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

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

Note

This study was supported in part by grants from the SENSHIN Medical Research Foundation (to M. Sugimoto), the Takeda Science Foundation (to M. Sugimoto), and by the MEXT KAKENHI (#15K10990 to K. Nishio).

• References

• 1 Bahde R, Spiegel HU. Hepatic ischaemia-reperfusion injury from bench to bedside. Br J Surg 2010; 97 (10) 1461-1475
• 2 Peralta C, Jiménez-Castro MB, Gracia-Sancho J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J Hepatol 2013; 59 (05) 1094-1106
• 3 Abe Y, Hines IN, Zibari G. , et al. Mouse model of liver ischemia and reperfusion injury: method for studying reactive oxygen and nitrogen metabolites in vivo. Free Radic Biol Med 2009; 46 (01) 1-7
• 4 Yadav SS, Howell DN, Steeber DA, Harland RC, Tedder TF, Clavien PA. P-Selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver. Hepatology 1999; 29 (05) 1494-1502
• 5 Ruggeri ZM. Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 2003; 1 (07) 1335-1342
• 6 Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008; 112 (01) 11-18
• 7 Tsai HM. Shear stress and von Willebrand factor in health and disease. Semin Thromb Hemost 2003; 29 (05) 479-488
• 8 Fujioka M, Hayakawa K, Mishima K. , et al. ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion. Blood 2010; 115 (08) 1650-1653
• 9 De Meyer SF, Savchenko AS, Haas MS. , et al. Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice. Blood 2012; 120 (26) 5217-5223
• 10 Akiyama M, Nakayama D, Takeda S, Kokame K, Takagi J, Miyata T. Crystal structure and enzymatic activity of an ADAMTS-13 mutant with the East Asian-specific P475S polymorphism. J Thromb Haemost 2013; 11 (07) 1399-1406
• 11 Doi M, Matsui H, Takeda H. , et al. ADAMTS13 safeguards the myocardium in a mouse model of acute myocardial infarction. Thromb Haemost 2012; 108 (06) 1236-1238
• 12 Kokame K, Nobe Y, Kokubo Y, Okayama A, Miyata T. FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol 2005; 129 (01) 93-100
• 13 Akahori T, Sho M, Hamada K. , et al. Importance of peroxisome proliferator-activated receptor-γ in hepatic ischemia/reperfusion injury in mice. J Hepatol 2007; 47 (06) 784-792
• 14 Takizawa H, Nishimura S, Takayama N. , et al. Lnk regulates integrin alphaIIbbeta3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo. J Clin Invest 2010; 120 (01) 179-190
• 15 Nishimura S, Manabe I, Nagasaki M. , et al. In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling. Blood 2012; 119 (08) e45-e56
• 16 Nishimura S, Nagasaki M, Kunishima S. , et al. IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs. J Cell Biol 2015; 209 (03) 453-466
• 17 Denis CV, André P, Saffaripour S, Wagner DD. Defect in regulated secretion of P-selectin affects leukocyte recruitment in von Willebrand factor-deficient mice. Proc Natl Acad Sci U S A 2001; 98 (07) 4072-4077
• 18 Petri B, Broermann A, Li H. , et al. von Willebrand factor promotes leukocyte extravasation. Blood 2010; 116 (22) 4712-4719
• 19 Kasuda S, Matsui H, Ono S. , et al. Relevant role of von Willebrand factor in neutrophil recruitment in a mouse sepsis model involving cecal ligation and puncture. Haematologica 2016; 101 (02) e52-e54
• 20 Shida Y, Nishio K, Sugimoto M. , et al. Functional imaging of shear-dependent activity of ADAMTS13 in regulating mural thrombus growth under whole blood flow conditions. Blood 2008; 111 (03) 1295-1298
• 21 Pendu R, Terraube V, Christophe OD. , et al. P-selectin glycoprotein ligand 1 and beta2-integrins cooperate in the adhesion of leukocytes to von Willebrand factor. Blood 2006; 108 (12) 3746-3752
• 22 Swystun LL, Liaw PC. The role of leukocytes in thrombosis. Blood 2016; 128 (06) 753-762
• 23 Drakeford C, O'Donnell JS. Targeting von Willebrand factor-mediated inflammation. Arterioscler Thromb Vasc Biol 2017; 37 (09) 1590-1591
• 24 Bernardo A, Ball C, Nolasco L, Choi H, Moake JL, Dong JF. Platelets adhered to endothelial cell-bound ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress. J Thromb Haemost 2005; 3 (03) 562-570
• 25 Dhanesha N, Prakash P, Doddapattar P. , et al. Endothelial Cell-Derived von Willebrand factor is the major determinant that mediates von Willebrand factor-dependent acute ischemic stroke by promoting postischemic thrombo-inflammation. Arterioscler Thromb Vasc Biol 2016; 36 (09) 1829-1837
• 26 Zhao B-Q, Chauhan AK, Canault M. , et al. von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke. Blood 2009; 114 (15) 3329-3334