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.
Highlights
Trauma ranks fifth as a cause of death among people of all ages living in the United States, and it is the leading cause of death among people less than 45 years of age [1]
High-mobility group B1 (HMGB1), which has been shown to be a late mediator of lethality in murine models of endotoxemia and sepsis, does not reach maximal levels in the circulation until about 15 to 18 h after the initiation of these inflammatory processes [20,21]
Our results indicate that circulating HMGB1 levels are increased in human trauma victims with physiological or biochemical evidence of shock within 6 h of injury
Summary
Trauma ranks fifth as a cause of death among people of all ages living in the United States, and it is the leading cause of death among people less than 45 years of age [1]. Intestinal barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and/or increased bacterial translocation to mesenteric lymph nodes (MLN), occurs following hemorrhagic shock and resuscitation (HS/R) in rodents [6,7,8,9,10,11,12,13]. These findings may have clinical implications, because increased intestinal permeability has been shown to be associated with an increased risk of complications, MODS, or even mortality in critically ill patients [14,15,16,17]. The underlying mechanisms responsible for gut barrier dysfunction after HS/R are not fully understood, but increased production of certain proinflammatory mediators, such as IL-6 [11] or nitric oxide [18], may be involved
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