title: Blockade of Extracellular High-Mobility Group Box 1 Attenuates Systemic Inflammation and Coagulation Abnormalities in Rats with Acute Traumatic Coagulopathy.
abstract: BACKGROUND As an extracellularly released mediator, high-mobility group box 1 (HMGB1) initiates sterile inflammation following severe trauma. Serum HMGB1 levels correlate well with acute traumatic coagulopathy (ATC) in trauma patients, which is independently associated with higher mortality. We investigated the involvement of HMGB1 in ATC through blocking extracellular HMGB1. MATERIAL AND METHODS The ATC model was induced by polytrauma and hemorrhage in male Sprague-Dawley rats, which were randomly assigned to sham, ATC, and ATCH (ATC with HMGB1 blockade) groups. Thrombelastography (TEG) was performed to monitor changes in coagulation function. Serum levels of HMGB1, TNF-α, and IL-6 were measured, as well as lung levels of HMGB1 and nuclear factor (NF)-κB and expression of receptor for advanced glycation end-products (RAGE). RESULTS Compared with the sham group, HMGB1 increased the serum levels of TNF-α and IL-6, whereas HMGB1 blockade inhibited the induction of TNF-α and IL-6. HMGB1 also induced elevated serum soluble P-selectin and fibrinolysis markers plasmin-antiplasmin complex, which both were reduced by HMGB1 blockade. Thrombelastography revealed the hypocoagulability status in the ATC group, which was attenuated by anti-HMGB1 antibody. Furthermore, the lung level of NF-κB and expression of RAGE were decreased by anti-HMGB1 antibody, suggesting the role of RAGE/NF-κB pathway in ATC. CONCLUSIONS HMGB1 blockade can attenuate inflammation and coagulopathy in ATC rats. Anti-HMGB1 antibody might exert protective effects partly through the RAGE/NF-κB pathway. Thus, HMGB1 has potential as a therapeutic target in ATC.
authors.affiliation: Department of General Surgery, Bayi Hospital Affiliated Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland).
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China (mainland).
authors.forename: Kun
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China (mainland).
authors.forename: Xiao
authors.initials: X
authors.lastname: Shen
authors.affiliation: Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China (mainland).
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Fan
authors.affiliation: Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China (mainland).
authors.forename: Kai
authors.initials: K
authors.lastname: Ding
authors.affiliation: Department of General Surgery, Bayi Hospital Affiliated Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland).
authors.forename: Ren-Min
authors.initials: RM
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Bayi Hospital Affiliated Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland).
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D001777:Blood Coagulation; D001778:Blood Coagulation Disorders / Q000097:blood / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D007249:Inflammation / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D016328:NF-kappa B / Q000097:blood; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D057134:Antibodies, Neutralizing; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D015850:Interleukin-6; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D014409:Tumor Necrosis Factor-alpha