Involvement of ADAMTS13 in the pathophysiology of several types of inflammation in the liver and the kidney

• Project/Area Number: 15K10990
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Nara Medical University
• Principal Investigator: NISHIO KENJI 奈良県立医科大学, 医学部, 教授 (60254489)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: von Willebrand factor / ADAMTS13 / ischemia/reperfusion / VWF / 虚血再灌流傷害 / 白血球

Outline of Final Research Achievements

Using a mouse model of hepatic ischemia/reperfusion injury (I/R injury), we explored the functional relevance of the VWF and ADAMTS13 molecules in this pathophysiologic condition. Time-course studies during hepatic I/R revealed significantly lower ALT values and greater hepatic blood flowin VWF knock-out mice (VWF-KO) mice than wild type mice (WT). Histological analysis revealed a significantly lesser extent of neutrophil infiltration of VWF-KO. Human recombinant ADAMTS13 significantly improved the I/R injury in WT similar level to VWF-KO. Real-time intravital imaging successfully visualized significantly reduced the number of leukocyte adhering to the vessel wall in VWF-KO mice. Taken together, our results indicate that VWF promotes microthrombosis and neutrophil recruitment and in ischemic mouse liver, critically aggravating reperfusion injury, and suggest that functional regulation of VWF by ADAMTS13 represents a promising therapeutic option for hepatic I/R injury.

Research Products

• [Journal Article] von Willebrand factor aggravates hepatic ischemia-reperfusion injury by promoting neutrophil recruitment in mice (2018)
  • Author(s): Urisono Y, Sakata A, Matsui H, Kasuda S, Ono S, Nishio K, Sho M, Okuchi K, Akiyama M, Miyata T, Nishimura S, Sugimoto M
  • Journal Title: Thromb Haemost Volume: 118 Issue: 04 Pages: 700-708
  • DOI: 10.1055/s-0038-1636529
  • Peer Reviewed
• [Presentation] Functional Relevance of Von Willebrand Factor in Mouse Model of Hepatic Ischmia-Reperfusion Injury (2016)
  • Author(s): Yasuyuki Urisono, Hideto Matui, Shogo Kasuda, Shiro ono, Kenji Nishio, Masashi Akiyama, Toshiyuki Miyata, phD, Kazuo Okuchi and Mitsuhiko Sugimoto
  • Organizer: 58th American Society of Hematology Annual Meeting
  • Place of Presentation: San Diego, USA
  • Int'l Joint Research
• [Presentation] 腎虚血再藻流障害マウスモデルにおけるvon Willebrand因子の機能解析 (2016)
  • Author(s): 大野 史郎, 松井 英人, 野田 正志, 粕田 承吾, 瓜園 泰之, 松成 泰典, 矢田 憲孝, 西尾 健治, 杉本 充彦
  • Organizer: 第38回日本血栓止血学会学術集会
  • Place of Presentation: 奈良
• [Presentation] Relevant Role of Von Willebrand Factor in Ischemia-Reperfusion Model of Acute Kidney Injury in Mice (2015)
  • Author(s): Shiro O, Hideto M, Masashi N, Shogo K, Yasunori M, Noritaka Y, Kenji N, Mitsuhiko S
  • Organizer: 57th American Society of Hematology Annual Meeting
  • Place of Presentation: Orland USA
  • Year and Date: 2015-12-05
  • Int'l Joint Research