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

Mol Med. Apr-Jun 2006;12(4-6):105-14. doi: 10.2119/2006-00010.Yang.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • Ringer's Lactate
  • Shock, Hemorrhagic / physiopathology*
  • Shock, Hemorrhagic / therapy*
  • Survival Analysis
  • Wounds and Injuries / physiopathology

Substances

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