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Pathologic elucidation of sepsis by suppressing NET formation: focus on tissue factor and autophagy

Research Project

Project/Area Number 17K11064
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Anesthesiology
Research InstitutionNagoya City University (2022)
Fujita Health University (2017-2021)

Principal Investigator

SHIMOMURA Yasuyo  名古屋市立大学, 医薬学総合研究院(医学), 准教授 (80534031)

Co-Investigator(Kenkyū-buntansha) 西田 修  藤田医科大学, 医学部, 教授 (20208185)
Project Period (FY) 2017-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords敗血症 / NETs / Autophagy / 多臓器不全 / DIC / 好中球細胞外トラップス / トロンボモジュリン / 敗血症性DIC / ヒストン / 敗血性ショック / オートファジー / 免疫学 / 感染症 / トランスレーショナルリサーチ / 細胞・組織
Outline of Final Research Achievements

Activity of Autophagy with neutrophils and pathologic improvement in approximately 80% of patients with ICU admission serious case were observed, and it was predicted that activation of Autophagy could be expected to improve the condition.
We used the LPS-induced murine septic shock model, rTM was administered after the LPS injection (rTM group) so that there was not estrangement with the clinical practice.The survival rate 72 hours after the LPS administration was improved from 50% to 100% in rTM group. In the rTM group, blood cytokine levels did not increase and NETs formation was reduced in various organs.These results suggest that rTM improved survival in LPS-induced sepsis model mice due to cytokine storm suppression and inhibition of NETs formation in various organs.Those data supported of publication (13 of international journals and 2 of Japanese journal), and the meeting presentation of 22 times (including 4 times of international societies).

Academic Significance and Societal Importance of the Research Achievements

敗血症は感染を要因に臓器障害が起こり、呼吸や循環に異常をきたして、死に至る場合もあるため、集中治療室(ICU)での全身管理と治療が必要になる。通常は感染で生命の危機にさらされることはなく、敗血症の重症化には過剰な免疫反応が原因と言われいるが、その機序や治療法はまだ未知なことが多い。本研究では、敗血症DICの治療薬で抗凝固作用を有するトロンボモジュリンに、敗血症時の過剰な免疫反応の一つであるサイトカインの異常産生やNETs形成の抑制効果があることを示した。敗血症における免疫機序の一端を本研究で解明できたことは、治療法の今後の発展につながることが期待され、学術的・社会的意義があると考える。

Report

(7 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (37 results)

All 2023 2022 2021 2020 2019 2018 2017

All Journal Article (15 results) (of which Peer Reviewed: 14 results,  Open Access: 13 results) Presentation (22 results) (of which Int'l Joint Research: 4 results,  Invited: 11 results)

  • [Journal Article] Association of circulating histone H3 and high mobility group box 1 levels with postoperative prognostic indicators in intensive care unit patients: a single-center observational study2023

    • Author(s)
      Sawada K, Shimomura Y, Hasegawa D, Harada T, Nakamura T, Kuriyama N, Hara H, Komura H, Nishida O.
    • Journal Title

      Fujita Medical Journal

      Volume: 9 Issue: 2 Pages: 95-100

    • DOI

      10.20407/fmj.2022-008

    • ISSN
      2189-7247, 2189-7255
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of recombinant human soluble thrombomodulin on neutrophil extracellular traps in the kidney of a mouse model of endotoxin shock2023

    • Author(s)
      Harada T, Shimomura Y, Nishida O, Maeda M, Kato Y, Nakamura T, Kuriyama N, Komura H.
    • Journal Title

      Fujita Medical Journal

      Volume: 9 Issue: 3 Pages: 225-230

    • DOI

      10.20407/fmj.2022-026

    • ISSN
      2189-7247, 2189-7255
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of Thrombomodulin in Reducing Lethality and Suppressing Neutrophil Extracellular Trap Formation in the Lungs and Liver in a Lipopolysaccharide-Induced Murine Septic Shock Model2021

    • Author(s)
      Kato Yu、Nishida Osamu、Kuriyama Naohide、Nakamura Tomoyuki、Kawaji Takahiro、Onouchi Takanori、Hasegawa Daisuke、Shimomura Yasuyo
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 9 Pages: 4933-4933

