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Annexin A5 Increases Survival in Murine Sepsis Model by Inhibiting HMGB1-Mediated Proinflammation and Coagulation

Authors
Jung Hwa Park, Jong-Hwa Jang, Eun Jung Choi, Young Seob Kim, Eun Ji Lee, In Duk Jung, Hee Dong Han, T-C Wu, Chien-Fu Hung, Tae Heung Kang, and Yeong-Min Park
Abstract
The identification of HMGB1 as a late mediator in sepsis has highlighted HMGB1 as a promising therapeutic target for sepsis treatment. Recent studies have revealed that annexin A5, a 35 kDa Ca2 -dependent phospholipid binding protein, exerts antiinflammatory effect by inhibiting LPS binding to TLR4/MD2 complex. Annexin A5 administration has been shown to protect against endotoxin lethality even when the treatment was given after the early cytokine response, which prompted our group to suspect that annexin A5 may inhibit the binding of HMGB1, as well as endotoxin, to TLR4. Here we suggest annexin A5 as a new inhibitor of HMGB1-mediated proinflammatory cytokine production and coagulation in sepsis. We first confirmed the inhibitory role of annexin A5 in LPS-induced production of proinflammatory cytokines both in vitro and in vivo. We observed that annexin A5 protects against tissue damage and organ dysfunction during endotoxemia in vivo. We then assessed the inhibiting role of annexin A5 in HMGB1/TLR4 interaction, and showed that annexin A5 treatment reduces HMGB1-mediated cytokines IL6 and TNF╬▒ both in vitro and in vivo. Finally, we confirmed that anticoagulant property of annexin A5 persists in various septic conditions including elevated HMGB1. Overall, we suggest annexin A5 as an alternative therapeutic approach for controlling HMGB1-mediated proinflammation and coagulation in patients with sepsis.
Volume
2016
Page Range
424 - 436
DOI
10.2119/molmed.2016.00026
Date Published
July 6, 2016
Article PDF
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Supplemental Data
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Keywords
Park,Jang,Choi,Kim,Lee, Jung,Han,Wu,Hung,Kang,Park,HMGB1,sepsis,annexin A5,antiinflammatory,endotoxin,tlr4
Article Type
Research Article