PB0303 - The role of VWF-ADAMTS13 axis in the pathogenesis of lung inflammation in mice

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Kohei Tatsumi, MD, PhD

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

Co-Author(s)

YO

Yu Onodera

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

Seiji Mitani

Assistant Professor
Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University
Kashihara, Nara, Japan
CH

Chihiro Hosoda

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

Yoko Takabayashi

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

Kenji Nishio

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

Mitsuhiko Sugimoto

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

Kenji Soejima

Department Manager
Research and Development Promotion Department, KM Biologics Co., Ltd.
Kumamoto, Kumamoto, Japan
Nigel Mackman, PhD

Professor
Univerisity of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Midori Shima

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

Background: VWF is released from endothelial cells in response to inflammatory stimuli, and is thought to contribute to inflammation by promoting leukocyte extravasation. The regulatory roles of VWF and ADAMTS13 have been recently elucidated in various inflammatory diseases.

Aims: To investigate the role of VWF-ADAMTS13 axis in the pathogenesis of lung inflammation in mice.

Methods: Mice (Vwf+/+ and Vwf−/−, Adamts13+/+ and Adamts13−/−) were intratracheally instilled with lipopolysaccharide (LPS) at a dose of 2 mg/kg (approximately 50 μL) or PBS. Three days after the instillation, mice were euthanized after terminal blood drawing. Then, bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected. The assessments of inflammatory markers, including inflammatory cytokines and chemokines, were performed by ELISA using BALF samples and qPCR using lung samples. In separate experiments, recombinant full-length human ADAMTS13 protein or murine anti-human VWF A1 domain antibody were intravenously injected at doses of 80 µg/kg or 0.4 mg/kg, respectively, immediately before LPS instillation. In addition, as a pulmonary emphysema model, mice were intratracheally instilled with 160 U/kg of elastase. Then, the lung histological analyses were performed 3 weeks after instillation.

Results: Lung inflammation was significantly ameliorated in Vwf−/− mice as compared to Vwf+/+ mice. Furthermore, inflammation was significantly suppressed in Vwf+/+ mice treated with anti-VWF A1 antibody as compared to Vwf+/+ mice treated with saline. There were no differences in the expression of inflammatory mediators in Adamts13−/− mice as compared to Adamts13+/+ mice, but inflammation was significantly suppressed in Adamts13+/+ mice treated with recombinant human ADAMTS13 as compared to Adamts13+/+ mice treated with saline. In an emphysema model, the alveolar enlargement was significantly smaller in the elastase-treated Vwf−/− mice than in the elastase-treated Vwf+/+ mice.

Conclusion(s): VWF-targeting agents, such as ADAMTS13 protein, may be a novel therapeutic option for treatment of pulmonary inflammatory diseases.