Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 2006-04, Vol.12 (4-6), p.105-114
• Main Authors: Yang, Runkuan, Harada, Tomoyuki, Mollen, Kevin P, Prince, Jose M, Levy, Ryan M, Englert, Joshua A, Gallowitsch-Puerta, Margot, Yang, LiHong, Yang, Huan, Tracey, Kevin J, Harbrecht, Brian G, Billiar, Timothy R, Fink, Mitchell P
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; Antibodies - therapeutic use; Blood Pressure; Caco-2 Cells; Cell Survival - drug effects; Dextrans - metabolism; Female; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Glasgow Coma Scale; HMGB1 Protein - blood; HMGB1 Protein - pharmacology; HMGB1 Protein - physiology; Humans; Interleukin-10 - blood; Interleukin-6 - blood; Intestinal Mucosa - metabolism; Isotonic Solutions - therapeutic use; Male; Mice; Mice, Inbred C57BL; Middle Aged; Nitrites - blood; Permeability - drug effects; Resuscitation; Shock, Hemorrhagic - physiopathology; Shock, Hemorrhagic - therapy; Survival Analysis; Wounds and Injuries - physiopathology
• ISSN: 1076-1551; 1528-3658
• DOI: 10.2119/2006-00010.yang

Intestinal barrier dysfunction occurs following hemorrhagic shock and resuscitation (HS/R). High-mobility group B1 (HMGB1) has been shown to increase the permeability of Caco-2 human enterocyte-like epithelial monolayers in vitro. In this study, we found that serum concentrations of HMGB1 were higher in blood samples obtained from 25 trauma victims with hemorrhagic shock than in 9 normal volunteers. We also studied whether treatment with anti-HMGB1 antibody can ameliorate HS/R-induced gut barrier dysfunction in mice. Animals were shocked by withdrawal of blood to maintain mean arterial pressure at 25 to 30 mmHg for 2 h. After resuscitation with shed blood plus Ringer's lactate solution, the mice were treated with either anti-HMGB1 antibody or nonimmune rabbit IgG. Serum HMGB1 concentrations were significantly higher in trauma victims than control mice. Treatment with anti-HMGB1 antibody improved survival at 24 h and ameliorated the development of ileal mucosal hyperpermeability to FITC-labeled dextran. At 24 h after HS/R, treatment with anti-HMGB1 antibody decreased bacterial translocation to mesenteric lymph nodes and was associated with lower circulating concentrations of IL-6 and IL-10. These data support the notion that HMGB1 is a mediator of HS/R-induced gut barrier dysfunction and suggest that anti-HMGB1 antibodies warrant further evaluation as a therapeutic to ameliorate the morbidity of HS/R in trauma patients.