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

2018 ◽  
Vol 47 (04) ◽  
pp. 700-708 ◽  
Author(s):  
Yasuyuki Urisono ◽  
Asuka Sakata ◽  
Hideto Matsui ◽  
Shogo Kasuda ◽  
Shiro Ono ◽  
...  
Keyword(s):  
Blood Flow ◽  
Reperfusion Injury ◽  
Von Willebrand Factor ◽  
Hepatic Blood Flow ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Neutrophil Recruitment ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractHepatic 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.

scholarly journals Functional Relevance of Von Willebrand Factor in Mouse Model of Hepatic Ischemia- Reperfusion Injury

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1356-1356
Author(s):  
Yasuyuki Urisono ◽  
Hideto Matsui ◽  
Shogo Kasuda ◽  
Shiro Ono ◽  
Kenji Nishio ◽  
...  
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Histological Analysis ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Hepatic ischemia-reperfusion (I/R) injury is a liver damage occurring during liver surgeries such as hepatic resection or transplantation, and denotes the major basis for graft dysfunction after transplantation. Although cellular and molecular mechanisms of hepatic I/R injury are complex and remain to be clarified, an excessive inflammatory response is assumed to play a role in this regard. An adhesive protein von Willebrand factor (VWF) plays a pivotal role in platelet thrombus formation and is recently understood as a key protein in a cross-talk between inflammation and thrombosis. In this context, we assumed that VWF may also be involved in the pathophysiology of hepatic I/R injury, in which VWF-dependent platelet activation or inflammatory responses could play a role at liver sinusoidal milieu. To test this hypothesis, we have used a mouse experimental model of hepatic I/R injury. Mice were anesthetized with sodium pentobarbital and a midline laparotomy was then performed on a heating pad. Blood supply for left lateral and median lobes of liver (approximately 70% of the liver mass) was interrupted by cross-clamping the hepatic artery and portal vein with a microvascular atraumatic clip for 90 min. Then a clip was taken off to provoke the reperfusion of hepatic blood flow, which was monitored on the surface of left lateral lobe by Laser Doppler flowmetry (ALF21, Advance Co, Tokyo, Japan). The hepatic blood flow was measured again 24 h after reperfusion and mice were then sacrificed for blood collection and histological analysis of liver tissue. We compared 16 wild-type (WT) and 12 VWF-gene deleted (knock-out; KO) mice (from The Jackson Laboratory, Bar Harbor, ME), all of which were 8-12 weeks of age, healthy and fertile. Excess blood loss was not observed in all mice (WT or KO) during whole surgical process. As compared to WT mice, restoration of hepatic blood flow was significantly greater in VWF-KO mice at 24 h after reperfusion (WT; 61± 17% vs. KO; 87 ± 17%, expressed as the percentage of pre-ischemic value). Consistent with the hepatic blood flow, the time-course analysis of serum alanine aminotransferase (ALT) at several time points after reperfusion revealed the lesser liver damages of KO mice (WT; 6898 ± 3270 and 1313 ± 621 IU/L vs. KO; 3043 ± 1320 and 478 ± 330 IU/L, at 3 h and 24 h after reperfusion, respectively). In addition, histological analysis confirmed that neutrophil infiltration in the liver tissue of KO mice was significantly reduced as compared to WT mice at 24 h after reperfusion. These impaired hepatic blood flow and ALT values as well as intensified neutrophil infiltration in WT mice were significantly improved to an extent comparable to those of KO mice by the bolus injection of recombinant human ADAMTS13 (3 μg/mouse equivalent to 2800 U/kg, n=12) just prior to the I/R operation. Our results altogether indicate that VWF-dependent inflammatory responses with neutrophil recruitment at ischemic sites are involved in pathophysiology of hepatic I/R injury, and functional regulation of VWF by ADAMTS 13 may serve as a promising therapeutic option for hepatic I/R injury. Disclosures No relevant conflicts of interest to declare.

