Von Willebrand Factor Aggravates Hepatic Ischemia–Reperfusion Injury by Promoting Neutrophil Recruitment in Mice

Yasuyuki Urisono; Asuka Sakata; Hideto Matsui; Shogo Kasuda; Shiro Ono; Kiyomi Yoshimoto; Kenji Nishio; Masayuki Sho; Masashi Akiyama; Toshiyuki Miyata; Kazuo Okuchi; Satoshi Nishimura; Mitsuhiko Sugimoto

doi:10.1055/s-0038-1636529

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2018; 118(04): 700-708
DOI: 10.1055/s-0038-1636529

Cellular Haemostasis and Platelets

Schattauer GmbH Stuttgart

Von Willebrand Factor Aggravates Hepatic Ischemia–Reperfusion Injury by Promoting Neutrophil Recruitment in Mice

Yasuyuki Urisono

¹Department of Emergency and Critical Care Medicine, Nara Medical University, Kashihara, Nara, Japan

,

Asuka Sakata

²Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

,

Hideto Matsui

³Department of General Medicine, Nara Medical University, Kashihara, Nara, Japan

,

Shogo Kasuda

⁴Department of Legal Medicine, Nara Medical University, Kashihara, Nara, Japan

,

Shiro Ono

³Department of General Medicine, Nara Medical University, Kashihara, Nara, Japan

,

Kiyomi Yoshimoto

³Department of General Medicine, Nara Medical University, Kashihara, Nara, Japan

,

Kenji Nishio

³Department of General Medicine, Nara Medical University, Kashihara, Nara, Japan

,

Masayuki Sho

⁵Department of Surgery, Nara Medical University, Kashihara, Nara, Japan

,

Masashi Akiyama

⁶Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan

,

Toshiyuki Miyata

⁷Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan

,

Kazuo Okuchi

¹Department of Emergency and Critical Care Medicine, Nara Medical University, Kashihara, Nara, Japan

,

Satoshi Nishimura

²Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

,

Mitsuhiko Sugimoto

³Department of General Medicine, Nara Medical University, Kashihara, Nara, Japan

› Author Affiliations

Abstract

Hepatic ischaemia–reperfusion (I/R) injury is a serious liver damage that critically influences the clinical outcome of liver surgery or transplantation. Since recent studies indicated the critical involvement of von Willebrand factor (VWF) in reperfusion injuries of brain and myocardium, we hypothesized that VWF-dependent thrombotic or inflammatory responses also play a role in hepatic I/R injury. Using a mouse model of hepatic I/R injury, we explored the functional relevance of the VWF–ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) axis in this pathologic condition. Time-course studies during hepatic I/R revealed significantly lower alanine aminotransferase (ALT) values, as well as greater hepatic blood flow, in VWF gene-deleted (KO) mice in comparison with wild-type (WT) mice. Histological analysis revealed a significantly lesser extent of neutrophil infiltration and hepatocellular necrosis in liver tissues of VWF-KO mice. Human recombinant ADAMTS13 significantly improved the impairment in ALT values and hepatic blood flow and decreased neutrophil infiltration within the liver tissue of WT mice. Real-time intravital imaging successfully visualized significantly reduced leukocyte–vessel wall interactions in I/R liver of VWF-KO mice. Taken together, our results indicate that VWF promotes neutrophil recruitment in ischaemic 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.

Keywords

von Willebrand factor - ADAMTS13 - hepatic ischaemia–reperfusion injury - neutrophil recruitment

Full Text

References

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