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Regulation of von Willebrand factor by ADAMTS13 ameliorates lipopolysaccharide-induced lung injury in mice

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Abstract

The relationship between von Willebrand factor (VWF) and inflammation has attracted considerable attention in recent years. VWF, which is stored in the Weibel–Palade bodies (WPBs) of endothelial cells (ECs), is released from WPBs in response to inflammatory stimuli and is thought to contribute to inflammation by promoting leukocyte extravasation. In this study, lung injury model mice were produced by intratracheal injection with lipopolysaccharides. The severity of lung inflammation was evaluated in mice with different genotypes (wild-type, Vwf−/−, Adamts13−/−) and mice treated with drugs that inhibit VWF function. Lung inflammation was significantly ameliorated in Vwf−/− mice compared with wild-type mice. Furthermore, inflammation was significantly suppressed in wild-type mice treated with anti-VWF A1 antibody or recombinant human ADAMTS13 compared with the untreated control group. The underlying mechanism appears to be an increased VWF/ADAMTS13 ratio at the site of inflammation and the interaction between blood cell components, such as leukocytes and platelets, and the VWF A1 domain, which promotes leukocyte infiltration into the lung. This study suggested that ADAMTS13 protein and other VWF-targeting agents may be a novel therapeutic option for treatment of pulmonary inflammatory diseases.

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Data availability

The datasets generated in the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Drs. Shogo Kasuda (Department of Legal Medicine, Nara Medical University, Japan) and Koichi Kokame (National Cerebral and Cardiovascular Center, Japan) for their technical advice.

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Authors and Affiliations

  1. Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara, 634-8521, Japan

    Yu Onodera, Seiji Mitani, Chihiro Hosoda, Yoko Takabayashi, Ryohei Kawasaki, Ryota Mori, Chiaki Ohshima & Kohei Tatsumi

  2. Medicinal Biology of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Japan

    Asuka Sakata, Ryohei Kawasaki, Midori Shima & Kohei Tatsumi

  3. Product Research Department, Medical Affairs Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan

    Ryohei Kawasaki

  4. Department of General Medicine, Nara Medical University, Kashihara, Japan

    Kenji Nishio & Mitsuhiko Sugimoto

  5. KM Biologics Co Ltd., Kikuchi, Japan

    Kenji Soejima

  6. Department of Medicine, Division of Hematology, UNC Blood Research Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Nigel Mackman

Authors
  1. Yu Onodera
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  2. Seiji Mitani
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Contributions

Conceptualization: YO and KT; investigation: YO, YT, RK, RM, CO, and KT; formal analysis: YO and KT; data curation: YO and KT; writing—original draft: YO; writing—review and editing: YO, SM, CH. YT, AS, RK, RM, CO, KN, MS, KS, NM, MS, KT.

Corresponding author

Correspondence to Kohei Tatsumi.

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Conflict of interest

AS, RK, KT and MS: members of Medicinal Biology of Thrombosis and Hemostasis established by Nara Medical University and Chugai Pharmaceutical Co., Ltd. RK: an employee of Chugai Pharmaceutical Co., Ltd. a stock owner of the company. KS: an employee of KM Biologics Co., Ltd. MS: patents for inventions relating to products of Chugai Pharmaceutical Co., Ltd.; representative of Medicinal Biology of Thrombosis and Hemostasis collaborative research laboratory; research support from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. and CSL Behring.; honoraria or consultation fees from Chugai Pharmaceutical Co., Ltd.; speaker’s bureau from Chugai Pharmaceutical Co., Ltd., CSL Behring, Sanofi, Bayer, Novo Nordisk Pharma, Takeda Pharmaceutical Co., Ltd., Pfizer and Fujimoto Seiyaku Corp. YO, SM, CH, YT, RM, CO, KN, MS, and NM: no conflict of financial interest.

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Onodera, Y., Mitani, S., Hosoda, C. et al. Regulation of von Willebrand factor by ADAMTS13 ameliorates lipopolysaccharide-induced lung injury in mice. Int J Hematol 118, 699–710 (2023). https://doi.org/10.1007/s12185-023-03668-x

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  • DOI: https://doi.org/10.1007/s12185-023-03668-x

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