HMGB1 activity inhibition alleviating liver injury in heatstroke

BACKGROUND: Heatstroke is generally considered as a sepsis-like syndrome induced by hyperthermia leading to multiorgan dysfunction. High-mobility group box 1 (HMGB1) has recently been identified as a mediator of systemic inflammation leading to multiorgan dysfunction in sepsis and nonsepsis. Elevation of plasma HMGB1 in heatstroke has been suggested in experimental models and clinical patients. By far, whether HMGB1 could be a potential therapeutic target in heatstroke is unknown. The objectives of this study are to use HMGB1 monoclonal antibody to specifically inhibit the activity of extracellular HMGB1 and to observe the possible protection of liver injury in a rat heatstroke model. METHODS: After treatment with neutralizing antibodies to HMGB1, rats were exposed to a high-temperature and high-humidity environment. At the time of heatstroke onset, the plasma and liver cytoplasm HMGB1 levels were detected by enzyme-linked immunosorbent assay. The histopathology of liver tissue was observed under light microscopy and transmission electron microscopy. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were determined using the commercially available kits. Plasma tumor necrosis factor-alpha, interleukin-1 beta (IL-1 beta), and IL-6 were determined using enzyme-linked immunosorbent assay kits. RESULTS: HMGB1 levels in plasma and liver cytoplasm were both elevated in heatstroke rats, which were both associated with increased plasma ALT and AST levels. Histopathologic results showed that HMGB1 monoclonal antibody pretreatment could obviously alleviate the pathologic impairments of heatstroke rats. HMGB1 monoclonal antibody pretreatment could also downregulate plasma AST and ALT levels in heatstroke rats. Plasma tumor necrosis factor-alpha, IL-1 beta, and IL-6 levels in heatstroke rats were elevated, which could be significantly suppressed by HMGB1 antibody pretreatment. CONCLUSION: HMGB1 could be a potentially effective treatment target in heatstroke. The pathogenic mechanism of heatstoke is complicated, which needs comprehensive prevention and treatment. (J Trauma Acute Care Surg. 2013; 74: 801-807. Copyright (C) 2013 by Lippincott Williams & Wilkins)