scholarly journals Relevant Role of Von Willebrand Factor in Ischemia-Reperfusion Model of Acute Kidney Injury in Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2243-2243
Author(s):  
Shiro Ono ◽  
Hideto Matsui ◽  
Masashi Noda ◽  
Shogo Kasuda ◽  
Yasunori Matsunari ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Blood Flow ◽  
Renal Blood Flow ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Relevant Role ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Acute kidney injury (AKI), an abrupt loss of renal function, is often seen in clinical settings and its mortality remains high even in the developed countries. An adhesive protein von Willebrand factor (VWF) plays a pivotal role in platelet thrombus formation and is recently understood as a key protein in a cross-talk between inflammation and thrombosis. Recent mouse model studies demonstrated that VWF-mediated thrombotic and inflammatory responses could play a role in the disease progression of myocardial infarction or brain stroke. Thus, we assumed that VWF may also be involved in the pathophysiology of AKI, the major cause of which could be an insufficient renal circulation and/or inflammatory cell infiltration in the kidney. To test this hypothesis, we studied the relevant role of VWF in AKI in mouse model of acute ischemia-reperfusion (I/R) kidney injury. All mice used were male, 8-12 weeks of age, healthy and whose right kidney was surgically removed by the standard mouse nephrectomy procedure 1 week prior to the kidney I/R experiment. The preliminary experiments confirmed that surgical removal of mouse right kidney did not affect their general conditions including renal functions. Mice were anesthetized with inhaled isoflurane and then placed in an abdominal position on a heating pad. Surgical incision was given on the left side of back and the left kidney was brought out and kept outside during the operation. Both renal artery and vein were clamped at the renal hilus by a clamping clip for 30 min ischemia. Then a clip was taken off to provoke the reperfusion of renal blood flow, which was monitored by Laser Doppler flowmetry (ALF21, Advance Co, Tokyo, Japan). The kidney was then put back in a body and skin incision was closed. The renal blood flow was measured again 30 h after reperfusion and mice were then sacrificed for blood collection. We compared 15 wild-type (WT) and 16 VWF-gene deleted (knock-out; KO) mice (from The Jackson Laboratory, Bar Harbor, ME). Excess blood loss was not observed in all mice (WT or KO) during whole surgical process. Although no difference was seen immediately after reperfusion, significantly (p < 0.05) higher renal blood flow at 30 h after reperfusion was confirmed in VWF-KO mice, as compared to WT (KO; 24.0±2.3 vs. WT; 15.1±1.46 ml/min/100g of kidney weight, and the reperfusion/base flow ratio: KO; 1.0±0.07 vs. WT; 0.6 ±0.07). Consistent with the renal blood flow data, the serum creatinine value at 30 h after reperfusion were significantly (p < 0.05) lower in VWF-KO mice than WT (KO; 2.77±0.11 vs. WT; 3.15±0.11 mg/dl). Our results suggest that VWF does play a role in the pathogenesis of AKI, in which VWF-dependent thrombotic or inflammatory responses may trigger thrombotic ischemia or endothelial damages of vascular bed in the kidney. Thus, proper functional regulation of VWF would be beneficial for better microcirculation and vessel functions in the kidney, suggesting a novel therapeutic potential against AKI. Disclosures No relevant conflicts of interest to declare.

scholarly journals Functional regulation of von Willebrand factor ameliorates acute ischemia-reperfusion kidney injury in mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shiro Ono ◽  
Hideto Matsui ◽  
Masashi Noda ◽  
Shogo Kasuda ◽  
Noritaka Yada ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Function ◽  
Renal Blood Flow ◽  
Von Willebrand Factor ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Acute Ischemia ◽  
Functional Regulation ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Acute kidney injury (AKI), an abrupt loss of renal function, is often seen in clinical settings and may become fatal. In addition to its hemostatic functions, von Willebrand factor (VWF) is known to play a role in cross-talk between inflammation and thrombosis. We hypothesized that VWF may be involved in the pathophysiology of AKI, major causes of which include insufficient renal circulation or inflammatory cell infiltration in the kidney. To test this hypothesis, we studied the role of VWF in AKI using a mouse model of acute ischemia-reperfusion (I/R) kidney injury. We analyzed renal function and blood flow in VWF-gene deleted (knock-out; KO) mice. The functional regulation of VWF by ADAMTS13 or a function-blocking anti-VWF antibody was also evaluated in this pathological condition. Greater renal blood flow and lower serum creatinine were observed after reperfusion in VWF-KO mice compared with wild-type (WT) mice. Histological analysis also revealed a significantly lower degree of tubular damage and neutrophil infiltration in kidney tissues of VWF-KO mice. Both human recombinant ADAMTS13 and a function-blocking anti-VWF antibody significantly improved renal blood flow, renal function and histological findings in WT mice. Our results indicate that VWF plays a role in the pathogenesis of AKI. Proper functional regulation of VWF may improve the microcirculation and vessel function in the kidney, suggesting a novel therapeutic option against AKI.

