High-mobility group box 1 protein promotes development of microvascular thrombosis in rats.
BACKGROUND
Sepsis is a life-threatening disorder resulting from systemic inflammatory and coagulatory responses to infection. High-mobility group box 1 protein (HMGB1), an abundant intranuclear protein, was recently identified as a potent lethal mediator of sepsis. However, the precise mechanisms by which HMGB1 exerts its lethal effects in sepsis have yet to be confirmed. We recently reported that plasma HMGB1 levels correlated with disseminated intravascular coagulation (DIC) score, indicating that HMGB1 might play an important role in the pathogenesis of DIC.


OBJECTIVE
To investigate the mechanisms responsible for the lethal effects of HMGB1, and more specifically, to explore the effects of HMGB1 on the coagulation system.


METHODS
Rats were exposed to thrombin with or without HMGB1, and a survival analysis, pathologic analyses and blood tests were conducted. The effects of HMGB1 on the coagulation cascade, anticoagulant pathways and surface expression of procoagulant or anticoagulant molecules were examined in vitro.


RESULTS
Compared to thrombin alone, combined administration of thrombin and HMGB1 resulted in excessive fibrin deposition in glomeruli, prolonged plasma clotting times, and increased mortality. In vitro, HMGB1 did not affect clotting times, but inhibited the anticoagulant protein C pathway mediated by the thrombin-thrombomodulin complex, and stimulated tissue factor expression on monocytes.


CONCLUSIONS
These findings demonstrate the procoagulant role of HMGB1 in vivo and in vitro. During sepsis, massive accumulation of HMGB1 in the systemic circulation would promote the development of DIC.
Ito
T
T
Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Kawahara
K
K
Nakamura
T
T
Yamada
S
S
Nakamura
T
T
Abeyama
K
K
Hashiguchi
T
T
Maruyama
I
I
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D002478:Cells, Cultured; D003029:Coagulants / Q000494:pharmacology* / Q000633:toxicity; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000097:blood* / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005337:Fibrin / Q000378:metabolism; D024243:HMGB1 Protein; D006461:Hemolysis / Q000187:drug effects; D006609:High Mobility Group Proteins / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007249:Inflammation / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011486:Protein C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D013917:Thrombin; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology
D003029:Coagulants; D016207:Cytokines; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D006609:High Mobility Group Proteins; D011486:Protein C; D012097:Repressor Proteins; D005337:Fibrin; D013925:Thromboplastin; D013917:Thrombin