Novel therapeutic strategy for hepatic ischemia-reperfusion injury based on ADAMTS13-related factors

Research Project

Project/Area Number	19K18100
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 55020:Digestive surgery-related
Research Institution	Nara Medical University
Principal Investigator	Yoshikawa Takahiro 奈良県立医科大学, 医学部附属病院, 研究員 (80773275)
Project Period (FY)	2019-04-01 – 2022-03-31
Project Status	Completed (Fiscal Year 2021)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Keywords	ADAMTS13 / 肝切除
Outline of Research at the Start	ADAMTS13を軸に，肝切除後のADAMTS13活性の低下とULVWFマルチマー出現による病的血栓の形成，肝の微小循環障害から虚血再灌流障害に至るという新しい観点から病態形成を見直すことにある．肝切除，特に術中Pringle法による虚血再灌流障害におけるADAMTS13関連因子の意義を明らかにすること
Outline of Final Research Achievements	Introduction : von Willebrand factor (VWF) is synthesised in vascular endothelial cells and released into the plasma as unusually large VWF multimers (UL-VWFMs). Sinusoidal endothelial cells are a major target of ischaemia reperfusion injury due to liver surgery. This study aimed to clarify the effect of hepatectomy on ULVWFMs. Results : By multivariable analysis, Pringle's maneuver duration was significantly associated with increased UL-VWFMs level after hepatectomy[odds ratio 1.049, p=0.043]. UL-VWFMs index was significantly correlated with Pringle's maneuver duration (r=0.444,p=0.017).Conclusions : Plasma UL-VWFMs levels increased after hepatectomy due to ischaemia reperfusion injury with Pringle's maneuver.
Academic Significance and Societal Importance of the Research Achievements	本研究で肝切除中のPringle法が血管内皮細胞傷害を惹起し，VWFマルチマーが増加することで，肝内に病的血栓が形成され易い状態にあることが示された．今まで虚血再灌流障害に対する治療法として，肝切除とADAMTS13関連因子に着目した検討は，国内外において報告がない．本研究はADAMTS13関連因子という観点から，術中Pringle法による虚血再灌流障害のメカニズムを解明することで，肝切除後肝不全に対する新たな治療戦略を創生することを目的とし，今後研究がすすめば，新たな肝切除後肝不全治療戦略となる可能性がある．