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Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism
http://hdl.handle.net/10232/25499
http://hdl.handle.net/10232/254999ad3247f-f91e-4be7-91b7-ec67d009c0c4
| 名前 / ファイル | ライセンス | アクション |
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Diss_中原_真由美_ISK281_2014.pdf (2.6 MB)
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Abstract_中原_真由美_4509810174_2014.pdf (73.9 kB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||
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| 公開日 | 2015-10-29 | |||||
| タイトル | ||||||
| タイトル | Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism | |||||
| タイトル言語 | en | |||||
| 著者 |
中原, 真由美
× 中原, 真由美 |
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| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||
| 資源タイプ | doctoral thesis | |||||
| アクセス権 | ||||||
| アクセス権 | open access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||
| 要約 | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | Introduction: Recent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM). rTM has been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan, and is currently undergoing a phase III clinical trial in the United States. Methods: Histone H3 levels in plasma of healthy volunteers and patients with sepsis and DIC were measured using enzyme-linked immunosorbent assay. Male C57BL/6 mice were injected intravenously with purified histones, and pathological examinations were performed. The protective effects of rTM against histone toxicity were analyzed both in vitro and in mice. Results: Histone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. These levels were higher in non-survivors than in survivors. Extracellular histones triggered platelet aggregation, leading to thrombotic occlusion of pulmonary capillaries and subsequent right-sided heart failure in mice. These mice displayed symptoms of DIC, including hrombocytopenia, prolonged prothrombin time, decreased fibrinogen, fibrin deposition in capillaries, and bleeding. Platelet depletion protected mice from histone-induced death in the first 30 minutes, suggesting that vessel occlusion by platelet-rich thrombi might be responsible for death during the early phase. Furthermore, rTM bound to extracellular histones, suppressed histoneinduced platelet aggregation, thrombotic occlusion of pulmonary capillaries, and dilatation of the right ventricle, and rescued mice from lethal thromboembolism. Conclusions: Extracellular histones cause massive thromboembolism associated with consumptive coagulopathy, which is diagnostically indistinguishable from DIC. rTM binds to histones and neutralizes the prothrombotic action of histones. This may contribute to the effectiveness of rTM against DIC. Mayumi Nakahara, Takashi Ito, Ko-ichi Kawahara, Mika Yamamoto, Tomoka Nagasato, Binita Shrestha, Shingo Yamada, Takahiro Miyauchi, Koji Higuchi, Toshihiro Takenaka, Tomotsugu Yasuda, Akira Matsunaga, Yasuyuki Kakihana, Teruto Hashiguchi, Yuichi Kanmura, Ikuro Maruyama Recombinant Thrombomodulin Protects Mice against Histone-Induced Lethal Thromboembolism PLoS ONE, 2013, 8(9), e75961 doi:10.1371/journal.pone.0075961 |
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| 内容記述言語 | en | |||||
| 作成日 | ||||||
| 日付 | 2015-09-14 | |||||
| 日付タイプ | Collected | |||||
| 出版タイプ | ||||||
| 出版タイプ | VoR | |||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
| NDC | ||||||
| 主題Scheme | NDC | |||||
| 主題 | 490 | |||||
| ファイル（説明） | ||||||
| 内容記述 | 博士論文全文, 博士論文要旨 | |||||
| 公開者・出版者 | ||||||
| 出版者 | PLoS ONE | |||||
| 出版者言語 | en | |||||
| 公開者・出版者 | ||||||
| 出版者 | 鹿児島大学 | |||||
| 出版者言語 | ja | |||||
| 公開者・出版者 | ||||||
| 出版者 | カゴシマ ダイガク | |||||
| 出版者言語 | ja-Kana | |||||
| 備考 | ||||||
| 備考 | 【指導教員:上村裕一】 | |||||
| date.appl | ||||||
| appl | 【学位申請日】2014-02-05 | |||||
| 学位名 | ||||||
| 学位名の言語 | ja | |||||
| 学位名 | 博士(医学) | |||||
| 学位名 | ||||||
| 学位名の言語 | en | |||||
| 学位名 | Doctor of Philosophy in Medical Science | |||||
| 学位授与機関名 | ||||||
| 学位授与機関識別子Scheme | kakenhi | |||||
| 学位授与機関識別子 | 17701 | |||||
| 学位授与機関名の言語 | ja | |||||
| 学位授与機関名 | 鹿児島大学 | |||||
| 学位授与年月日 | ||||||
| 学位授与年月日 | 2014-04-25 | |||||
| 学位授与番号 | ||||||
| 学位授与番号 | 甲総研第281号 | |||||
