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

Abstract

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.

• Authors: Runkuan Yang, Tomoyuki Harada, Kevin P Mollen, Jose M Prince, Ryan M Levy, Joshua A Englert, Margot Gallowitsch-Puerta, LiHong Yang, Huan Yang, Kevin J Tracey, Brian G Harbrecht, Timothy R Billiar, Mitchell P Fink
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) 2006 Apr-Jun Vol. 12 Issue 4-6 Pg. 105-14 ISSN: 1076-1551 [Print] England
• PMID: 16953558 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies
• Dextrans
• Fluorescent Dyes
• HMGB1 Protein
• Interleukin-6
• Isotonic Solutions
• Nitrites
• Ringer's Lactate
• Interleukin-10
• Fluorescein-5-isothiocyanate

Topics

• 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, pharmacology, 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
• Ringer's Lactate
• Shock, Hemorrhagic (physiopathology, therapy)
• Survival Analysis
• Wounds and Injuries (physiopathology)