von Willebrand factor deficiency leads to impaired blood flow recovery after ischaemia in mice

2017 ◽  
Vol 117 (07) ◽  
pp. 1412-1419 ◽  
Author(s):  
Margreet R. de Vries ◽  
Erna A. B. Peters ◽  
Paul H. A. Quax ◽  
A. Yaël Nossent
Keyword(s):  
Blood Flow ◽  
Von Willebrand Factor ◽  
Negative Regulator ◽  
Pia Mater ◽  
Artery Ligation ◽  
Factor Deficiency ◽  
Adductor Muscles ◽  
Gastrocnemius Muscles ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryNeovascularisation, i. e. arteriogenesis and angiogenesis, is an inflammatory process. Therefore attraction and extravasation of leukocytes is essential for effective blood flow recovery after ischaemia. Previous studies have shown that von Willebrand factor (VWF) is a negative regulator of angiogenesis. However, it has also been shown that VWF facilitates leukocyte attraction and extravasation. We aimed to investigate the role of VWF in arteriogenesis and angiogenesis during post-ischaemic neovascularisation. Wild-type (WT) and VWF deficient (VWF-/-) C57BL/6 mice were subjected to hindlimb ischaemia via double ligation of the left femoral artery, and blood flow recovery was followed over time, using Laser Doppler Perfusion Imaging. Blood flow recovery was impaired in VWF-/- mice. After 10 days, VWF-/- mice showed a 43 ± 5% recovery versus 68 ± 5% in WT. Immunohistochemistry revealed that both arteriogenesis in the adductor muscles and angiogenesis in the gastrocnemius muscles were reduced in VWF-/- mice. Furthermore, leukocyte infiltration in the affected adductor muscles was reduced in VWF-/- mice. Residual paw perfusion directly after artery ligation was also reduced in VWF-/- mice, indicating a decrease in pre-existing collateral arteriole density. When we quantified collateral arterioles, we observed a 31% decrease in the average number of collateral arterioles in the pia mater compared to WT mice (57 ± 3 in WT vs 40 ± 4 pial collaterals in VWF-/-). We conclude that VWF facilitates blood flow recovery in mice. VWF deficiency hampers both arteriogenesis and angiogenesis in a hindlimb ischaemia model. This is associated with impaired leukocytes recruitment and decreased pre-existing collateral density in the absence of VWF.

Plasma von Willebrand Factor and Intestinal Ischaemia-Reperfusion Injury in Rats

1999 ◽  
Vol 94 (6) ◽  
pp. 353-358 ◽  
Author(s):  
Fikri M Abu-Zidan ◽  
Glenn Farrant ◽  
L.Jonathan Zwi ◽  
Misho O Simovic ◽  
Tony Day ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Von Willebrand Factor ◽  
Intestinal Ischaemia ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Emerging Microfluidic Approaches for Platelet Mechanobiology and Interplay With Circulatory Systems

2021 ◽  
Vol 8 ◽  
Author(s):  
Yingqi Zhang ◽  
Savindi De Zoysa Ramasundara ◽  
Renee Ellen Preketes-tardiani ◽  
Vivian Cheng ◽  
Hongxu Lu ◽  
...  
Keyword(s):  
Blood Flow ◽  
Von Willebrand Factor ◽  
Plasma Proteins ◽  
Circulatory System ◽  
Microfluidic Platforms ◽  
Hemodynamic Forces ◽  
Vessel Walls ◽  
Sense And Respond ◽  
Von Willebrand ◽  
Willebrand Factor

Understanding how platelets can sense and respond to hemodynamic forces in disturbed blood flow and complexed vasculature is crucial to the development of more effective and safer antithrombotic therapeutics. By incorporating diverse structural and functional designs, microfluidic technologies have emerged to mimic microvascular anatomies and hemodynamic microenvironments, which open the floodgates for fascinating platelet mechanobiology investigations. The latest endothelialized microfluidics can even recapitulate the crosstalk between platelets and the circulatory system, including the vessel walls and plasma proteins such as von Willebrand factor. Hereby, we highlight these exciting microfluidic applications to platelet mechanobiology and platelet–circulatory system interplay as implicated in thrombosis. Last but not least, we discuss the need for microfluidic standardization and summarize the commercially available microfluidic platforms for researchers to obtain reproducible and consistent results in the field.

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