新規治療薬の検索

    Grant number:24791066  2012

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    津下 充

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    Grant amount:\3900000 ( Direct expense: \3000000 、 Indirect expense:\900000 )

    痙攣重積型インフルエンザ脳症のモデルマウスとして腹腔内にカイニン酸(10mg/kg)を投与し投与1,4,7日目の脳組織中のサイトカイン(IL-6、TNF-α)・一酸化窒素(NO)を測定した。投与1-2時間で全てのマウスで痙攣重積を認めた。投与1日目にIL-6は脳組織で有意に増加していた。TNF-α・NOは増加しなかった。この結果は痙攣重積患者での髄液におけるIL-6上昇と矛盾しない結果であった。
    次にIL-6による神経細胞障害性を検討するため、ラット初代大脳皮質神経細胞に段階希釈したIL-6を添加し37℃で24時間培養後、細胞生存率をXTT assayで測定した。その結果、コントロール群と比較して有意に細胞生存率が低下した。
    また、インフルエンザ脳症で予後不良因子として知られる薬剤(ジクロフェナク)、痙攣重積型脳症との関連が指摘される薬剤(テオフィリン)も同様に検討した。その結果、ジクロフェナクでは有意に細胞生存率が低下した。
    また、テオフィリンとアセトアミノフェンでは、有意差はみられなかった。血液脳関門の破綻による中枢神経系のジクロフェナク濃度の上昇は神経細胞障害を助長する可能性が示唆された。アセトアミノフェンはインフルエンザにおける安全性の高い解熱剤として周知されており、今回の結果は矛盾しなかった。テオフィリンは神経細胞障害に直接関与しないと考えられた。
    ミクログリアは刺激により一酸化窒素(NO)・IL-6・TNF-αを産生し中枢神経系の炎症に関与する。まず、IL-6が初代ラットミクログリアにおけるNOの産生に関与するか検討した。ミクログリア細胞に段階希釈したIL-6を添加したがNOの産生は認めなかった。次に、ミクログリアに2型ヘルペスウイルスを感染させたところ、細胞上清中のTNF-α, IL-6, NOは有意に増加した。
    以上より痙攣重積によって脳内で増加したIL-6は神経細胞障害に関与するが、痙攣重積モデルマウスでは脳内でNOやTNF-αが増加せず、痙攣重積を示すヘルペス脳炎のサイトカインプロファイルとは一部異なる可能性が示唆された。

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Class subject in charge

  • Perinatal and Neonatal Medicine (2024academic year) special  - その他

  • Pediatrics and Development (2024academic year) special  - その他

  • Pediatrics and Child Neurology (Core Clinical Practice) (2024academic year) special  - その他

  • Elective Clinical Practice (Pediatrics) (2024academic year) special  - その他