HMGB1 neutralization is associated with bacterial translocation during acetaminophen hepatotoxicity

BMC Gastroenterology

Research Article

Tor Inge Tonnessen¹  Runkuan Yang²  Shengtao Zhu³  Xiaoping Zou⁴  Jyrki Tenhunen⁵  Marja-Leena Koskinen⁶  Henri Kajander⁶ 

[1] Department of Anesthesiology and Intensive Care Medicine, Rikshospital, Oslo University, 4950 Nydalen, 0424, Oslo, Norway;Department of Critical Care Medicine, University of Pittsburgh Medical School, 3550 Terrace Street, 15261, Pittsburgh, PA, USA;Department of Intensive Care Medicine, Tampere University Hospital, University of Tampere, 10 Bio Katu, 33014, Tampere, Finland;Department of Anesthesiology and Intensive Care Medicine, Rikshospital, Oslo University, 4950 Nydalen, 0424, Oslo, Norway;Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, 100050, Beijing, China;Department of Gastroenterology, Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Street, 210008, Nanjing, China;Department of Intensive Care Medicine, Tampere University Hospital, University of Tampere, 10 Bio Katu, 33014, Tampere, Finland;Department of Surgical Science, Anesthesiology and Intensive Care Medicine, Uppsala University, 751 85, Uppsala, Sweden;Department of Pathology, University of Tampere Medical School, 10 Bio Katu, 33521, Tampere, Finland;

关键词: HMGB1;    Acetaminophen;    Hepatotoxicity;    Gut bacterial translocation;   

DOI  :  10.1186/1471-230X-14-66

 received in 2013-03-30, accepted in 2014-03-27,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAcetaminophen (APAP) hepatotoxicity is associated with a high rate of gram-negative enteric bacterial infection; however, the underlying mechanism is still unknown. APAP overdose induces massive hepatocyte necrosis, necrotic tissue releases high mobility group B1 (HMGB1) and exogenous HMGB1 is able to induce gut bacterial translocation (BT) in normal mice; therefore, it is possible that HMGB1 mediates gut BT in APAP hepatotoxicity. This study aims to test this hypothesis by using anti-HMGB1 neutralizing antibody to treat APAP overdose for 24-48 hours.MethodsMale C57BL/6 mice were intraperitoneally (i.p.) injected with a single dose of APAP (350 mg/kg dissolved in 1 mL sterile saline). 2 hrs after APAP injection, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose) or non-immune (sham) IgG every 24 h for a total of 2 doses.Results24 and 48 hrs after APAP challenge, anti-HMGB1 treatment instead of sham IgG therapy significantly decreased serum HMGB1 concentrations and reduced BT by 85%; serum HMGB1 levels were positively correlated with the amount of BT; anti-HMGB1 therapy decreased hepatic BT at 48 h, which was associated with better recovered liver structure and better restored hepatic immune system that was shown by enhanced hepatic mRNA expression of TNF-α, IL-6 and extensive proliferation of inflammatory and reticuloendothelial cells; however, anti-HMGB1 treatment did not decrease gut mucosal permeability as compared to the sham IgG therapy at either 24 or 48 hrs.ConclusionHMGB1 neutralization is associated with bacterial translocation during APAP hepatotoxicity.

【 授权许可】

CC BY   
© Yang et al.; licensee BioMed Central Ltd. 2014