PB0302 - ADAMTS13 can be a novel therapeutic option for acetaminophen-induced acute liver injury in mice

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Akihiro Sawa, MD

Postgraduate Student
Department of General Medicine, Nara Medical University
Kashihara, Nara, Japan

Co-Author(s)

Kohei Tatsumi, MD, PhD

Associate Professor
Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University
Kashihara, Nara, Japan
KS

Kenji Soejima

Department Manager
Research and Development Promotion Department, KM Biologics Co., Ltd.
Kumamoto, Kumamoto, Japan
YT

Yoko Takabayashi

Research Assistant
Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University
Kashihara, Nara, Japan
YO

Yu Onodera

Postgraduate Student
Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University
Kashihara, Nara, Japan
AK

Ayaka Kakiwaki

Postgraduate Student
Department of General Medicine, Nara Medical University
Kashihara, Nara, Japan
SS

Satoshi Senzaki

Postgraduate Student
Department of General Medicine, Nara Medical University
Kashihara, Nara, Japan
NN

Nobushiro Nishimura

Assistant Professor
Department of General Medicine, Nara Medical University
Kashihara, Nara, Japan
HK

Hiromasa Kawashima

Assistant Professor
Department of General Medicine, Nara Medical University
Kashihara, Nara, Japan
KY

Kiyomi Yoshimoto

Senior Lecturer／Junior Associate Professor
Department of General Medicine, Nara Medical University
Kashihara, Nara, Japan
Midori Shima

Director
Thrombosis and Hemostasis Research Center, Nara Medical University
Kashihara, Nara, Japan
MS

Mitsuhiko Sugimoto

Research Professor
Department of General Medicine, Nara Medical University
Kashihara, Nara, Japan
KN

Kenji Nishio

Emeritus Professor
Department of General Medicine, Nara Medical University
Kashihara, Nara, Japan

Background: Acetaminophen (APAP) is one of the major causes of drug-induced acute liver injury. Our recent study using mice revealed that ADAMTS13 deficiency exacerbates APAP-induced hepatic injury by enhanced inflammation and VWF-rich thrombosis formation in the liver sinusoid. Accordingly, we hypothesized that ADAMTS13 can be a therapeutic option for APAP-induced hepatic injury.

Aims: To investigate the therapeutic effect of ADAMTS13 on APAP-induced hepatic injury.

Methods: Wild-type (WT) and ADAMTS13 gene-deleted (KO) mice were fasted for 24 hours before intravenous injection of recombinant human ADAMTS13 (rhADAMTS13, 2 μg/200 μL) or saline. Thirty minutes after injection, 300 mg/kg of APAP were intraperitoneally administered. Forty-eight hours after APAP administration, hepatic blood flow was measured using Laser Doppler flowmetry, followed by sampling of blood and hepatic tissue. Blood cell counts and biochemical analysis were performed. Also, histological analysis and gene expression analysis by qPCR were conducted using the liver samples.

Results: In APAP-challenged mice, highly elevated serum levels of AST and ALT, enhanced gene expression of inflammation and fibrotic markers, and hepatic necrosis dominantly around central vein were observed.

In rhADAMTS13-treated KO mice (N=19), serum levels of ALT, gene expression of inflammation and fibrotic markers were significantly lower than saline-treated KO mice (N=18)(ALT; 1221 vs 1850 IU/L). The area of liver necrosis in rhADAMTS13-treated mice was smaller than saline-treated mice.

Furthermore, in rhADAMTS13-treated WT mice (N=17), serum levels of AST and ALT were significantly lower (AST; 1150 vs 2469 IU/L, ALT; 1588 vs 2808 IU/L), while hepatic blood flow was significantly faster (21.20 vs 13.04 ml/hr) than saline-treated WT mice (N=16). The area of hepatic necrosis in rhADAMTS13-treated mice was smaller than saline-treated mice.

Conclusion(s): Administration of rhADAMTS13 suppressed APAP-induced acute liver injury by improving hepatic blood flow, suggesting that rhADAMTS13 can be a novel therapeutic option for APAP poisoning.