    • DOI

      10.3390/ijms22094933

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of Blood Type O on Mortality of Sepsis Patients: A Multicenter Retrospective Observational Study2020

    • Author(s)
      Hasegawa Daisuke、Nishida Kazuki、Kawaji Takahiro、Hara Yoshitaka、Shimomura Yasuyo、Moriyama Kazuhiro、Niimi Daisuke、Kuriyama Naohide、Shintani Ayumi、Komura Hidefumi、Nishida Osamu
    • Journal Title

      Diagnostics

      Volume: 10 Issue: 10 Pages: 826-826

    • DOI

      10.3390/diagnostics10100826

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nafamostat mesilate inhibits linezolid metabolism via its antioxidant effects2020

    • Author(s)
      Kuriyama Naohide、Matsumoto Kana、Morita Kunihiko、Shimomura Yasuyo、Hara Yoshitaka、Hasegawa Daisuke、Nakamura Tomoyuki、Yamashita Chizuru、Kato Yu、Komura Hidefumi、Nishida Osamu
    • Journal Title

      Therapeutic Apheresis and Dialysis

      Volume: 24 Issue: 5 Pages: 499-502

    • DOI

      10.1111/1744-9987.13545

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of ionic interactions in cytokine adsorption of polyethyleneimine-coated polyacrylonitrile and polymethyl methacrylate membranes in vitro2020

    • Author(s)
      Moriyama Kazuhiro、Kato Yu、Hasegawa Daisuke、Kurimoto Yasuyoshi、Kawaji Takahiro、Nakamura Tomoyuki、Kuriyama Naohide、Shimomura Yasuyo、Nishida Osamu
    • Journal Title

      Journal of Artificial Organs

      Volume: 23 Issue: 3 Pages: 240-246

    • DOI

      10.1007/s10047-020-01173-0

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adsorption kinetics of high mobility group box 1 protein in a polyacrylonitrile hemofiltration membrane2020

    • Author(s)
      Nakamura Tomoyuki、Moriyama Kazuhiro、Shimomura Yasuyo、Kato Yu、Kuriyama Naohide、Hara Yoshitaka、Yamada Shingo、Nishida Osamu
    • Journal Title

      Therapeutic Apheresis and Dialysis

      Volume: 0 Issue: 1 Pages: 1-7

    • DOI

      10.1111/1744-9987.13489

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 敗血症における血中マイクロRNAの経時的変化2020

    • Author(s)
      栗山直英、川治崇泰、長谷川大祐、加藤由布、下村泰代、森山和広、西田修
    • Journal Title

      藤田学園医会誌

      Volume: 44 Pages: 41-44

    • NAID

      120006954408

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Suppressive effects of the neutrophil elastase inhibitor sivelestat sodium hydrate on interleukin-1β production in lipopolysaccharide-stimulated porcine whole blood2020

    • Author(s)
      Yasuyoshi Kurimoto, Yasuyo Shimomura, Kazuhiro Moriyama, Tomoyuki Nakamura, Naohide Kuriyama, Yoshitaka Hara, Hidefumi Komura, Daisuke Hasegawa, Takahiro Kawaji, Osamu Nishida
    • Journal Title

      Fujita Medical Journal

      Volume: 6 Issue: 1 Pages: 12-16

    • DOI

      10.20407/fmj.2019-002

    • NAID

      130007794041

    • ISSN
      2189-7247, 2189-7255
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] In vitro Evaluation of Linezolid and Doripenem Clearance with Different Hemofilters2020

    • Author(s)
      Hiraiwa Toshihisa、Moriyama Kazuhiro、Matsumoto Kana、Shimomura Yasuyo、Kato Yu、Yamashita Chizuru、Hara Yoshitaka、Kawaji Takahiro、Kurimoto Yasuyoshi、Nakamura Tomoyuki、Kuriyama Naohide、Shibata Junpei、Komura Hidefumi、Morita Kunihiko、Nishida Osamu
    • Journal Title

      Blood Purification

      Volume: 3 Issue: 3 Pages: 295-301

    • DOI

      10.1159/000504039

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential effect of lactate in predicting mortality in septic patients with or without disseminated intravascular coagulation: a multicenter, retrospective, observational study2019

