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Published on: November 27, 2019
Recombinant ADAMTS13 Ameliorates Liver Injury and Improves Hepatic Microcirculation in a Murine Acute-on-Chronic
Jun-Ichi Hanatani1, Norihisa Nishimura1, Kosuke Kaji1
1Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan.
Aim:
The therapeutic significance of recombinant a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (rADAMTS13) in acute-on-chronic liver failure (ACLF) remains unclear. We aimed to investigate the therapeutic effects of rADAMTS13 in a murine model of ACLF-like liver injury.
Methods:
Male C57BL/6J mice were subjected to chronic carbon tetrachloride (CCl4) administration followed by acute CCl4 and lipopolysaccharide challenge to induce ACLF-like liver injury. Mice were assigned to control, ACLF, and ACLF + rADAMTS13 groups. Plasma ADAMTS13 activity, VWF antigen, platelet counts, hepatic microcirculatory blood flow, histological changes, and hepatic gene expression were evaluated. Endothelial tube formation assays were performed using human umbilical vein endothelial cells (HUVECs) under oxidative stress conditions.
Results:
rADAMTS13 treatment improved plasma ADAMTS13 activity, reduced VWF antigen levels, and attenuated intrahepatic platelet accumulation in ACLF mice. These changes were accompanied by improved hepatic microcirculatory blood flow, reduced plasma transaminase levels, and decreased hepatic necrosis and macrophage infiltration. rADAMTS13 also reduced oxidative stress-related markers and fibrosis-related readouts in the acute setting. The treatment was associated with increased hepatic CD34 staining, upregulation of Vegfa, and increased regeneration-related markers, including Ki67, A6, Hgf, and Egf. In vitro, rADAMTS13 partially restored impaired tube formation and increased VEGFA and VEGFR2 expression in HUVECs exposed to oxidative stress.
Conclusion:
rADAMTS13 attenuated liver injury in a murine ACLF-like model and was associated with restoration of the ADAMTS13/VWF axis, improved hepatic microcirculation, and increased angiogenesis- and regeneration-related responses. These findings suggest that rADAMTS13 may represent a potential therapeutic approach for ACLF.
