Plasmin inhibition protects against severe acute inflammation in solid organs.

• Project/Area Number: 25861215
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Juntendo University
• Principal Investigator: TASHIRO Yoshihiko 順天堂大学, 医学部, 助教 (20636245)
• Co-Investigator(Renkei-kenkyūsha): HATTORI Koichi 順天堂大学大学院, 医学研究科, 特任先任准教授 (10360116)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 急性肝炎 / 急性膵炎 / 炎症性サイトカイン / MMP9 / TNFα / 線維素溶解系 / プラスミン / 実質臓器 / 血液線維素溶解系 / マトリックスメタロプロテイナーゼ / 骨髄由来細胞 / マトリックスメタロプテイナーゼ

Outline of Final Research Achievements

Treatment of severe inflammation in solid organs such as acute hepatitis and pancreatitis is still high mortality. It is known inflammatory cytokines in severe inflammation of solid organs is important, and its secretion is dependent on proteases like matrix metalloproteinases (MMP). There are some suggestions that MMPs are the predominant proteinases expressed in solid organ during sever inflammation. Others and we showed that plasmin can activate several MMPs.
Here, we investigated the function of MMP9 and plasminogen(plg) in an animal model of severe acute hepatitis. Pharmacological inhibition of plasmin or targeted gene deletion of Plg or MMP9 prevented high mortality of severe acute hepatitis. This was associated with a reduced inflammatory cell infiltration in hepatocyte and correlated with impaired cytokine level elevation. In summary, our data show that pharmacological inhibition of plasmin or the absence of Plg/MMP9 strongly inhibit the inflammatory response.

Research Products

• [Journal Article] Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking. (2015)
  • Author(s): A Sato, C Nishida, K Sato-Kusubata, M Ishihara, Y Tashiro, I Gritli, H Shimazu, S Munakata, H Yagita, K Okumura, Y Tsuda, Y Okada, A Tojo, H Nakauchi, S Takahashi, B Heissig and K Hattori
  • Journal Title: Leukemia Volume: 29 Issue: 1 Pages: 145-56
  • DOI: 10.1038/leu.2014.151
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of Plasmin Protects Against Colitis in Mice by Suppressing Matrix Metalloproteinase 9-Mediated Cytokine Release From Myeloid Cells. (2015)
  • Author(s): Munakata S, Tashiro Y, Nishida C, Sato A, Komiyama H, Shimazu H, Dhahri D, Salama Y, Eiamboonsert S, Takeda K, Yagita H, Tsuda Y, Okada Y, Nakauchi H, Sakamoto K, Heissig B, Hattori K.
  • Journal Title: Gastroenterology Volume: 148 Issue: 3 Pages: 565-78
  • DOI: 10.1053/j.gastro.2014.12.001
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking (2014)
  • Author(s): Aki Sato, Chiemi Nishida, Kaori Sato-Kusubata, Makoto Ishihara, Yoshihiko Tashiro, Ismael Gritli, Hiroshi Shimazu, Shinya Munakata, Hideo Yagita, Ko Okumura, Yuko Tsuda, Yoshio Okada, Arinobu Tojo, Hiromitsu Nakauchi, Satoshi Takahashi, Beate Heissig, Koichi Hattori
  • Journal Title: Leukemia Volume: in press
  • Peer Reviewed
• [Journal Article] Investigation of free cancer cells in peripheral blood using CEA mRNA expression in perioperative colorectal cancer patients. (2013)
  • Author(s): Nagayasu K, Komiyama H, Ishiyama S, Ogura D, Takahashi R, Tashiro Y, Niwa K, Sugimoto K, Kojima Y, Goto M, Tomiki Y, Niwa S, Sakamoto K.
  • Journal Title: Molecular and clinical oncology Volume: 1 Issue: 4 Pages: 668-674
  • DOI: 10.3892/mco.2013.109
  • Peer Reviewed
• [Journal Article] T1 colorectal cancer with synchronous liver metastasis (2013)
  • Author(s): Sugimoto K, Kawai M, Takehara K, Tashiro Y, Munakata S, Ishiyama S, Komiyama H, Takahashi M, Kojima Y, Goto M, Tomiki Y, Sakamoto K, Kawasaki S
  • Journal Title: Case Reports in Gastroentelorgy Volume: 7 Issue: 2 Pages: 266-271
  • DOI: 10.1159/000353635
  • Peer Reviewed
• [Presentation] Parmacological targeting of plasmin prevents macrophage activation syndrome in mice. (2014)
  • Author(s): Shimazu H, Munakata S, Nishida C, Sato A, Tashiro Y , Sato Y, Nakauchi H, Heissig B, Hattori K
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Pharmacological targeting of plasmin prevents macrophage activation syndrome in mice． (2014)
  • Author(s): 島津浩
  • Organizer: 第74回幹細胞治療研究分野フォーラム
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2014-10-01
• [Presentation] Pharmacological targeting of plasmin prevents macrophage activation syndrome in mice (2013)
  • Author(s): 島津浩,宗像慎也,佐藤亜紀,西田知恵美,田代良彦,Heissig Beate,服部浩一
  • Organizer: 平成25年度東京医科学研究所研究成果発表会
  • Place of Presentation: 東京
• [Presentation] Pharmacological targeting of plasmin prevents macrophage activation syndrome in mice (2013)
  • Author(s): 島津浩,宗像慎也,佐藤亜紀,西田知恵美,田代良彦,Heissig Beate,服部浩一
  • Organizer: 平成25年度東京大学生命科学シンポジウム
  • Place of Presentation: 東京