    • Author(s)
      Hasegawa Daisuke、Nishida Kazuki、Hara Yoshitaka、Kawaji Takahiro、Moriyama Kazuhiro、Shimomura Yasuyo、Niimi Daisuke、Komura Hidefumi、Nishida Osamu
    • Journal Title

      Journal of Intensive Care

      Volume: 7 Issue: 1 Pages: 1-6

    • DOI

      10.1186/s40560-019-0389-x

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Influence of Blood Purification and Differential Injection Sites of Cold Saline on Transpulmonary Thermodilution Values2018

    • Author(s)
      Kawaji Takahiro、Sakai Toshikazu、Moriyama Kazuhiro、Hara Yoshitaka、Nakamura Tomoyuki、Kuriyama Naohide、Shimomura Yasuyo、Kato Yu、Komura Hidefumi、Yamashita Chizuru、Kurimoto Yasuyoshi、Hasegawa Daisuke、Nishida Osamu
    • Journal Title

      Therapeutic Apheresis and Dialysis

      Volume: 22 Issue: 3 Pages: 290-294

    • DOI

      10.1111/1744-9987.12696

    • NAID

      120006798122

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] In Vitro Study of Endotoxin Adsorption by a Polymyxin B-Immobilized Fiber Column2018

    • Author(s)
      Yamashita Chizuru、Moriyama Kazuhiro、Hasegawa Daisuke、Kato Yu、Sakai Toshikazu、Kawaji Takahiro、Shimomura Yasuyo、Kurimoto Yasuyoshi、Nagata Mariko、Nishida Osamu
    • Journal Title

      Blood Purification

      Volume: 46 Issue: 4 Pages: 269-273

    • DOI

      10.1159/000489920

    • NAID

      120006798121

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evidence and Perspectives on the Use of Polymyxin B-Immobilized Fiber Column Hemoperfusion among Critically Ill Patients2018

    • Author(s)
      Yamashita Chizuru、Moriyama Kazuhiro、Hasegawa Daisuke、Hara Yoshitaka、Kuriyama Naohide、Nakamura Tomoyuki、Shibata Junpei、Komura Hidefumi、Nishida Osamu
    • Journal Title

      Contributions to Nephrology

      Volume: 196 Pages: 215-222

    • DOI

      10.1159/000485725

    • ISBN
      9783318062977, 9783318062984
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] NETs形成とトロンボモジュリン2017

    • Author(s)
      下村 泰代、西田 修
    • Journal Title

      Thrombosis Medicine

      Volume: 7 Pages: 191-195

    • Related Report
      2017 Research-status Report
    • Open Access
  • [Presentation] In vitro実験におけるアムホテリシンBリポソーム製剤の血液濾過膜への吸着評価2022

    • Author(s)
      平岩歳久、森山和広、松元加奈、中村智之、栗山直英、下村泰代、幸村英文、山下千鶴、山田成樹、西田修
    • Organizer
      第49回日本集中治療医学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 当施設ICUの術後患者におけるヒストンH3、HMGB1の血中濃度と重症度、予後との比較検討2021

    • Author(s)
      澤田健、長谷川大祐、藤原凌、鈴木紳也、下村泰代、西田修
    • Organizer
      日本麻酔科学会第68回学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 集中治療医学におけるImmunothrombosis(免疫血栓)とトロンボモジュリンの役割2021

    • Author(s)
      下村泰代
    • Organizer
      日本集中治療医学会第5回東海北陸支部学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 第48回日本集中治療医学会学術集会2021

    • Author(s)
      下村泰代
    • Organizer
      集中治療医学におけるImmunothrombosisとThrombomodulinの役割
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 集中治療医学におけるImmunothrombosisとThrombomodulinの役割2021

    • Author(s)
      下村 泰代
    • Organizer
      第48回日本集中治療医学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] ICUでの口腔ケアの研究と臨床実践2021

    • Author(s)
      村松恵多、松尾浩一郎、河合佑亮、矢田部智昭、池田真弓、原嘉孝、下村泰代、山下千鶴、幸村英文、西田修
    • Organizer
      第48回日本集中治療医学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Does the endotoxin adsorption of pmx column saturate in 2hours? -preliminary study2020

