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Blood. 2017 Jul 6;130(1):59-72. doi: 10.1182/blood-2016-09-738096. Epub 2017 Mar 21.

Pharmacological targeting of plasmin prevents lethality in a murine model of macrophage activation syndrome.

Author information

Center for Stem Cell Biology and Regenerative Medicine.
Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, and.
Department of Diagnostic Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan; and.
Atopy Center and.
Center for Genome and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan.


Macrophage activation syndrome (MAS) is a life-threatening disorder characterized by a cytokine storm and multiorgan dysfunction due to excessive immune activation. Although abnormalities of coagulation and fibrinolysis are major components of MAS, the role of the fibrinolytic system and its key player, plasmin, in the development of MAS remains to be solved. We established a murine model of fulminant MAS by repeated injections of Toll-like receptor-9 (TLR-9) agonist and d-galactosamine (DG) in immunocompetent mice. We found plasmin was excessively activated during the progression of fulminant MAS in mice. Genetic and pharmacological inhibition of plasmin counteracted MAS-associated lethality and other related symptoms. We show that plasmin regulates the influx of inflammatory cells and the production of inflammatory cytokines/chemokines. Collectively, our findings identify plasmin as a decisive checkpoint in the inflammatory response during MAS and a potential novel therapeutic target for MAS.

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