    • Author(s)
      Yamashita C, Moriyama K, Hasegawa D, Kawaji T, Kuriyama N, Nakamura T, Shimomura Y, Suzuki S, Kato Y, Nishida O.
    • Organizer
      40th International Symposium on Intensive Care and Emergency Medicine
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 敗血症性DICとNETs2020

    • Author(s)
      下村 泰代
    • Organizer
      第3回DICセミナー
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Nafamostat mesylate inhibition of LZD metabolism via its antioxidant effects2019

    • Author(s)
      Naohide Kuriyama, Osamu Nishida, Yasuyo Shimomura, Yu Kato.
    • Organizer
      The 40th Annual Meeting of Japanese Society for Apheresis,
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] The Impact of Blood Type O on Mortality of Septic Patients: A Retrospective Observational Study2019

    • Author(s)
      Daisuke Hasegawa, Naohide Kuriyama, Yoshitaka Hara, Yasuyo Shimomura, Tomoyuki Nakamura,Junpei Shibata, Kazuhiro Moriyama, Hidefumi Komura, Osamu Nishida.
    • Organizer
      Society of Critical Care Medicine 48th Critical Care Congress
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effects of Recombinant Human Thrombomodulin on NET Formation in Organs of Septic Mice2019

    • Author(s)
      Yu Kato, Yasuyo Shimomura, Takanori Onouchi, Takahiro Kawaji, Daisuke Hasegawa, Yasuyoshi Kurimoto,Kazuhiro Moriyama, Osamu Nishida.
    • Organizer
      Society of Critical Care Medicine 48th Critical Care Congress
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 敗血症性DICと好中球の機能2019

    • Author(s)
      下村泰代
    • Organizer
      救命救急センター感染症講演会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] DIC基礎的病態とATの作用2019

    • Author(s)
      下村泰代
    • Organizer
      侵襲制御医学セミナー
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 敗血症性DICにおける NETs 形成の検討2018

    • Author(s)
      下村泰代
    • Organizer
      第33回日本Shock学会総会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 敗血症性 DIC における NETs 形成の検討2018

    • Author(s)
      下村泰代
    • Organizer
      第12回日本血栓止血学会学術標準化委員会(SSC)シンポジウム
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 敗血症性DICにおけるImmunothrombosis2018

    • Author(s)
      下村泰代
    • Organizer
      消化器疾患セミナー in Kyoto
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 血液浄化施行時の心拍出量測定値(経肺熱希釈法)低下は返血温度の低下が原因であった2018

    • Author(s)
      川治崇泰、原嘉孝、加藤由布、原田達彦、栗本恭好、長谷川大祐、下村泰代、西田修
    • Organizer
      第29回日本急性血液浄化学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Cytokine-adsorbing hemofiltersによるサイトカイン吸着特性2018

    • Author(s)
      森山和広、加藤由布、長谷川大祐、川治崇泰、下村泰代、西田修
    • Organizer
      第29回日本急性血液浄化学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 免疫制御血液浄化システムの臨床応用に向けての取り組み2018

    • Author(s)
      原嘉孝、森山和広、加藤由布、栗本恭好、長谷川大祐、下村泰代、西田修
    • Organizer
      第29回日本急性血液浄化学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 敗血症治療におけるImmunothrombosis2018

    • Author(s)
      下村 泰代
    • Organizer
      消化器疾患セミナー in Kyoto
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 重症病態における顆粒球除去カラムの可能性~我々の知見および海外の動向を含めて~2017

    • Author(s)
      原 嘉孝、森山 和広、酒井 俊和、加藤 由布、勝田 賢、磯部 恵里、竹田 彩香、 山添 泰佳、中村 藍、柳 明男、小松 聖史、河田 耕太郎、下村 泰代、西田 修
    • Organizer
      第28回日本急性血液浄化学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 免疫から考える敗血症性DIC治療2017

    • Author(s)
      下村 泰代
    • Organizer
      浜松感染症DICセミナー
    • Related Report
      2017 Research-status Report
    • Invited

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Published: 2017-04-28   Modified: 2024-01-30  

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